Powder composition containing a hemostatic agent

Abstract

The present invention relates to a powder composition comprising a specific biodegradable A and B block copolymer, at least one lubricant, and at least one hemostatic agent. The powder composition according to the present invention is particularly useful in methods for preventing and / or treating bleeding, preferably uterine bleeding. The present invention also relates to (i) the powder composition of the present invention, and (ii) a kit comprising means for inserting the powder composition into a body cavity, preferably the uterine cavity.

Description

[Technical Field]

[0001] The present invention relates to a powder composition containing a hemostatic agent, and to the use of the powder composition in a method for preventing and / or treating bleeding, preferably uterine bleeding. [Background technology]

[0002] Acute, severe uterine bleeding (or uterine bleeding) originating from the uterus and unrelated to pregnancy is excessive or prolonged bleeding of sufficient volume to require emergency intervention. Such uterine bleeding is commonly classified in relation to menstruation. Menorrhagia is upper genital bleeding that coincides with menstruation but is abnormal in volume or duration. Metrorrhagia refers to upper genital bleeding that occurs outside of menstruation. It can be caused in particular by lesions of the endometrium or myometrium (hyperplasia, cancer, polyps, uterine fibroids, adenomyosis). Very severe menstrual bleeding is an emergency and is considered incidental dysmenorrhea. Menometrorrhagia (i.e., a combination of menorrhagia and metrorrhagia) is bleeding from the uterus that is not caused by tumors, infections, or pregnancy.

[0003] This is a common clinical problem and a source of distress for patients because it can be life-threatening. In fact, uterine bleeding is one of the leading causes of maternal mortality. Therefore, it is desirable to control such bleeding as soon as it occurs.

[0004] The standard treatment for uterine bleeding in the emergency room is, firstly, intravenous administration of a high dose of conjugated estrogen to regenerate the endometrium and cover the exposed area at the source of bleeding. Intravenous estrogen alone can stop bleeding, but only 5 hours after the initial dose. Conjugated estrogen can cause nausea and vomiting. This is the only treatment specifically approved by the FDA for the treatment of acute severe uterine bleeding. Antifibrinolytic agents may also be prescribed and used, and are most effective when administered within 3 hours of the onset of bleeding. Hemostatic effects generally appear within 2-3 hours after administration. A rare but serious side effect is the possibility of secondary venous thrombosis. Another method is tamponade, which usually involves using a balloon-shaped device to stop bleeding. These devices are invasive and may need to be left in place for several hours, so patients must remain at rest in the emergency room bed throughout the treatment. Removing the balloon requires further medical intervention from the patient.

[0005] Therefore, there is a real need for an intrauterine system that can be easily introduced into the uterine cavity and that can rapidly and uniformly release hemostatic agents. [Overview of the project]

[0006] In this context, the inventors have discovered that hemostatic agents can be advantageously delivered into body cavities, particularly the uterine cavity, by using a copolymer based on blocks of polyester such as polylactic acid (PLA) and blocks of high molecular weight poly(oxyethylene) (PEO), in powder form, as a vehicle. Specifically, such powder copolymers make it possible to produce materials that possess dispersibility, blood absorption, and reabsorption properties, which are particularly suitable for use in the uterine cavity to treat uterine bleeding. Thus, the inventors have developed a powder composition containing a hemostatic agent that is easily introduced into body cavities such as the uterine cavity, has good and homogeneous dispersibility, and advantageously releases the hemostatic agent directly to the body cavity wall, particularly the uterine wall. The powder composition of the present invention can cover an entire body cavity, particularly the uterine cavity (particularly the body cavity wall), and can maintain hemostasis for at least 24 hours. Furthermore, the powder composition of the present invention does not adhere to surrounding tissues and does not stimulate cell proliferation.

[0007] Compared to similar systems in film form, the powder composition of the present invention has the advantage of being able to better cover body cavities, particularly the uterine cavity, because the particles (i.e., the hemostatic agent) can be dispersed everywhere. As the experimental data described in the Examples section shows, the powder also allows for faster coagulation than a film. Such a powder composition is further suitable for body cavities of any shape and size and is easily injectable into body cavities. More specifically, such a powder composition is suitable for uteruses of any shape and size and is easily injectable into the uterine cavity.

[0008] The powder composition according to the present invention can enable very rapid release of a hemostatic agent from the moment it is administered to a body cavity, particularly the uterine cavity. Specifically, the release of the hemostatic agent can begin immediately after the system is administered to a body cavity, particularly the uterine cavity. In particular, for example, more than 60% of the hemostatic agent initially present in the material can be released within 5 minutes after administration. Furthermore, preferably, the material of the powder composition has anti-adhesion properties, and the uterine wall is kept separated by the intrauterine system so that scarring following hemostasis does not cause intrauterine adhesions or synechia. Finally, the collapse and expulsion time of the intrauterine system according to the present invention is generally 1 to 30 days, which not only allows the intrauterine system to remain in the uterine cavity for a sufficient period to treat bleeding, but also ensures that it is expelled naturally, especially before or during the next menstrual cycle.

[0009] Therefore, one object of the present invention is a powder composition containing the following: - A degradable A and B block copolymer, Block A is made of polyester, Block B is poly(oxyethylene) (PEO), The weight-average molecular weight of block B is 50 kDa or more. The molar ratio of ethylene oxide units to ester units is between 0.5 and 5. Degradable A and B block copolymers; - at least one type of lubricant; and - At least one hemostatic agent.

[0010] Another purpose of the present invention is to provide a powder composition for administering the hemostatic agent into a body cavity, preferably into the uterine cavity.

[0011] Another purpose of the present invention is to provide a powder composition for use in methods of preventing and / or treating bleeding, preferably uterine bleeding.

[0012] Another purpose of the present invention is a powder composition for use in a method of preventing and / or treating uterine bleeding, wherein the composition is for administration into the body cavity of a subject.

[0013] Another purpose of the present invention is a powder composition for use in a method of preventing and / or treating uterine bleeding, the composition being for administration into the uterine cavity of a subject.

[0014] Another object of the present invention is, (i) the powder composition of the present invention, preferably containing 500 mg to 1000 mg; and (ii) means for inserting the powder composition into a body cavity, preferably into the uterine cavity, This is a kit that includes [the following items]. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 shows microscopic observations of powdered triblock ABA in its dry state (left image) and 10 minutes after contact with water (right image) to illustrate its swelling characteristics. The images were taken with a Leica microscope using a 4x objective lens. The scale is 1000 μm. [Figure 2] Figure 2 shows microscopic observations of powdered triblock ABA in a dry state (left image) and 30 seconds after contact with water (right image) to demonstrate its swelling characteristics. The images were taken with a Leica microscope using a 10x objective lens. The scale is 400 μm. [Figure 3] Figure 3 shows the results of an in-vitro release test, in which the ratio of thrombin released from the powder composition to time was measured using the ELISA method. [Figure 4] Figure 4 shows the blood coagulation times of different prototypes obtained after in-vitro blood coagulation tests. The prototypes include powders with several amounts of thrombin and similar systems in film form. [Figure 5-6] Figures 5 and 6 show the results of in-vitro hemostasis tests: different powder compositions are compared based on their coagulation time. [Figure 7-8]Figures 7 and 8 show the results of in-vivo tests (wounds formed in the pig liver), observing the bleeding grade of the wounds as a function of time. The effectiveness of different prototypes of the powder is evaluated. [Figure 9] Figure 9 shows the coagulation times of prototypes G0 to G6 obtained after in-vitro coagulation tests. The prototypes include powders mixed with triblock and different lubricants with calcium alginate.

Mode for Carrying Out the Invention

[0016] The inventors have developed a powder composition containing a hemostatic agent having mechanical and chemical properties particularly suitable for use in the medical field, especially for the treatment of bleeding such as uterine bleeding. Specifically, the combination of the dispersion properties and coating properties of the copolymer used to prepare the powder composition with the hemostatic agent makes it possible to use it to reliably and rapidly treat bleeding such as uterine bleeding.

[0017] <Definition> In the context of the present invention, the expression "x to y" means that the values x and y are included.

[0018] In the context of the present invention, the terms "molecular mass" and "molecular weight" are used interchangeably to refer to the weight average molecular mass (Mw) unless otherwise specified. According to the present invention, Mw is determined by size exclusion chromatography performed in dimethylformamide as the analytical solvent using a poly(ethylene glycol) calibration curve range.

[0019] According to the present invention, the "aqueous medium" refers to a medium having an osmotic pressure similar to that of biological fluids. As the aqueous medium, phosphate buffered saline (PBS), which is considered representative of biological fluids, is generally used.

[0020] According to the present invention, "moist medium" means a medium equivalent to an aqueous medium, that is, a culture medium having an osmotic pressure similar to that of biological fluids, but the moist medium is not a liquid. The uterine cavity is characterized as a non-liquid moist medium.

[0021] <Powder composition> One object of the present invention is a powder composition containing the following: Block A is made of polyester, Block B is poly(oxyethylene) (PEO), The weight-average molecular weight of block B is 50 kDa or more. The molar ratio of ethylene oxide units to ester units is between 0.5 and 5. Degradable A and B block copolymers; - at least one type of lubricant; and - At least one hemostatic agent.

[0022] According to the present invention, the term "polyester" refers to any polymer whose main chain repeating units contain ester functional groups and which is usable in the medical field. In particular, polyester is understood to mean aliphatic polyesters such as polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polylactic acid-co-glycolic acid (PLGA), polybutyrolactone (PBL), polyhydroxyalkanoates (PHA), and copolymers thereof.

[0023] In a preferred embodiment, the polyester (Block A) is selected from polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), and copolymers thereof. Preferably, the polyester of Block A is selected from PLA and PCL.

[0024] Preferably, the polyester is non-crosslinked.

[0025] Polylactic acid (PLA) may be poly(L-lactic acid), poly(D-lactic acid), or poly(D,L-lactic acid). Preferably, poly(D,L-lactic acid) (PDLLA) is used. In this case, the polymer preferentially contains at least 50 mol% L-lactic acid, and may particularly contain at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% L-lactic acid. Specifically, the decomposition rate of the A and B block copolymer can be changed by changing the ratio of L-lactic acid to D-lactic acid. The decomposition rate of the copolymer can be slowed by increasing the level of L-lactic acid. In specific embodiments of the present invention, the composition contains 100% PLLA as block A.

[0026] In the context of the present invention, poly(oxyethylene) (PEO) is typically a linear polyether produced from ethylene oxide or ethylene glycol monomer, preferably ethylene oxide monomer. Accordingly, according to the present invention, block B may also be polyethylene glycol (PEG) having a high molecular weight of 50 kDa or more, particularly a molecular weight as defined below.

[0027] According to the present invention, the poly(oxyethylene) (PEO) used in block B has a high molecular weight, and the total molecular weight of PEO in the copolymer is 50 kDa or more.

[0028] Advantageously, the total molecular weight of PEO in the A and B block copolymer is 50 kDa to 300 kDa. For example, the PEO blocks have molecular weights of 50 kDa, 75 kDa, 80 kDa, 85 kDa, 90 kDa, 95 kDa, 100 kDa, 105 kDa, 110 kDa, 115 kDa, 120 kDa, 125 kDa, 150 kDa, 200 kDa, 225 kDa, 250 kDa, 275 kDa, or 300 kDa. In one specific embodiment, the PEO blocks used have molecular weights of 75 kDa to 150 kDa, preferably 80 kDa to 125 kDa, more preferably 90 kDa to 115 kDa, and more preferably 90 kDa to 110 kDa. In one specific embodiment, the PEO block used has a molecular weight of 95 kDa to 105 kDa.

[0029] According to the present invention, the PEO block used in the A and B block copolymer has an intrinsic viscosity of 0.04 mg / ml to 0.6 mg / ml, preferably 0.08 mg / ml to 0.5 mg / ml, and more preferably 0.1 mg / ml to 0.3 mg / ml, when measured by an Ubbelohde type capillary viscometer at a concentration of 1 g / L in chloroform at 25°C.

[0030] Advantageously, the A and B block copolymer is selected from AB diblock copolymers, ABA or BAB triblock copolymers, or mixtures thereof, particularly from [ABA and BAB], [AB and ABA], [AB and BAB], and [ABA, BAB, and AB]. In a preferred embodiment, the A and B block copolymer is selected from ABA or BAB triblock copolymers, preferably ABA triblock copolymers.

[0031] According to the present invention, in AB and / or ABA copolymers, each PEO block (B block) has a molecular weight of 50 kDa or more, preferably 50 kDa to 300 kDa, preferredly 75 kDa to 150 kDa, preferably 80 kDa to 125 kDa, more preferably 90 kDa to 115 kDa, more preferably 90 kDa to 110 kDa, and even more preferably 95 kDa to 105 kDa; on the other hand, in BAB copolymers, the total molecular weight of the PEO blocks in the copolymer is 50 kDa or more, preferably 50 kDa to 300 kDa, preferredly 75 kDa to 150 kDa, preferredly 80 kDa to 125 kDa, more preferably 90 kDa to 115 kDa, more preferably 90 kDa to 110 kDa, and even more preferably 95 kDa to 105 kDa.

[0032] In the context of this invention, the molar ratio represents the molar ratio of each repeating unit (or unit) of blocks A and B. Since block B is PEO, the repeating unit is ethylene oxide ("ethylene oxide unit" or EO), and the repeating unit of block A ("ester unit") is a carboxylic acid such as lactic acid unit. According to this invention, the molar ratio of EO / ester units in the degradable A and B block copolymer is 0.5 to 5, preferably 1 to 3. This molar ratio is measured from the proton NMR (nuclear magnetic resonance) spectrum of the copolymer in deuterated chloroform, in which the chemical shift of the characteristic peak of the PLA-PEO-PLA copolymer can be identified: CH(PLA): 5.1 ppm; CH2(PEO): 3.5 ppm; CH3(PLA): 1.5 ppm). According to this invention, by controlling the EO / LA ratio, it is possible to control the dispersibility and blood absorption properties of the powder composition, as well as the decomposition time. Typically, the lower the EO / LA ratio, the longer the decomposition time.

[0033] In specific embodiments of the present invention, the EO / ester unit molar ratio in the degradable A and B block copolymer is 0.5-3, 0.5-2, 0.5-1.6, 0.8-3, 0.8-2, 0.8-1.6, 1-3, 1-2, or 1-1.6.

[0034] In specific embodiments, the degradable A and B block copolymer consists of an ABA triblock copolymer, where block A is PDLLA and block B is PEO with a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio is 0.8 to 2.

[0035] In a specific embodiment, the degradable A and B block copolymer consists of an ABA triblock copolymer, where block A is PDLLA and block B is PEO with a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio is 1.56.

[0036] In a specific embodiment, the degradable A and B block copolymer consists of an ABA triblock copolymer, where block A is PDLLA and block B is PEO with a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio is 1.

[0037] In a specific embodiment, the degradable A and B block copolymer consists of an ABA triblock copolymer, where block A is PDLLA and block B is PEO with a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio is 2.

[0038] In other embodiments, the degradable A and B block copolymer consists of an ABA triblock copolymer, where block A is PDLLA and block B is PEO with a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio is 3.

[0039] In the context of the present invention, the degradable A and B block copolymer is in powder form, preferably with a particle size of 50 μm to 500 μm, more preferably 150 μm to 500 μm, as measured by sieving. According to the present invention, the dispersibility and coating properties of the powder composition can be controlled by controlling the particle size of the degradable A and B block copolymer. Typically, the smaller the particle size of the A and B block copolymer, the better the dispersibility and coating properties. However, if the particle size is too small, for example less than 50 μm, the powder tends to compress more, which can make insertion into body cavities difficult. In contrast, if the particle size is too large, for example more than 500 μm, the different components of the powder become difficult to mix; furthermore, the surface being coated becomes less important for the same amount of powder. Advantageously, the degradable A and B block copolymers in powder form exhibit particle sizes, as measured by sieving, of 50 μm to 500 μm, 80 μm to 500 μm, 100 μm to 500 μm, 120 μm to 500 μm, 125 μm to 500 μm, 150 μm to 500 μm, 200 μm to 500 μm, 250 μm to 500 μm, 125 μm to 250 μm, 50 μm to 450 μm, 50 μm to 400 μm, 50 μm to 350 μm, 50 μm to 300 μm, 50 μm to 250 μm, or 50 μm to 200 μm. More advantageously, the degradable A and B block copolymer in powder form exhibits a particle size of 120 μm to 500 μm, preferably 125 μm to 500 μm, more preferably 125 μm to 250 μm or 250 μm to 500 μm. Typically, the degradable A and B block copolymer in powder form exhibits a particle size of 125 μm to 250 μm or 250 μm to 500 μm. According to the present invention, the particle size of the A and B block copolymer can be measured by means well known to those skilled in the art, such as sieving, laser diffraction, dynamic light scattering, or image analysis. Typically, the particle size can be measured by sieving.

[0040] The A and B block copolymers according to the present invention can be obtained by any method for synthesizing block copolymers known to those skilled in the art. For example, the ABA copolymer can be obtained by chain polymerization from the end of block B. Typically, lactide ring-opening polymerization initiated by the terminal hydroxyl of the PEO block is carried out in the presence of a catalyst such as tin octanoate. This polymerization can be carried out in the absence or presence of a solvent. The BAB type copolymer can be prepared, for example, by coupling methoxy-PEO to a PLA chain in which two chain ends are carboxylic acid functional groups. Such “bifunctionalized” PLA can be obtained, for example, by treating the PLA chain with succinic anhydride or adipic anhydride.

[0041] In the context of the present invention, the powder composition preferably contains A and B block copolymers in a weight ratio of 59% to 99.94%, preferably 60% to 99.94%, preferably 59% to 99.44%, preferably 60% to 99.44%, and preferably 67.5% to 98.99% of the total weight of the powder composition. For example, the powder composition may contain A and B block copolymers in a mass ratio of 59% to 99%, or 59% to 98%, or 59% to 95%, or 59% to 90%, or 59% to 89%, or 59% to 88%, or 59% to 85%, or 59% to 80%, or 59% to 75%, or 59% to 70%, or 99% to 99.94%, or 98% to 99.94%, or 95% to 99.94%, or 90% to 99.94%, or 89% to 99.94%, or 88% to 99.94%, or 85% to 99.94%, or 80% to 99.94%, or 75% to 99.94%, or 70% to 99.94%, based on the total mass of the powder composition.

[0042] In the context of the present invention, the powder composition also contains a lubricant. Advantageously, the powder composition contains 0.5% to 5% of the lubricant as a mass ratio to the total mass of the powder composition. In particular, the powder composition may contain 0.5% to 5%, 0.5% to 4.5%, 0.5% to 4%, 0.5% to 3.5%, 0.5% to 3%, 1% to 5%, 1% to 4%, 1% to 3.5%, or 1% to 3% of the lubricant as a mass ratio to the total mass of the powder composition. Advantageously, the powder composition contains 1% to 3% of the lubricant as a mass ratio to the total mass of the powder composition. For example, the powder composition may contain 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% of the lubricant as a mass ratio to the total mass of the powder composition. Advantageously, the lubricant is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, micronized polyoxyethylene glycol (micronized macrogol 6000), leucine, talc, sodium benzoate, and mixtures thereof. Preferably, the lubricant is magnesium stearate. The lubricant is preferably in powder form and can be mixed with additional components of the powder composition using any means known to those skilled in the art. Adding the lubricant to the powder composition can reduce friction, avoid adhesion with the inner surface of the inserter, and ensure a regular flow during intrauterine injection.

[0043] In another specific embodiment of the present invention, the powder composition of the present invention may not contain a lubricant. In this embodiment, the injection of the powder composition into the uterine cavity may be facilitated, for example, by the improved particle size of the biodegradable A and B block copolymers contained in the powder composition.

[0044] For example, another object of the present invention is - A degradable A and B block copolymer, Block A is made of polyester, Block B is poly(oxyethylene) (PEO), The weight-average molecular weight of block B is 50 kDa or more. The molar ratio of ethylene oxide units to ester units is between 0.5 and 5. Degradable A and B block copolymers; -At least one hemostatic agent; and - At least one type of lubricant; A powder composition containing this is also possible.

[0045] In a specific embodiment, the powder composition is - A degradable A and B block copolymer, Block A is made of polyester, Block B is poly(oxyethylene) (PEO), The weight-average molecular weight of block B is 50 kDa or more. The molar ratio of ethylene oxide units to ester units is between 0.5 and 5. Degradable A and B block copolymers; -At least one hemostatic agent; and - At least one type of lubricant; It may contain, The degradable A and B block copolymer may be in the form of a powder having a particle size of 120 μm to 500 μm, preferably 125 μm to 500 μm, and more preferably 125 μm to 250 μm or 250 μm to 500 μm.

[0046] In specific embodiments, the powder composition does not contain a lubricant. Therefore, the powder composition from which the lubricant has been removed may contain 60% to 99.9999% of A and B block copolymers as a weight ratio to the total weight of the powder composition, and 0.0001% to 40% of a hemostatic agent as a mass ratio to the total mass of the powder composition.

[0047] In other specific embodiments, the powder composition is -The following degradable A and B block copolymers, Block A is made of polyester, Block B is poly(oxyethylene) (PEO), The weight-average molecular weight of block B is 50 kDa or greater; The molar ratio of ethylene oxide units to ester units is 0.8 to 2, preferably 0.8 to 1.6, and more preferably 1 to 1.6. Block copolymer; -At least one hemostatic agent; and - at least one type of lubricant It contains.

[0048] In this embodiment, the degradable A and B block copolymer is advantageously in the form of a powder having a particle size of 120 μm to 500 μm, preferably 125 μm to 500 μm, and more preferably 125 μm to 250 μm or 250 μm to 500 μm.

[0049] In the context of the present invention, the powder composition also contains a hemostatic agent, preferably in powder form. The hemostatic agent is an active principle that promotes coagulation and stops blood flow. The hemostatic agent according to the present invention is advantageously selected from the group consisting of thrombin, calcium alginate, calcium salts such as carboxymethylated starch and calcium chloride, carboxymethylcellulose, gelatin, calcium ions, tranexamic acid, collagen, fibrinogen, and oxidized cellulose. The hemostatic agent according to the present invention is advantageously selected from the group consisting of thrombin, calcium alginate, carboxymethylated starch, and calcium chloride. In a preferred embodiment, the hemostatic agent is thrombin. In another preferred embodiment, the hemostatic agent is calcium alginate.

[0050] The hemostatic agent content in the powder composition depends on the selected hemostatic agent. Typically, the powder composition according to the present invention advantageously contains a hemostatic agent, preferably in powder form, in a mass ratio of 0.0001% to 40%, preferably 0.0001% to 39.5%, and preferably 0.0001% to 30% of the total mass of the powder composition.

[0051] In a specific embodiment, when the hemostatic agent is thrombin, its content in the powder composition is advantageously 0.0001% to 1%, preferably 0.0001% to 0.1%, preferably 0.001% to 0.1%, and more specifically 0.005% to 0.05%.

[0052] In another specific embodiment, when the hemostatic agent is calcium alginate or carboxymethylated starch, the content in the powder composition is advantageously 5% to 40%, preferably 8% to 40%, preferably 5% to 39.5%, preferably 8% to 39.5%, preferably 8% to 32%, or 20% to 30%, or 25% to 30%, as a mass ratio to the total mass of the powder composition.

[0053] In another specific embodiment, when the hemostatic agent is calcium chloride, the content in the powder composition is advantageously 0.01% to 5%, preferably 0.1% to 5%, preferably 0.5% to 5%, preferably 1% to 5%, preferably 1% to 4%, preferably 1% to 3%, and preferably 2% by mass relative to the total mass of the powder composition.

[0054] In specific embodiments, the powder composition according to the present invention may also contain a carrier for hemostatic agents, also known as a filler. Advantageously, the powder composition contains 0% to 40% of the carrier as a mass ratio to the total mass of the powder composition. In particular, the powder composition may contain 0% to 40%, 0% to 39.5%, 1% to 40%, 5% to 40%, 5% to 30%, 5% to 20%, 7% to 19%, 8% to 40%, 10% to 40%, or 0% to 35% of the carrier as a mass ratio to the total mass of the powder composition. Advantageously, the powder composition contains 5% to 30% of the carrier as a mass ratio to the total mass of the powder composition. For example, the powder composition may contain 0%, 5%, 7%, 8%, 10%, 15%, 19%, 20%, 25%, 30%, 35%, or 40% of the carrier as a mass ratio to the total mass of the powder composition. Advantageously, the carrier is selected from the group consisting of lactose, carboxymethylated starch, polyethylene glycol (PEG), poly(oxyethylene) (PEO), and carboxymethylcellulose. Preferably, the carrier is lactose or carboxymethylated starch. By adding a carrier for the hemostatic agent to the powder composition, it is possible to improve the dispersibility and homogeneity of the powder composition and the dispersibility of the hemostatic agent, and thus it is possible to promote contact of the powder composition according to the present invention with the wall of the uterine cavity. Mixing of the hemostatic agent and the carrier can be carried out by any means known to those skilled in the art, for example, by dissolving the hemostatic agent in the carrier solution and then drying or freeze-drying it.

[0055] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -59% to 99.44% biodegradable A and B block copolymers; -0.5% to 5% lubricant, -0.0001% to 1% thrombin, and Carriers ranging from -0% to 39.5%.

[0056] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -94.9999% to 99.44% degradable A and B block copolymers, -0.5% to 5% lubricant, -0.0001% to 1% thrombin.

[0057] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -80%~90% biodegradable A and B block copolymers, -1% to 3% lubricant, -0.0001% to 0.1% thrombin, and Carriers with a load of -7% to 19%.

[0058] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -80%~90% degradable A and B block copolymers, -1% to 3% lubricant, -0.5% to 3% calcium chloride, and Carriers with a load of -7% to 19%.

[0059] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -67% to 8% biodegradable A and B block copolymers; -1% to 3% lubricant, -8% to 32% calcium alginate.

[0060] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -67%~89% degradable A and B block copolymers, -1% to 3% lubricant, -8% to 32% carboxymethylated starch

[0061] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: Degradable A and B block copolymers in powder form with particle size of 250 μm to 500 μm, with a concentration of -59% to 99.44%; -0% to 5% lubricant, -0.0001% to 1% thrombin, and Carriers ranging from -0% to 39.5%.

[0062] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: Degradable A and B block copolymers in powder form with particle size of 250 μm to 500 μm, with a concentration of -94.9999% to 99.44%; -0% to 5% lubricant, -0.0001% to 1% thrombin.

[0063] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -80% to 90% of biodegradable A and B block copolymers in powder form with particle size of 250 μm to 500 μm, -0% to 3% lubricant, -0.0001% to 0.1% thrombin, and Carriers with a load of -7% to 19%.

[0064] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -80%~90% degradable A and B block copolymers in powder form with particle size of 250 μm~500 μm, -0% to 3% lubricant, -0.5%~% calcium chloride, and Carriers with a load of -7% to 19%.

[0065] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -67% to 89% of biodegradable A and B block copolymers in powder form with particle size of 250 μm to 500 μm, -0% to 3% lubricant, -8% to 32% calcium alginate.

[0066] In a specific embodiment, the powder composition according to the present invention contains the following in a mass ratio to the total mass of the powder composition: -67% to 89% of biodegradable A and B block copolymers in powder form with particle size of 250 μm to 500 μm, -0% to 3% lubricant, -8% to 32% carboxymethylated starch.

[0067] Specific examples of the powder composition of the present invention may include the following: -97.97% ABA triblock copolymer + 0.03% thrombin + 2% magnesium stearate; or -68.5% ABA triblock copolymer + 0.03% thrombin + 29.97% carboxymethylated starch + 1.5% magnesium stearate; or -68.5% ABA triblock copolymer + 30% carboxymethylated starch + 2% magnesium stearate; or -68.25% ABA triblock copolymer + 29.25% calcium alginate + 2.5% magnesium stearate; or -95.5% ABA triblock copolymer + 2% CaCl2 + 2.5% magnesium stearate; or -79% ABA triblock copolymer + 18% lactose + 2% CaCl2 + 1% magnesium stearate; or -85% ABA triblock copolymer + 15% calcium alginate in powder form with particle size of 250 μm to 500 μm.

[0068] In specific embodiments, the powder composition according to the present invention contains only a degradable A and B block copolymer, a lubricant, a hemostatic agent, and optionally a hemostatic agent carrier. In specific embodiments, the powder composition according to the present invention consists of a degradable A and B block copolymer, a lubricant, a hemostatic agent, and optionally a hemostatic agent carrier. In other specific embodiments, the powder composition according to the present invention consists of a degradable A and B block copolymer, a hemostatic agent, and optionally a hemostatic agent carrier in the form of powder with a particle size of 250 μm to 500 μm.

[0069] In other specific embodiments, the powder composition according to the present invention may contain additional additives or active principles, such as therapeutic molecules like antibiotics or vasoconstrictors. These additives or active principles can be added to the composition in powder form, for example, so as to be dispersed within the powder composition. Preferably, the additional active principle can diffuse outward from the material when it is in an aqueous or wet medium. An example of an additional active principle is a vasoconstrictor.

[0070] The preparation of the powder composition according to the present invention can be carried out by any means known to those skilled in the art, in particular by mixing the components in powder form together. Other methods for preparing the powder composition of the invention may be, for example, spray drying, granulation (preferably wet granulation), physical mixing, or solubilization / precipitation in a non-solvent with stirring.

[0071] In the context of the present invention, the powder composition according to the present invention advantageously allows for the release of at least 30% of the initially present hemostatic agent within 10 minutes after the introduction of the powder composition according to the present invention into a body cavity, preferably the uterine cavity. In particular, the powder composition according to the present invention advantageously allows for the release of at least 30% of the initially present hemostatic agent into a body cavity, preferably the uterine cavity, within 8, 6, 5, 4, 3, 2, or 1 minute (including boundary values) after the introduction of the powder composition according to the present invention into a body cavity, preferably the uterine cavity.

[0072] Advantageously, the powder composition according to the present invention allows for the release of at least 50%, preferably at least 60%, of the initially present hemostatic agent into the body cavity, preferably the uterine cavity, within 10 minutes after introduction of the powder composition according to the present invention into the body cavity, preferably the uterine cavity. In particular, the powder composition according to the present invention advantageously allows for the release of at least 50%, preferably at least 60%, of the initially present hemostatic agent into the body cavity, preferably the uterine cavity, within 8, 6, 5, 4, and 3 minutes (including boundary values) after introduction of the powder composition according to the present invention into the body cavity, preferably the uterine cavity.

[0073] Advantageously, the powder composition according to the present invention allows for the release of at least 80%, preferably at least 90%, of the initially present hemostatic agent into the body cavity, preferably the uterine cavity, within 10 minutes after the introduction of the powder composition according to the present invention into the body cavity, preferably the uterine cavity. In particular, the powder composition according to the present invention advantageously allows for the release of at least 80%, preferably at least 90%, of the initially present hemostatic agent into the body cavity, preferably the uterine cavity, within 10 minutes, 9 minutes, or 8 minutes after the introduction of the powder composition according to the present invention into the body cavity, preferably the uterine cavity.

[0074] In a preferred embodiment, the powder composition according to the present invention advantageously allows for the following release into the body cavity, particularly the uterine cavity, after the powder composition of the present invention has been introduced into a body cavity, preferably the uterine cavity: - Release at least 30% of the hemostatic agent initially present within 8 minutes; - Release at least 50% of the hemostatic agent initially present within 10 minutes; and / or - At least 80% of the hemostatic agents initially present are released within 30 minutes.

[0075] In a preferred embodiment, the powder composition according to the present invention advantageously allows for the following release into the body cavity, particularly the uterine cavity, after the powder composition of the present invention has been introduced into a body cavity, preferably the uterine cavity: - Release at least 50% of the hemostatic agent initially present within 6 minutes; - Release at least 60% of the hemostatic agent initially present within 10 minutes; and / or - At least 80% of the hemostatic agents initially present are released within 30 minutes.

[0076] In a preferred embodiment, the powder composition according to the present invention advantageously allows for the following release into the body cavity, particularly the uterine cavity, after the powder composition of the present invention has been introduced into a body cavity, preferably the uterine cavity: - Release at least 30% of the hemostatic agent initially present within 1 minute; - Release at least 60% of the hemostatic agent initially present within 5 minutes; and / or - At least 80% of the hemostatic agents initially present are released within 10 minutes.

[0077] In the context of the present invention, the release profile of hemostatic agents into body cavities, particularly the uterine cavity, is measured according to the ELISA (enzyme-linked immunosorbent assay) method.

[0078] In the context of the present invention, rapid release of a hemostatic agent onto the body cavity wall, particularly the uterine wall, enables rapid and efficient treatment of bleeding, especially uterine bleeding.

[0079] An additional and particularly advantageous feature of the powder composition according to the present invention, administered intrauterine, is that it possesses anti-adhesion properties. Once hemostasis is achieved, the scarring process proceeds, which carries the risk of the two walls of the uterus becoming fused together in the form of fibrous bridges known as adhesions or synechiae. The presence of a powder composition with anti-adhesion properties makes it possible to form a physical and mechanical barrier between the walls, thereby enabling scarring without synechiae.

[0080] An additional and particularly advantageous feature of the powder composition according to the present invention is that it is decomposable in aqueous or wet media. In particular, the powder composition according to the present invention decomposes after a residence time in the body cavity, especially the uterine cavity, of 2 hours to 30 days, preferably 12 hours to 20 days, and more preferably 1 to 15 days. The decomposition of the powder composition is due to the hydrolysis of the ester bonds of the polyester block, followed by the dissolution of the PEO-containing block. The decrease in the mechanical properties of the material is directly related to its decomposition. This decomposition can be evaluated, for example, by measuring the decrease in molecular weight of a strip of the material over time after immersion in physiological saline (1×PBS) with stirring at 37°C using size exclusion chromatography. It is also possible to evaluate the decrease in the dynamic viscosity of the material. Thus, the decomposition characteristics of the powder composition according to the present invention allow the powder composition to remain in the body cavity, especially the uterine cavity, for a sufficient time to treat bleeding, especially uterine bleeding, and then decompose so that it can be naturally discharged.

[0081] In the context of the present invention, the powder composition can be considered as a degradable system for releasing a hemostatic agent into a body cavity. In particular, the powder composition can be considered as a degradable intrauterine system for releasing a hemostatic agent into the uterine cavity.

[0082] <Use of the powder composition of the present invention> Another object of the present invention is the powder composition defined above for administering a hemostatic agent into a body cavity, preferably into the uterine cavity.

[0083] Another object of the present invention is the powder composition defined above for use in a method for preventing and / or treating bleeding, preferably uterine bleeding.

[0084] Another object of the present invention is a powder composition as defined above for use in a method for preventing and / or treating bleeding, the composition being intended to be administered into a body cavity of a subject.

[0085] Another object of the present invention is the powder composition defined above for use in a method for preventing and / or treating uterine bleeding, the composition being intended to be administered into the uterine cavity of a subject.

[0086] Another object of the present invention is a method for preventing and / or treating bleeding in a subject, comprising the step of administering the powder composition defined above into a body cavity to be treated in a subject in need thereof.

[0087] Another object of the present invention is a method for preventing and / or treating uterine bleeding in a subject, comprising the step of administering the powder composition defined above into the uterine cavity of a subject in need thereof.

[0088] Another object of the present invention is the use of powder compositions as defined above for the manufacture of pharmaceuticals for use in methods of preventing and / or treating bleeding, preferably uterine bleeding. In particular, the compositions are intended for administration into the body cavity of a subject, especially into the uterine cavity.

[0089] In the context of this invention, bleeding is defined as acute blood loss from a damaged blood vessel. Bleeding can occur in any part of the body, particularly in mammals, preferably in humans. Common sources of bleeding include organ injury (liver, spleen, kidneys, adrenal glands), vascular injury, complications from gynecological / obstetric procedures, or coagulation disorders. For example, bleeding may be selected from the group consisting of uterine bleeding, hemothorax, abdominal bleeding, cerebral hemorrhage, organ bleeding (liver, spleen, nephrocytes, adrenal glands, etc.), oral bleeding, epistaxis, rectal bleeding, and vaginal bleeding, with uterine bleeding being preferred.

[0090] <Kit> Another object of the present invention is a kit comprising (i) the powder composition of the present invention as defined above (preferably containing 500 mg to 2000 mg); and (ii) means for inserting the powder composition into a body cavity. A kit according to the present invention is advantageously equipped with means for inserting and positioning the material into a body cavity.

[0091] Another object of the present invention is a kit comprising (i) the powder composition of the present invention as defined above (preferably containing 500 mg to 1000 mg); and (ii) means for inserting the powder composition into a body cavity, preferably the uterine cavity. A kit according to the present invention advantageously includes means for inserting and positioning the material into a body cavity, particularly the uterine cavity.

[0092] The kit according to the present invention advantageously comprises a pharmaceutically effective dose of the powder of the present invention. In a specific embodiment, the kit comprises a single dose of the powder of the present invention. In another specific embodiment, the kit may contain at least two doses of the powder of the present invention.

[0093] For example, the kit according to the present invention may include a hollow cylindrical inserter in a tube containing a powder composition. Advantageously, the powder composition is contained in the tube in a compressed form to minimize the dimensions of the inserter. "Compressed form" means that the powder is held in a specified volume.

[0094] This kit conveniently includes a plunger mounted to translate and slide at the distal end of the inserter, the opposite proximal end being the end into which the inserter is intended to be introduced into a body cavity, particularly the uterine cavity. The plunger includes, or consists of, a rod that, when pushed towards the proximal end within the hole of the inserter, translates the powder composition outward from the inserter.

[0095] Advantageously, the plunger is equipped with a stopper at the proximal end of the extrusion section, which is intended to abut against the wall of a hole in contact with the proximal end of the inserter, thereby informing the person handling the kit that the powder composition has been completely ejected from the inserter and is in place in the body cavity, particularly the uterine cavity. The insertion means / inserter assembly can then be removed simply by pulling it outwards.

[0096] Such a kit allows for the reliable introduction and homogeneous dispersion of the powder composition according to the present invention into a body cavity, particularly the uterine cavity.

[0097] The kit according to the present invention can be used in patients suffering from uterine bleeding. The compact form of the material and the use of a small applicator facilitate insertion into the often sensitive uterine cavity of these patients. Furthermore, since it is naturally expelled during the menstrual cycle, there is no need for additional instrument removal by medical staff from the patient.

[0098] The present invention will be described below using examples. These examples are presented merely as non-limiting representations of the present invention. [Examples]

[0099] [Example 1: Preparation of the powder composition according to the present invention] 1. Synthesis of ABA triblock copolymer a. Material Commercially available poly(ethylene oxide) (PEO): Sigma-Aldrich, CAS number 25322-68-3. Commercially available PEO was analyzed in the laboratory by size exclusion chromatography (SEC) to determine the weight-average molar mass (Mw). The analysis was performed in the analytical solvent (dimethylformamide), and Mw was determined using the poly(ethylene glycol) calibration curve. The weight-average molar mass Mw was 95000 Da, and the intrinsic viscosity was 0.16 ml / mg. Commercially available D,L-lactide: supplied by Corbion Purac, CAS number 95-96-5.

[0100] b. Method ABA triblocks are synthesized using the following method: PEO (Mw95000) (200g) and D,L-lactide (458g) are dried under vacuum at room temperature for 24 hours. PEO and D,L-lactide are introduced into a polymerization flask in the presence of tin octanoate (85mg). Then, under vacuum (10 -3The mixture is deactivated 10 times consecutively with bar and argon. Then, the mixture is heated to 140°C and subjected to 10 more consecutive vacuum and argon deactivation cycles. The mixture is allowed to return to room temperature and placed in an ice bath. Once crystallized, the reaction mixture is placed under dynamic vacuum for 30 minutes and then sealed under dynamic vacuum. The mixture is then placed in an oven with mechanical rotation at 140°C for 3 days. The mixture is dissolved in dichloromethane, the precipitate is collected from the ether / ethanol mixture and dried under vacuum for 24 hours.

[0101] c. Characterization The final composition of the copolymer is 1 The molar ratio of EO / LA was determined by 1H NMR proton nuclear magnetic resonance spectroscopy and estimated to be 1. The molar ratio between ethylene oxide units (EO) and lactic acid units (La) was determined as follows: EO / LA = [peak area of ​​methylene in EO units (3.5 ppm) / number of protons in EO units] / [peak area of ​​methine in LA units (5.1 ppm) / number of protons in LA units].

[0102] Two-dimensional NMR analysis (DOSY) confirmed that the synthesis indeed yielded an ABA triblock (PLA50-PEO-PLA50).

[0103] This copolymer was also analyzed by size exclusion chromatography (SEC) to determine its average molar mass Mw and degree of dispersion Ip.

[0104] Using an analytical solvent such as dimethylformamide and employing the poly(ethylene glycol) calibration range, a dispersion index of 123,000 Da Mw and 5 was obtained.

[0105] Furthermore, thermogravimetric analysis (TGA) allowed us to determine the decomposition temperature of the copolymer (256°C).

[0106] 2. Preparation of the powder composition according to the present invention a. Material - Human thrombin, lyophilized form, manufactured by Sigma Aldrich (CAS number 9002-04-4). The activity of this protein is stated on the product's certificate of analysis as 400 NIH units / mg protein. -The Triblock ABA powder prepared in Section 1 above is used in the compositions of powders A1-A4, B1-B5, C1-C5, D1-D3 and E1-E2. -The triblock ABA powder prepared in the above section (Section 1) with an EO / LA molar ratio of 1.56 is used in the composition of powders G0 to G6. - PEO with an average molecular weight Mw of 100 kDA, manufactured by Sigma Aldrich (CAS #25322-68-3), with an average particle size of approximately 150 μm. -Calcium alginate, sodium alginate salt derived from brown algae, algin, sodium alginate, manufactured by Sigma Aldrich (CAS #9005-38-3) -Particle size D 98% <160 μm. -CaCl2, anhydrous, granular, ≦7.0 mm or less, ≧93.0% or more, manufactured by Sigma Aldrich (CAS#10043-52-4). - Lactose, white crystalline powder, manufactured by ArmorPharma (see EXCIPRESS SD2L). -Carboxymethylated starch, sodium starch glycolate, manufactured by Roquette (see GLYCOLYS) - Particle size D 98% <105 μm. - Magnesium stearate, magnesium salt of stearyl acid, manufactured by Sigma Aldrich (CAS #557-04-0). -Sodium stearyl fumarate (E)-2-butenoic acid monooctadecyl sodium salt, manufactured by Sigma Aldrich (CAS #4070-80-8). - Talc, magnesium hydrated silicate powder, manufactured by Cooper.

[0107] b. Preparation of powder (Powder containing carrier and thrombin) The support is solubilized in physiological saline (pH 6.5-7.5) at room temperature under stirring. Next, lyophilized thrombin is dissolved in this solution. The resulting support-thrombin solution is lyophilized at -52°C under 0.06 mbar for 16 hours.

[0108] Next, the freeze-dried carrier / thrombin mixture is mixed with Triblock ABA powder (particle size 125 μm to 500 μm) and a lubricant using a three-dimensional mixer. The components and contents are disclosed in Table 1 below.

[0109] (Hemostatic agent-containing powder without carrier) Triblock ABA powder (particle size 125 μm to 500 μm), a hemostatic agent, and a lubricant are mixed in a three-dimensional mixer. The components and their contents are disclosed in Table 1 below.

[0110] [Table 1]

[0111] [Example 2: Evaluation of the swelling properties of powdered triblock ABA] At T=0, 500 mg of Triblock ABA prepared in Example 1 was placed in a crystallizer, and 30 mL of water was added. The powder was left in the water for 10 minutes. The water was absorbed with absorbent paper, and the powder was collected. The weight of the powder was measured to be 1.49 g after 10 minutes. The powder had almost tripled in mass from its initial mass (a 200% mass increase).

[0112] Figure 1 shows that, compared to the powder at T=0 minutes, the powder swells and the particles aggregate at T=10 minutes.

[0113] A single Triblock ABA granule was placed under a microscope; a photograph was taken at T=0; and then 10 μL of water was dropped onto the granule. After 30 seconds, a photograph was taken to observe whether the granule had absorbed the water (Figure 2).

[0114] To evaluate the surface rise between T = 0 and T = 30 seconds, the powder surface was measured using software ImageJ (based on the scale of the image). The results are as follows: Surface at T = 0: 71963 μm 2 (0.072 mm 2 ) Surface after T = 30 seconds: 9196 μm 2 (0.092 mm 2 ) We confirmed an increase of 20 mm in 30 seconds 2 . This means that the powder has absorbed water.

[0115] [Example 3: Evaluation of Thrombin Release Kinetics] (in vitro release method) The powder is placed in a 50 ml vial containing 10 ml of phosphate buffer (pH 7.4). The vial is placed at 37 °C under mechanical stirring (87 rpm). 1 μL of the sample is taken three times at 30 seconds, 3 minutes, 5 minutes, and 10 minutes after introduction. Each sample is analyzed using enzyme-linked immunosorbent assay (ELISA). The amount of thrombin released is calculated from the equation of the calibration curve obtained within the standard range for each sampling time.

[0116] (Quantification method of thrombin) The ELISA used (manufactured by Abcam; reference ab270210) is designed for the quantitative measurement of thrombin. Thrombin (analyte) present in the solution collected during the release assay is captured by the capture antibody, detected by the detection antibody conjugated to the reporter, and the amount of thrombin present in the analytical sample is revealed. Next, the entire complex (capture antibody / analyte / detection antibody) is immobilized by the immunoaffinity of the anti-label antibody covering the well. Thus, a signal proportional to the amount of analyte (thrombin) bound to the antibody complex is generated. The intensity of the signal is measured at 450 nm using a microplate reader.

[0117] (Calculation method) A series of dilutions are performed from a stock thrombin solution (1,689,600 pg / mL) to obtain concentrations ranging from 0 to 8,500 pg / mL. From the optical density (OD) measurements at 450 nm obtained at each concentration, a standard curve showing the relationship between optical density and thrombin concentration can be constructed. The equation of this curve allows for the determination of the thrombin concentration of an unknown sample. Next, based on the amount of thrombin contained in the powder, the rate of thrombin release can be evaluated as a function of time.

[0118] (Powder composition) The powder used was powder prototype A1 described in Example 1.

[0119] (result) The calibration curve was linear (R²=0.98) in the concentration range of 0–8500 pg / mL. Using the same calibration curve, the thrombin concentration in the solution released from powder A1 was measured. The percentage of thrombin released from A1 over time is shown in Figure 3 and Table 2. Under in vitro release conditions, thrombin is released from the powder over time. Thrombin release begins at approximately 30 seconds, and at least 95% of the thrombin contained in the powder is released after 10 minutes.

[0120] [Table 2]

[0121] [Example 4: Evaluation of hemostatic properties (in vitro)] a. Materials and methods (Hemostasis support) Whole blood containing CPD (dextrose citrate phosphate) was obtained from a French blood agency. Before use in coagulation tests, this blood must be recalcified; for this purpose, calcium chloride (CaCl2-CAS 10043-52-4, manufactured by Sigma-Aldrich) is added to the blood. For subsequent tests, 3 mL of CaCl2 (concentration 0.122 mol / L) is added to 30 mL of whole blood.

[0122] (in vitro model) 30 mL of whole blood (not recalcified) containing CPD, placed in a 50 mL Falcon container, is warmed in a 37°C water bath for 30 minutes before starting the assay. After adding CaCl2, 10 mL of recalcified blood is introduced into a plastic uterine cavity model (dimensions: height 75 mm, main base 45 mm, small base 12 mm). To avoid blood loss during the test, the uterine cavity model is held upside down (small base / opening upwards). Next, the powder prototype to be tested is inserted into the model using an inserter. The entire assembly is placed in a 37°C oven.

[0123] (Measurement of coagulation time) Coagulation is observed visually. Coagulation time is the time it takes for all the blood in the uterine cavity model to coagulate. To measure this time, the model (including blood and prototype) is rotated 180° every minute for the first 10 minutes, and then every 2 minutes until coagulation is observed. The test is performed three times, and the average coagulation time obtained is calculated.

[0124] (Prototype testing) Powder prototypes A1-A4, B1-B5, and C1-C5 used in in vitro testing were prepared using the method described in Example 1. The powder compositions are detailed in Table 1 included in Example 1.

[0125] The comparative film prototypes F1 and F2 described below were obtained by preparing Triblock ABA powder as described in Example 1, and then forming a film by hot pressing: 2.5 mg of powder was pressed between two plates heated to 85°C for 9 minutes under a pressure of 20 MPa. The resulting 500 μm thick film was cut with a sample punch to obtain a film with the following dimensions: height 25 mm, large base 20 mm, small base 10 mm. • F1: Uterine film impregnated with THR100NIH units. Composition: 99.984% triblock ABA and 0.016% pure thrombin. F2: THR-coated uterine film, 100 NIH units. Composition: 80% triblock ABA, 19.987% PEO, and 0.013% pure thrombin.

[0126] b.Results b1. Comparison of powder prototypes A1-A4 and uterine films F1 and F2 Figure 4 shows the solidification time (minutes) as a function of the tested prototype.

[0127] The following observations are possible: • Blood clotting time is shorter when blood is brought into contact with the tested prototype compared to whole blood alone. • The higher the thrombin units, the faster the blood clotting time (A1 - 100 units vs. A2 - 200 units vs. A3 - 400 units). The coagulation time of the powder mixtures containing thrombin (A1, A2, A3) is superior to that of the powder mixture without thrombin (A4). • For the same thrombin NIH units, the coagulation time of the powder mixture (A1) is superior to that of the films (F1 and F2). Unlike film formation, where blood is absorbed slowly and thrombin takes time to be released, it is thought that the blood is partially absorbed into the powder and thrombin is readily available from the powder.

[0128] b2. Comparison of prototypes B1 and B5 Figure 5 shows the solidification time (minutes) as a function of the tested prototypes. Prototypes containing lactose or carboxymethylated starch as a carrier were tested.

[0129] The following observations are possible: Compared to whole blood alone, a shorter blood clotting time was observed when blood was brought into contact with the tested prototype. • The blood clotting time of powder mixtures containing thrombin (B1, B2, B4) is superior to that of powder mixtures without thrombin (B3, B5). • The higher the thrombin units, the faster the coagulation time (B1-100 units vs. B2-50 units). The coagulation time of a mixture of carboxymethylated starch and Triblock (B5, without thrombin) is superior to that of a mixture of lactose and Triblock (B3, without thrombin). When lactose and carboxymethylated starch are used as hemostatic carriers, no difference is observed between these same prototypes containing thrombin (B1, B4).

[0130] b3. Comparison of prototypes C1 and C5 Figure 6 shows the coagulation time (minutes) as a function of the tested prototypes. The prototypes included various hemostatic agents mixed with Triblock and magnesium stearate.

[0131] The following observations are possible: Compared to whole blood alone, a shorter blood clotting time was observed when blood was brought into contact with the tested prototype. A mixed powder containing thrombin (C5) in 100 NIH units is superior to other mixed powders. • The clotting time of Triblock mixed with a hemostatic agent is superior to that of Triblock alone. The solidification time of the calcium-containing prototypes (C1, C2) is superior to that of the carboxymethylated starch-containing prototype (C3). The coagulation time of prototype (C1) containing calcium alginate is equivalent to that of prototype (C4) containing thrombin 50 NIH units.

[0132] [Example 5: Evaluation of hemostatic properties (in vivo)] i. Bleeding scale A standardized, semi-quantitative bleeding scale is used to pre-assess bleeding and define the severity of initial bleeding that should reflect clinical use. This bleeding scale is also used during the trial to monitor the course of bleeding. See below for the scale: 0 = No bleeding 0.5 = Smear (Blood is observed at the edge, but it is not flowing) 1 = Very slight bleeding (blood flows very slowly from the site) 2 = Slight bleeding (blood flows slowly) 3 = Moderate (blood flows rapidly without a pulsation) 4 = Severe (blood flows rapidly, pulsates, and gushes from the wound) For this test, a bleeding grade of 1-2 is desirable.

[0133] ii. In vivo models We chose pigs because their anatomical size and organ structure are similar to humans, and their coagulation system is also similar to that of humans. The pig's liver is dissected to allow the prototype to be inserted into the parenchyma. The hemostatic prototype makes direct contact with the bleeding wound. To obtain a grade of 1 or 2, section dimensions of 1 cm in length and 0.5 cm in depth are used.

[0134] iii. Measurement of hemostatic properties To evaluate the hemostatic performance of the prototype (i.e., its ability to reduce the bleeding grade), the progression of the bleeding grade will be observed.

[0135] Initial bleeding is scored approximately one minute after section preparation, when the bleeding level is stable. The prototype is then inserted into the wound using a syringe. A timer starts once the prototype is inserted. Hemostasis (bleeding score) is scored at at least three time points (e.g., 1 minute, 3 minutes, 6 minutes) using the bleeding scale defined above. The test is stopped at 6 minutes.

[0136] iv. Prototype preparation Powder prototypes D1-D3 and E1-E2 were prepared using the method described in Example 1, and their quantities are detailed in Table 1. The control test corresponds to the case where no prototypes are inserted into the wound.

[0137] v.Results a. Comparison of prototypes D1, D2, and D3 The results are summarized in Figure 7. To evaluate the hemostatic performance of the tested prototype, the initial bleeding grade was compared with the bleeding grade at 6 minutes.

[0138] The following observations are possible: • After 6 minutes, blood flow remained unchanged in the case without thrombin (controlled study, D3). When thrombin-containing powder is introduced into a wound, blood flow is reduced by half (D1) or bleeding stops completely (D2). • For the same number of thrombin units (400 NIH units), a larger amount of triblock ABA absorbs blood, fills the entire wound, and consequently reduces blood flow by aiding in the diffusion of thrombin within the wound (D1 vs D2).

[0139] b. Comparison of prototypes E1 and E2 The results are summarized in Figure 8. To evaluate the hemostatic performance of the tested prototype, the initial bleeding grade was compared with the bleeding grade at 3 minutes and 6 minutes.

[0140] The following observations are possible: • After 6 minutes, blood flow was no different from the control group (without hemostatic agent). • After 6 minutes, if prototype E1 or E2 is introduced, the bleeding will stop. The prototype containing calcium alginate (E2) appears to perform better than the prototype containing CaCl2 (E1): blood flow stops more quickly (E2 shows no bleeding after 3 minutes, while E1 still shows very slight bleeding after 3 minutes). Powder E1 (250 μm~500 μm) has a different particle size than powder E2 (125 μm~250 μm): Particle size may affect the reduction of bleeding, and it is thought that the smaller the particle size, the larger the contact surface.

[0141] [Example 6: Evaluation of the effect of particle size of the powder according to the present invention] a. Materials and methods (Particle size measurement) The particle size of Triblock is determined using sieving: Triblock powder is separated by particle size using a vibrating column sieve. Fractions corresponding to different particle sizes are separated and used to produce prototype powder.

[0142] (Evaluation of release difficulty) A 500 mg sample of powder prototype was introduced into a tube with an inner diameter of 4.5 mm. The difficulty of discharging the powder from the tube was evaluated using a pusher (tube) with an outer diameter of 4.2 mm.

[0143] The difficulty levels are as follows: • Easy: The powder can be easily dispensed from the tube without applying any force. • Medium: The powder is dispensed from the tube with just a little force. • Difficulty: Applying too much force causes the powder to be discharged from the tube. • Impossible: Powder cannot be discharged from the tube.

[0144] The time taken for the insertion procedure will also be measured.

[0145] (Tested prototype) Powder prototypes C1-C2 and E1-E2 used in the in vitro test were prepared by the method described in Example 1. The powder compositions are detailed in Table 1 included in Example 1.

[0146] Powder prototypes E1 and C2 were prepared using Triblock contained in a 250 μm to 500 μm range, and powder prototypes E2 and C1 were prepared using Triblock contained in a 125 μm to 250 μm range.

[0147] b.Results The results of the expulsion test are detailed in Table 3 below:

[0148] [Table 3]

[0149] The following observations are possible: Without magnesium stearate (E1, E2), discharging the powder from a 4.5 mm inner diameter tube is more difficult than with magnesium stearate (see C2, C1): the lubricant facilitates powder discharging. • The higher the particle size (E1, C2), the easier it is to discharge from the tube. Smaller particle sizes are thought to be more easily compressed than larger particle sizes.

[0150] [Example 7: Evaluation of the effect of lubricant on hemostatic properties (in vitro)] a. Materials and methods (Hemostasis support) See Example 4. (in vitro model) See Example 4. (Measurement of coagulation time) See Example 4. (Tested prototype) Powder prototypes G0 to G6 used in the in vitro test were prepared by the method described in Example 1. The powder composition is detailed in Table 1 included in Example 1. The particle size of the Triblock powder prototypes ranges from 250 μm to 500 μm.

[0151] b.Results Figure 9 shows the solidification time (minutes) as a function of the tested prototypes. The prototypes contained various lubricants mixed with Triblock and calcium alginate.

[0152] The following observations are possible: • Blood clotting time was observed to be shorter when blood was in contact with the tested prototype compared to whole blood alone. • Blood clotting time was the same in all prototypes tested, regardless of the added lubricant: it can be concluded that the type and amount of lubricant added do not affect clotting time.

[0153] [Example 8: Evaluation of curing based on powder particle size and lubricant type] a. Materials and methods (Particle size measurement) See Example 6. (Evaluation of release difficulty) A 500 mg sample of a powder prototype was placed in a tube with an inner diameter of 4.6 mm. The difficulty of discharging the powder from the tube using a pusher (solid tube) with an outer diameter of 4.5 mm was evaluated.

[0154] The difficulty levels are as follows: • Easy: The powder can be easily dispensed from the tube without applying any force. • Medium: The powder is dispensed from the tube with just a little force. • Difficulty: Applying too much force causes the powder to be discharged from the tube. • Impossible: Powder cannot be discharged from the tube.

[0155] The time taken for the insertion procedure will also be measured.

[0156] (Tested prototype) Powder prototypes G0 to G6 were prepared using the method described in Example 1. The powder compositions are detailed in Table 1 included in Example 1.

[0157] Particle sizes between 125 μm and less than 250 μm are designated as particle-a, and particle sizes between 250 μm and 500 μm (including boundary values) are designated as particle-b, thus distinguishing the particle sizes in powder preparation.

[0158] G0-a to G6-a were prepared using triblocks ranging from 125 μm to less than 250 μm, while powder prototypes G0-b to G6-b were prepared using triblocks ranging from 250 μm to 500 μm (including boundary values).

[0159] Note: Prototypes G0-a and G0-b (and similarly, samples G1-G6) differ only in the particle size of the triblock; their composition is the same.

[0160] b.Results The results of the emissions test are detailed in Table 4 below:

[0161] [Table 4]

[0162] The following observations are possible: Without lubricant (G0-a, G0-b), discharging powder from a 4.5 mm inner diameter tube is more difficult than when lubricant facilitates powder discharge (G1-a~G6-a, G1-b~G6-b). • The higher the particle size (G0-b to G6-b), the faster the discharge from the tube. • If the lubricant content is the same, no difference is observed depending on the type of lubricant: these properties are identical, and the powder can be easily discharged from the tube (see G1-G3 and G4-G6). • The more lubricant there is, the faster the powder will be expelled from the tube (see G4-G6 vs. G1-G3). The particle size of the Triblock and the ratio of lubricant are two factors that affect the ease and speed of powder discharge.

Claims

1. - A biodegradable A and B block copolymer, Block A is made of polyester, Block B is poly(oxyethylene) (PEO), The weight-average molecular weight of block B is 50 kDa or more. The molar ratio of ethylene oxide units to ester units is 0.5 to 5. Degradable A and B block copolymers; - At least one type of lubricant; and - At least one type of hemostatic agent A powder composition containing the following:

2. The aforementioned degradable A and B block copolymers have a particle size of 50 μm to 500 μm, as measured by sieving. The powder composition according to claim 1.

3. The aforementioned degradable A and B block copolymers have a particle size of 120 μm to 500 μm, particularly 125 μm to 500 μm, preferably 250 μm to 500 μm, as measured by sieving. The powder composition according to claim 1.

4. - A biodegradable A and B block copolymer, Block A is made of polyester, Block B is poly(oxyethylene) (PEO), The weight-average molecular weight of block B is 50 kDa or more. The molar ratio of ethylene oxide units to ester units is 0.5 to 5. Degradable A and B block copolymers; - At least one hemostatic agent; and - At least one type of lubricant; It contains, The aforementioned degradable A and B block copolymer is in the form of a powder having a particle size of 120 μm to 500 μm, particularly 125 μm to 500 μm, and preferably 250 μm to 500 μm. Powder composition.

5. The aforementioned powder composition does not contain a lubricant. The powder composition according to claim 4.

6. The hemostatic agent is selected from the group consisting of thrombin, calcium alginate, calcium salts such as carboxymethylated starch and calcium chloride, carboxymethylcellulose, gelatin, calcium ions, tranexamic acid, collagen, fibrinogen, and oxidized cellulose. The powder composition according to any one of claims 1 to 5.

7. The lubricant is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, finely powdered polyoxyethylene glycol, leucine, talc, sodium benzoate, and mixtures thereof. The powder composition according to any one of claims 1 to 4 and 6.

8. The powder composition contains a lubricant in an amount of 0.5% to 5%, preferably 1% to 3%, relative to its total weight. The powder composition according to any one of claims 1 to 4 and 6 to 7.

9. The degradable A and B block copolymer is selected from AB diblock copolymer, ABA and BAB triblock copolymer, and mixtures thereof, preferably the degradable A and B block copolymer is ABA and / or BAB triblock copolymer, more preferably ABA triblock copolymer. The powder composition according to any one of claims 1 to 8.

10. The weight-average molecular weight of block B in the A-B block copolymer is 75 to 150 kDa, preferably 80 to 125 kDa, more preferably 90 to 115 kDa, and even more preferably 90 to 110 kDa. The powder composition according to any one of claims 1 to 9.

11. The ratio of ethylene oxide units to ester units in the A and B block copolymers is 1 to 3. The powder composition according to any one of claims 1 to 10.

12. The A block of the A and B block copolymer is polylactic acid, and is particularly selected from poly(L-lactic acid), poly(D-lactic acid), and poly(D,L-lactic acid). The powder composition according to any one of claims 1 to 11.

13. The powder composition contains the degradable A and B block copolymers in a weight ratio of 59% to 99.94%, preferably 67.5% to 98.99%, relative to the total weight of the powder composition. The powder composition according to any one of claims 1 to 12.

14. Preferably, the hemostatic agent further contains a carrier selected from the group consisting of lactose, carboxymethylated starch, polyethylene glycol (PEG), poly(oxyethylene) (PEO), and carboxymethylcellulose, preferably in an amount of 0% to 40%, preferably 8% to 30%, relative to the total weight of the powder composition. The powder composition according to any one of claims 1 to 13.

15. For administering the hemostatic agent into a body cavity, preferably into the uterine cavity, The powder composition according to any one of claims 1 to 14.

16. For use in methods of preventing and / or treating bleeding, preferably uterine bleeding, The powder composition according to any one of claims 1 to 14.

17. A powder composition according to any one of claims 1 to 14 for use in a method for preventing and / or treating uterine bleeding, wherein the composition is for administration into the uterine cavity of a subject.

18. A method for preventing and / or treating bleeding into a body cavity of a subject, comprising the step of administering the powder composition according to any one of claims 1 to 14 into the body cavity to be treated in a subject requiring such treatment.

19. A method for preventing and / or treating uterine bleeding, comprising the step of administering a powder composition according to any one of claims 1 to 14 into the uterine cavity of a person requiring treatment.

20. Use of the powder composition according to any one of claims 1 to 14 for the manufacture of a pharmaceutical product used in a method for preventing and / or treating bleeding, preferably uterine bleeding.

21. (i) a powder composition defined in any one of claims 1 to 14, preferably containing 500 mg to 1000 mg; and (ii) Means for inserting the powder composition into a body cavity, preferably into the uterine cavity A kit that includes this.

Images