Degradable intrauterine system for sustained release of active ingredients in the uterine cavity - Patent Application 20070233337

Abstract

The present invention relates to a degradable intrauterine system for sustained release of an active ingredient in the uterine cavity, comprising (a) a degradable A and B block copolymer, the A block being a polyester and the B block being a poly(oxyethylene) (PEO) having a weight average molecular weight of 50 kDa or more and having a molar ratio of ethylene oxide units / ester units of 0.05 to 5, (b) at least one polyester homopolymer, and (c) at least one active ingredient for release in the uterine cavity. The present invention also relates to a kit comprising at least one intrauterine system according to the present invention and a means for inserting the system into the uterine cavity.

Description

[Technical field]

[0001] The present invention relates to a new degradable intrauterine system for the sustained release of active ingredients in the uterine cavity. [Background technology]

[0002] Pelvic pain is pain in the pelvic region. Pelvic pain from the female reproductive system is generally regulated by physiological changes as part of a woman's menstrual cycle. Dysmenorrhea, also known as painful periods or menstrual cramps, is the most common type of pelvic pain. Dysmenorrhea is pain that occurs before or during menstruation. The pain is usually severe and can be in the form of pulsating or dull cramps, or continuous spasms.

[0003] Dysmenorrhea can be primary (i.e., no associated underlying cause) or secondary (i.e., due to a pelvic abnormality). Primary dysmenorrhea symptoms cannot be explained by gynecologic structural pathology, and the pain is due to uterine contractions and uterine ischemia. Secondary dysmenorrhea symptoms are due to a pelvic abnormality. Virtually any abnormality or any process that can affect the pelvic organs can cause secondary dysmenorrhea. Common causes of secondary dysmenorrhea include endometriosis (the most common cause), adenomyosis, and uterine fibroids. Less common causes include congenital anomalies (bicornuate uterus, septate uterus, transverse vaginal septum), ovarian cysts and tumors, pelvic inflammatory disease, pelvic congestion, intrauterine adhesions, psychogenic pain, and intrauterine devices (IUDs) (“Dysmenorrhoea”, JoAnn V. Pinkerton, MD, University of Virginia Health System, December 2020).

[0004] To date, one of the main treatments for treating dysmenorrhea consists of administering non-steroidal anti-inflammatory drugs (NSAIDs) that reduce pain and inhibit prostaglandins. NSAIDs are generally administered orally for several days. However, the effectiveness of this treatment is not guaranteed, and other hormonal treatments, such as danazol, progestins (e.g., levonorgestrel, etonogestrel, depo-medroxyprogesterone acetate), gonadotropin-releasing hormone agonists, or levonorgestrel-releasing IUDs, may reduce the symptoms of dysmenorrhea.

[0005] For a significant number of patients, existing treatments provide insufficient relief of symptoms, especially pain. Furthermore, because the drugs are administered orally rather than topically, the doses administered are generally high and cause undesirable side effects, such as gastrointestinal side effects of varying severity (nausea, stomach pain or heartburn, ulcers or gastrointestinal bleeding), which in certain rare circumstances can cause headaches, allergic reactions (skin rash, asthma), and kidney failure. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, there is a continuing need for alternative treatments that better relieve the symptoms of dysmenorrhea, especially pain, while protecting the patient's uterus by being less invasive and causing fewer undesirable side effects.

[0007] An example of an alternative treatment is an intrauterine system that releases active compounds such as hormones, especially levonorgestrel, but this system is a permanent implant, allowing release for about five years, is rigid and requires the intervention of a medical professional to remove it. [Means for solving the problem]

[0008] In this context, the inventors have developed an intrauterine system that meets these demands, and in particular that can be easily inserted into the uterine cavity, unfolds on its own in the uterine cavity without swelling and being expelled, degrades in a controlled manner to allow natural expulsion through the cervix, and sustainably releases the active ingredient in the area of ​​the uterine wall over a period of days or months.

[0009] In particular, the inventors have discovered that by using copolymers based on blocks of polyesters, such as polylactic acid (PLA) or polycaprolactone (PCL), and blocks of poly(oxyethylene) (PEO), in combination with polyester homopolymers, it is possible to create a material that combines swelling and resorption properties that are particularly suitable for long-term use in the uterine cavity and subsequent natural expulsion through the cervix.

[0010] Therefore, the inventors have developed a degradable intrauterine system from such materials further comprising an active ingredient, which in its "dry" form has dimensions for easy insertion through the cervix, and upon entering the uterine cavity, absorbs uterine fluid, unfolds in the uterine cavity and releases the active ingredient directly on or near the uterine wall. The direct release of the active ingredient in the uterine cavity allows for a localized treatment requiring a lower amount of the active ingredient compared to orally or systemically administered drugs, thus reducing the risk of undesirable side effects.

[0011] Furthermore, the material of the present invention allows for sustained release of the active ingredient. Specifically, the intrauterine system of the present invention is capable of releasing the active ingredient in the uterine cavity, preferably for a period of 10 days to 12 months, after being introduced into the uterine cavity. Furthermore, the system of the present invention has dimensions that prevent expulsion through the cervix, preferably for a period of 10 days to 12 months, after being deployed and swollen in the uterine cavity.

[0012] In particular, the materials of the present invention allow for sustained release of the active ingredient in the uterine cavity, providing a burst effect on the first day after administration of the system, followed by continuous release advantageously between 10 days and 12 months thereafter. Such a release profile allows, for example, for effective pain relief immediately after administration, followed by sustained analgesic and anti-inflammatory effects over the following days.

[0013] Furthermore, the time for disintegration and removal of the intrauterine system of the present invention in / from the uterine cavity is generally advantageously between 10 days and 12 months, thereby making it possible to ensure sufficient residence time of the intrauterine system in the uterine cavity to release a desired and sufficient amount of active ingredient over a desired period of time.

[0014] Therefore, one object of the present invention is a degradable intrauterine system for sustained release of an active ingredient in the uterine cavity, which comprises: (a) degradable A and B block copolymers, The A block is polyester. the B block is poly(oxyethylene) (PEO) having a weight average molecular weight of 50 kDa or greater; and degradable A and B block copolymers having an ethylene oxide unit / ester unit molar ratio of 0.05-5; (b) at least one polyester homopolymer; (c) at least one active ingredient adapted for release in the uterine cavity.

[0015] The present invention also relates to a kit comprising at least one intrauterine system according to the invention and means for inserting said system into the uterine cavity. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 is a schematic diagram of a degradable intrauterine system according to the present invention in the form of a trapezoidal film, particularly suitable for use in the human uterine cavity. [Diagram 2] FIG. 2 is a schematic longitudinal cross-sectional view of an example embodiment of a kit according to the invention, including a means for inserting a degradable intrauterine system according to the invention into the uterine cavity. [Diagram 3] FIG. 3 is a graph of the in vitro release of flurbiprofen over time from a degradable intrauterine system of the present invention. [Figure 4] Figures 4a and 4b show photographs of a degradable intrauterine system of the present invention in the form of a film after 24 hours (Figure 4.a) and after 15 days (Figure 4.b) of degradation under in vitro degradation conditions. [Diagram 5] FIG. 5 shows the change in cumulative percentage of flurbiprofen released in vitro over time from ABA60 / 40 PCL and ABA40 / 60 PCL films composed of triblock ABA mixture and homopolymer PCL, and ABA100 / 0 PCL film composed of triblock ABA alone. [Figure 6] FIG. 6 shows the change in cumulative percentage of flurbiprofen released in vitro over time from ABA30 / 70PCL / PLA50 and ABA20 / 80PCL / PLA50 films composed of the triblock mixture ABA and the homopolymers PCL and PLA50. [Figure 7] FIG. 7 shows the change in cumulative percentage of flurbiprofen released in vitro over time from 1,000 μm and 2,000 μm thick ABA6 / 94PCL / PLA50+30%F films composed of the triblock mixture ABA and the homopolymers PCL and PLA50. [Figure 8] FIG. 8 shows the change in cumulative percentage of flurbiprofen released in vitro over time from 1 mm thick films of ABA20 / 80PCL / PLA50+20%F and ABA6 / 94PCL / PLA50+30%F, which are composed of the triblock mixture ABA and the homopolymers PCL and PLA50. [Figure 9]FIG. 9 shows the change in mass loss of ABA20 / 80PCL / PLA50+20%F films at various times (11 hours, 25 hours, 15 days, 28 days, and 56 days) after placement in the uterine horns of rats. [Figure 10] FIG. 10 shows the amount of flurbiprofen absorbed into rat uterine tissue after placement of the “ABA6 / 94PCL / PLA50+30%F” film (at 11 hours, 25 hours, 15 days, 28 days, and 56 days), and the amount of flurbiprofen absorbed into uterine tissue after oral administration of flurbiprofen (at 11 hours, 25 hours, and 15 days). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The inventors have developed a degradable intrauterine system for sustained release of an active ingredient in the uterine cavity, the system having mechanical and chemical properties particularly suitable for use in the medical field, and in particular for the treatment of pelvic pain and / or gynecological disorders in female mammals, especially women. In particular, the swelling and expansion properties of the polymeric composition used to form the intrauterine system mean that it can be used in the uterine cavity in combination with an active ingredient to reliably treat gynecological disorders in women, such as dysmenorrhea, on a sustained basis.

[0018] Degradable Intrauterine System One object of the present invention is a degradable intrauterine system for sustained release of an active ingredient in the uterine cavity, which comprises: (a) degradable A and B block copolymers, -A block is polyester, the -B block is poly(oxyethylene) (PEO) having a weight average molecular weight of 50 kDa or greater; and degradable A and B block copolymers having an ethylene oxide unit / ester unit molar ratio of 0.05-5; (b) at least one polyester homopolymer; (c) at least one active ingredient adapted for release in the uterine cavity.

[0019] In the context of the present invention, the expression "from x to y" is meant to include the values ​​of x and y.

[0020] According to the invention, the term "polyester" refers to any polymer whose main chain repeating units contain ester functional groups and which can be used in the medical field. In particular, polyester is understood to mean aliphatic polyesters such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), polybutyrolactone (PBL), polyhydroxyalkanoates (PHAs) and their copolymers.

[0021] In a preferred embodiment, the polyester (A block) is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polycaprolactone (PCL), and copolymers thereof. Preferably, the polyester of the A block is selected from PLA and PCL.

[0022] Preferably the polyester is in a non-crosslinked form.

[0023] The poly(lactic acid) may be poly(L-lactic acid), poly(D-lactic acid) or poly(D,L-lactic acid). Advantageously, (D,L-lactic acid) (PDLLA) is used. In this case, the polymer preferentially contains at least 50 mol% L-lactic acid, and in particular may contain at least 60%, 70%, 75%, 80%, 85%, 90%, 95% or 99% L-lactic acid. In particular, by changing the percentage of L-lactic acid relative to D-lactic acid, it is possible to change the rate of degradation of the A and B block copolymer. Increasing the level of L-lactic acid makes it possible to slow down the rate of degradation of the copolymer. In a particular embodiment of the invention, the composition comprises 100% PLLA as the A block.

[0024] In the context of the present invention, poly(oxyethylene) (PEO) is typically a linear polyether made from ethylene oxide or ethylene glycol monomers, preferably ethylene oxide monomers. Thus, according to the present invention, the B block can also be a polyethylene glycol (PEG) having a high molecular weight of 50 kDa or more, in particular having a molecular weight as defined below.

[0025] According to the present invention, the poly(oxyethylene) (PEO) used in the B block has a high molecular weight, such that the total molecular weight of the PEO in the copolymer is 50 kDa or more. In the context of the present invention, the terms "molecular mass" and "molecular weight" are used equally to mean the weight average molecular weight (Mw), unless otherwise stated. According to the present invention, Mw is determined by size exclusion chromatography performed using a standard range of poly(ethylene glycol) in dimethylformamide as the analytical solvent.

[0026] Advantageously, the total molecular weight of the PEO in the A and B block copolymer is between 50 kDa and 300 kDa. For example, the PEO blocks have a molecular weight 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 a particular embodiment, the PEO blocks used have a molecular weight of between 75 kDa and 150 kDa, preferentially between 80 kDa and 125 kDa, more preferentially between 90 kDa and 115 kDa, more preferably between 90 kDa and 110 kDa. In one particular embodiment, the PEO blocks used have a molecular weight of between 95 kDa and 105 kDa.

[0027] According to the invention, the PEO blocks used in the A and B block copolymers advantageously have an inherent viscosity, measured in chloroform at 25° C. and at a concentration of 1 g / l by means of an Ubbelohde capillary viscometer, of 0.04 mg / ml to 0.6 mg / ml, preferentially 0.08 mg / ml to 0.5 mg / ml and more preferentially 0.1 mg / ml to 0.3 mg / ml.

[0028] Advantageously, the A and B block copolymers are chosen from AB diblock copolymers, or ABA or BAB triblock copolymers, or mixtures thereof, in particular [ABA and BAB], [AB and ABA], [AB and BAB], [ABA and BAB and AB]. In a preferred embodiment, the A and B block copolymers are chosen from ABA or BAB triblock copolymers, preferentially ABA triblock copolymers.

[0029] According to the invention, in the AB and / or ABA copolymers, each PEO block (B block) has a molecular weight of 50 kDa or more, advantageously between 50 kDa and 300 kDa, preferentially between 75 kDa and 150 kDa, preferably between 80 kDa and 125 kDa, more preferentially between 90 kDa and 115 kDa, more preferably between 90 kDa and 110 kDa or even between 95 kDa and 105 kDa, while in the BAB copolymers, the sum of the molecular weights of the PEO blocks in said copolymer is 50 kDa or more, advantageously between 50 kDa and 300 kDa, preferentially between 75 kDa and 150 kDa, preferably between 80 kDa and 125 kDa, more preferentially between 90 kDa and 115 kDa, more preferably between 90 kDa and 110 kDa or even between 95 kDa and 105 kDa.

[0030] In the context of the present invention, the molar ratio of ethylene oxide units / ester units in copolymer (a), also referred to herein as EO / LA ratio, represents the respective molar ratio of the repeating units in the A and B blocks. The B block is PEO and the repeating units are ethylene oxide ("ethylene oxide units" or EO), whereas the repeating units of the A block ("ester units") are carboxylic acids, such as lactic acid units. According to the present invention, the EO / LA ratio in the A and B block copolymers is between 0.05 and 5, advantageously between 0.1 and 4, preferably between 0.1 and 3. The EO / LA ratio is determined from the proton NMR (nuclear magnetic resonance) spectrum in deuterated chloroform of the copolymer and is calculated by the chemical shifts of the characteristic peaks of the PLA-PEO-PLA copolymer (CH(PLA): 5.1 ppm, CH 2 (PEO): 3.5 ppm, CH 3 (PLA):1.5 ppm) can be specified. According to the present invention, by controlling the EO / LA ratio, it is possible to control the swelling and expansion properties of the intrauterine system, and also the degradation time. Typically, the lower the EO / LA ratio, the longer the degradation time.

[0031] According to the present invention, "aqueous medium" refers to a medium having an osmolality similar to that of a biological fluid, for which phosphate buffered saline (PBS) is commonly used, which is considered representative of a biological fluid.

[0032] According to the present invention, a "wet medium" refers to a medium that is comparable to an aqueous medium, i.e., a medium that has an osmolality similar to that of a biological fluid, but the wet medium is not a liquid. The uterine cavity may be characterized as a non-liquid wet medium.

[0033] In a particular embodiment, the system of the present invention comprises an ABA triblock copolymer, the A block being PDLLA or PCL, the B block being PEO having a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio being 0.05 to 5, preferably 0.1 to 3.

[0034] In a particular embodiment, the system of the present invention comprises an ABA triblock copolymer, the A block being PDLLA containing 50%-100% L-lactic acid (PLA50-PLA100), the B block being PEO with a molecular weight of 90 kDa-110 kDa, and the EO / LA molar ratio being 0.05-5, preferably 0.1-3.

[0035] In a particular embodiment, the system of the present invention comprises an ABA triblock copolymer, the A block being PDLLA containing 80%-100% L-lactic acid (PLA80-PLA100), the B block being PEO with a molecular weight of 90 kDa-110 kDa, and the EO / LA molar ratio being 0.05-5, preferably 0.1-3.

[0036] In a particular embodiment, the system of the present invention comprises an ABA triblock copolymer, the A block being a PDLLA containing at least 90% L-lactic acid, the B block being a PEO having a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio being 0.05 to 5, preferably 0.1 to 3.

[0037] In a particular embodiment, the system of the present invention comprises an ABA triblock copolymer, the A block being polycaprolactone (PCL) and the B block being PEO having a molecular weight of 90 kDa to 110 kDa, with an EO / LA molar ratio of 0.05 to 5, preferably 0.1 to 3.

[0038] The A and B block copolymers of the present invention can be obtained by any block copolymer synthesis method known to those skilled in the art. For example, ABA type copolymers can be obtained by chain polymerization from the end of the B block. Typically, ring-opening polymerization is carried out in the presence of a catalyst such as stannous octoate, initiated by the terminal hydroxyl of the PEO block. This polymerization can be carried out in the absence or presence of a solvent. BAB type copolymers can be prepared, for example, by coupling methoxy-PEO to a polyester chain, the two ends of which are carboxylic acid functional groups. Such "difunctional" polyesters can be obtained, for example, by treating the polyester chain with succinic anhydride or adipic anhydride.

[0039] In the context of the present invention, the degradable intrauterine system also comprises at least one polyester homopolymer, in particular at least one degradable polyester homopolymer. The addition of at least one polyester homopolymer to the system according to the present invention makes it possible to improve the release and degradation characteristics of the system, in particular to extend the release time of the active ingredient and to delay the degradation of the system and its expulsion through the cervix. Advantageously, the polyester homopolymer (b) is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polybutyrolactone (PBL) and polyhydroxyalkanoates (PHAs), advantageously from poly(lactic acid) (PLA) and polycaprolactone (PCL). In a particular embodiment, the degradable intrauterine system comprises one or two polyester homopolymers selected from the abovementioned list. For example, the degradable intrauterine system may comprise PLA and / or PCL as homopolymer (b).

[0040] In an advantageous embodiment, the molar mass of the polyester homopolymer (b) is selected to obtain the desired release and degradability profile of the intrauterine system according to the invention. For example, the higher the molar mass of the polyester homopolymer (b), the longer the period before the system according to the invention degrades and is expelled through the cervix, and the more sustained the release. Advantageously, the polyester homopolymer (b) has a number-average molar mass of 25000 g / mol to 150000 g / mol, preferably 50000 g / mol to 125000 g / mol, in particular 50000 g / mol to 100000 g / mol, in particular 80000 g / mol to 100000 g / mol. The number-average molar mass of the polyester homopolymer (b) can be determined by size-exclusion chromatography carried out in tetrahydrofuran (THF) or dimethylformamide (DMF) as analytical solvent, using polystyrene or polymethylmethacrylate (PMMA) standards.

[0041] In one particular embodiment, the polyester homopolymer (b) is a poly(lactic acid) (PLA) homopolymer with a number average molar mass between 25 000 g / mol and 150 000 g / mol, preferably between 50 000 g / mol and 125 000 g / mol.

[0042] In another particular embodiment, the polyester homopolymer (b) is a polycaprolactone (PCL) homopolymer with a number average molar mass between 25 000 g / mol and 150 000 g / mol, preferably between 50 000 g / mol and 125 000 g / mol.

[0043] In another particular embodiment, the polyester homopolymer (b) is a mixture of a polycaprolactone (PCL) homopolymer and a poly(lactic acid) (PLA) homopolymer, said homopolymer having a number average molar mass between 25000 g / mol and 150000 g / mol, preferably between 50000 g / mol and 125000 g / mol.

[0044] The polyester homopolymer (b) in the present invention is prepared according to the methods known to those skilled in the art, for example, by polycondensation or ring-opening polymerization methods in the presence of a catalyst.For example, PCL can be prepared by ring-opening polymerization of ε-caprolactone using a catalyst.Similarly, PLA can be prepared by polycondensation or ring-opening polymerization of lactide in the presence of a catalyst.

[0045] In the context of the present invention, the A and B block copolymers (a) and the homopolymers (b) coexist in the system of the present invention, but do not react together or crosslink together. The mixing of the A and B block copolymers (a) and the homopolymers (b) can be carried out by any means known to those skilled in the art, for example by solubilizing the copolymer and homopolymer powders in a common solvent (e.g. dichloromethane) followed by a step of evaporating the solvent, or by cooling or heating the homopolymer and copolymer powders (at temperatures between 30°C and 190°C).

[0046] In the context of the present invention, the weight ratio of copolymer (a) / homopolymer (b) is advantageously between 99 / 1 and 1 / 99. In particular, the weight ratio of copolymer (a) / homopolymer (b) is advantageously between 98 / 2 and 2 / 98, more particularly between 97 / 3 and 3 / 97, more particularly between 96 / 4 and 4 / 96. In the context of the present invention, the weight ratio of copolymer (a) / homopolymer (b) is advantageously between 95 / 5 and 1 / 99. In the context of the present invention, the weight ratio of copolymer (a) / homopolymer (b) is advantageously between 95 / 5 and 5 / 95. According to the present invention, the weight ratio of copolymer (a) / homopolymer (b) is also selected so as to obtain the release and degradability profile desired for the intrauterine system of the present invention. For example, the lower this weight ratio, the longer the period before degradation of the system of the present invention and expulsion through the cervix. Thus, to obtain a sustained release system over a short period of time (i.e., approximately 10 to 30 days), the weight ratio of copolymer (a) / homopolymer (b) is advantageously 95 / 5 to 50 / 50, in particular 90 / 10 to 50 / 50, in particular 80 / 20 to 50 / 50. In this embodiment, the weight ratio of copolymer (a) / homopolymer (b) may be, for example, 95 / 5, 90 / 10, 85 / 15, 80 / 20, 75 / 25, 70 / 30, 65 / 35, 60 / 40, 55 / 45, or 50 / 50. To obtain a sustained release system over a short period of time (i.e., approximately 10 to 30 days), the weight ratio of copolymer (a) / homopolymer (b) is advantageously 99 / 1 to 50 / 50, in particular 98 / 2 to 50 / 50, in particular 97 / 3 to 50 / 50, in particular 96 / 4 to 50 / 50. In this embodiment, the weight ratio of copolymer (a) / homopolymer (b) may be, for example, 96 / 4, 97 / 3, 98 / 2, or 99 / 1.

[0047] Likewise, to obtain a sustained release system over a longer period (i.e., approximately 30 days to 12 months), the weight ratio of copolymer (a) / homopolymer (b) is advantageously 50 / 50 to 5 / 95, in particular 50 / 50 to 10 / 90, in particular 50 / 50 to 20 / 80. In this embodiment, the weight ratio of copolymer (a) / homopolymer (b) may be, for example, 50 / 50, 45 / 55, 40 / 60, 35 / 65, 30 / 70, 25 / 75, 20 / 80, 15 / 85, 10 / 90, or 5 / 95. To obtain a sustained release system over a longer period (i.e. approximately 30 days to 12 months), the weight ratio of copolymer (a) / homopolymer (b) may also advantageously be 50 / 50 to 1 / 99, in particular 50 / 50 to 2 / 98, in particular 50 / 50 to 3 / 97, in particular 50 / 50 to 4 / 96. In this embodiment, the weight ratio of copolymer (a) / homopolymer (b) may be, for example, 4 / 96, 3 / 97, 2 / 98, or 1 / 99.

[0048] In one particular embodiment, the system of the present invention comprises: (a) an ABA triblock copolymer, the A block being PDLLA and the B block being PEO having a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio being 0.05 to 5, preferably 0.1 to 3; (b) a PLA homopolymer and / or a PCL homopolymer; (c) at least one active ingredient adapted for release in the uterine cavity; The weight ratio of copolymer (a) / homopolymer (b) is advantageously between 50 / 50 and 1 / 99.

[0049] In one particular embodiment, the system of the present invention comprises: (a) an ABA triblock copolymer, the A block being PDLLA and the B block being PEO having a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio being 0.05 to 5, preferably 0.1 to 3; (b) a PLA homopolymer and / or a PCL homopolymer; (c) at least one active ingredient adapted for release in the uterine cavity; The weight ratio of copolymer (a) / homopolymer (b) is advantageously between 50 / 50 and 5 / 95.

[0050] In one particular embodiment, the system of the present invention comprises: (a) an ABA triblock copolymer, the A block being PDLLA and the B block being PEO having a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio being 0.05 to 5, preferably 0.1 to 3; (b) a PLA homopolymer and / or a PCL homopolymer; (c) at least one active ingredient adapted for release in the uterine cavity; The weight ratio of copolymer (a) / homopolymer (b) is advantageously between 95 / 5 and 50 / 50.

[0051] In one particular embodiment, the system of the present invention comprises: (a) an ABA triblock copolymer, the A block being PCL and the B block being PEO having a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio being 0.05 to 5, preferably 0.1 to 3; (b) a PLA homopolymer and / or a PCL homopolymer; (c) at least one active ingredient adapted for release in the uterine cavity; The weight ratio of copolymer (a) / homopolymer (b) is advantageously between 50 / 50 and 5 / 95.

[0052] In one particular embodiment, the system of the present invention comprises: (a) an ABA triblock copolymer, the A block being PCL and the B block being PEO having a molecular weight of 90 kDa to 110 kDa, and the EO / LA molar ratio being 0.05 to 5, preferably 0.1 to 3; (b) a PLA homopolymer and / or a PCL homopolymer; (c) at least one active ingredient adapted for release in the uterine cavity; The weight ratio of copolymer (a) / homopolymer (b) is advantageously between 95 / 5 and 50 / 50.

[0053] In the context of the present invention, an intrauterine system for sustained release of an active ingredient in the uterine cavity comprises an A and B block copolymer, a polyester homopolymer as described above, and an active ingredient, which is used for release in the uterine cavity.

[0054] In a preferred embodiment, in the system according to the invention, the active ingredient is not covalently bound to the copolymer (a) or to the homopolymer (b).

[0055] In the context of the present invention, the active ingredient used for releasing in the uterine cavity is advantageously an active ingredient for the treatment or prevention of pelvic pain (such as dysmenorrhea, endometriosis or adenomyosis) or gynecological disorders (such as uterine fibroids, endometrial cancer, endometrial hypo-implantation, thin endometrium, infections, bleeding (menorrhagia, uterine bleeding), cancer side effects, aging, menopause or vaginal dryness) in female mammals, especially women. More advantageously, the active ingredient is selected from anti-infective agents, such as antibiotics, anti-fungal agents or anti-viral agents, steroidal or non-steroidal anti-inflammatory agents, vasoconstrictors, vasodilators, uterine relaxants, labor inducers, hormone agents, hormone analogs, hormone agonists and hormone antagonists, and anti-cancer agents. In a particular embodiment, the system of the present invention may comprise a combination of at least two active ingredients as described above. Preferentially, the active ingredient used in the system of the present invention can diffuse out of the system when in an aqueous or moist medium.

[0056] Examples of anti-infective active ingredients that may be selected within the context of the present invention include chlorhexidine, doxycycline, azithromycin, clindamycin, gentamicin, ampicillin, amoxicillin, metronidazole, nystatin, miconazole, cidofovir, and imiquimod.

[0057] Examples of nonsteroidal anti-inflammatory (NSAID) active ingredients that may be selected within the context of the present invention are aminoarylcarboxylic acid derivatives, such as enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, and tolfenamic acid; arylacetic acid derivatives, such as acemetacin, aceclofenac, amfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucamethacin, ibufenac, indomethacin, isofenacine, isofezolacin, proglumetacin, sulindac, tiaramide, tolmetin, and zomepirac; arylbutyric acid derivatives, such as bumadizone, butibufen, fenbufen, and xenbucin; arylcarboxylic acids, such as clidanac, ketorolac, and tinoridine; arylpropionic acid derivatives, such as aluminoprofen , benoxaprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miloprofen, naproxen, etc.; pyrazoles, such as difenamizole, and epirizole; pyrazolones, such as apazone, benzpiperylone, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone, and and thiazolinobutazones; salicylic acid derivatives, such as acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl salicylate, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamine o-acetate, salicyl sulfate, salsalate, and sulfasalazine;Thiazine carboxamides, such as droxicam, isoxicam, meloxicam, piroxicam, and tenoxicam; ε-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpyramide, ditazol, emorfazone, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, proquazone, proxazole, tiaprofenic acid, rofecoxib, celecoxib, parecoxib, and tenidap; hydroxychloroquine; and pharmaceutically acceptable salts and esters thereof; and combinations thereof.

[0058] Examples of steroidal anti-inflammatory (SAID) active ingredients that may be selected within the context of the present invention include budesonide, triamcinolone, cortivazol, fluticasone, mometasone, prednisolone, methylprednisolone, hydrocortisone, flumethasone pivalate, triamcinolone, dexamethasone, betamethasone, amcinonide, and difluprednate.

[0059] Examples of vasoconstrictor active ingredients that may be selected within the context of the present invention include norephedrine, phenylephrine, phenylpropanolamine, phenyltoloxamine, pseudoephedrine, ephedrine, fenoxazoline, naphazoline, oxymetazoline, and tymazoline.

[0060] Examples of vasodilatory active ingredients that may be selected within the context of the present invention include sildenafil citrate, glyceryl trinitrate, nitroglycerin, and nifedipine.

[0061] Examples of uterine relaxing (anticontractile or tocolytic) active ingredients that may be selected within the context of the present invention include atosiban, ritodrine, salbutamol, and terbutaline.

[0062] Examples of labour-inducing (or uterine contraction) active ingredients that may be selected within the context of the present invention include methylergomatrine, oxytocin, dinoprostone, sulprostone, gemeprost, and misoprostol.

[0063] Examples of hormones, hormone analogs, hormone agonists, and hormone antagonists that may be selected within the context of the present invention include estradiol, levonorgestrel, gestodene, drospirenone, norgestimate, GnRH agonists (e.g., triptorelin, leuprorelin, buserelin, gonadorelin, nafarelin, etc.), GnRH antagonists (e.g., cetrotide, ganirelix, etc.), menotropins, urofillitropine, danazol, medroxyprogesterone, norethisterone acetate, dienogest, megestrol, tamoxifen, and ulipristal acetate.

[0064] Examples of anti-cancer drugs that may be selected within the context of the present invention include cisplatin, carboplatin, 5-fluorouracil, mitomycin C, paclitaxel, docetaxel, vinorelbine, gemcitabine, capecitabine, pemetrexed, and topotecan.

[0065] In the context of the present invention, the active ingredient used for release in the uterine cavity can also be a selective progesterone receptor modulator, such as mifepristone, asoprisnil, onapristone, and ulipristal acetate.

[0066] In a preferred embodiment, the active ingredient used is selected from nonsteroidal anti-inflammatory drugs (NSAIDs), and hormones, hormone analogs, hormone agonists and hormone antagonists, advantageously from NSAIDs.The particularly preferred NSAIDs in the context of the present invention are selected from ibuprofen, flurbiprofen, diclofenac, ketoprofen, aspirin, naproxen, ketorolac, tiaprofenic acid, mefenamic acid, tenoxicam, piroxicam, meloxicam, rofecoxib, celecoxib, parecoxib, fenoprofen, aluminoprofen, hydroxychloroquine and indomethacin, preferably flurbiprofen.

[0067] Advantageously, the content of active ingredients in the intrauterine system according to the invention is between 0.01% and 60% by weight, preferably between 1% and 60% by weight, relative to the total weight of the system, in particular, the content of active ingredients in the intrauterine system according to the invention is advantageously between 10% and 50% by weight, preferably between 20% and 50% by weight, in particular between 30% and 50% by weight, relative to the total weight of the system.

[0068] In a particular embodiment, when the active ingredient is selected from NSAIDs, the content of the active ingredient in the intrauterine system according to the invention is between 1% and 60% by weight, preferably between 10% and 50% by weight, in particular between 20% and 50% by weight, relative to the total weight of the system.

[0069] In another specific embodiment, when the active ingredient is selected from hormones, hormone analogues, hormone agonists and hormone antagonists, the content of the active ingredient in the intrauterine system of the present invention is 0.01% to 60% by weight, preferably 0.1% to 50% by weight, in particular 0.5% to 40% by weight, based on the total weight of the system.

[0070] The preparation of the intrauterine system of the present invention can be carried out by any means known to the skilled artisan, in particular by incorporating the desired active ingredient during or after the formation of the polymer matrix comprising the copolymer (a) and the homopolymer (b).

[0071] According to another particular embodiment, the system of the invention is adapted to carry out, by means known to those skilled in the art, inter alia: - impregnating / swelling the base polymers of the polymer matrix (copolymers (a) and homopolymers (b)) with a solution containing at least one active ingredient; - mixing the base polymers of the polymer matrix (copolymers (a) and homopolymers (b)) and the dry powder of the active ingredient, - mixing by melting or softening the base polymers of the polymer matrix (copolymers (a) and homopolymers (b)) and the powder of the active ingredient, - mixing a solution of the polymers (copolymer (a) and homopolymer (b)) with a powder of the active ingredient to obtain a suspension or solution, and - by mixing a solution of the active ingredient with powders of the base polymers (copolymers (a) and homopolymers (b)) of the polymer matrix to obtain a suspension or solution, thereby incorporating the active ingredient during the formation of the polymer matrix.

[0072] The system according to the invention can then be formed by means known to the skilled person, in particular from the dispersion as obtained in the previous step, comprising the active ingredient in the polymer matrix (copolymer (a) and homopolymer (b)), by hot pressing, hot injection, extrusion, solvent evaporation, e.g. using dichloromethane, electrospinning, molding or 3D printing.

[0073] According to a particular embodiment, the formation of the polymer matrix can be carried out by any means known to those skilled in the art, for example by extrusion, solvent evaporation, for example using dichloromethane, hot pressing, hot injection, electrospinning, molding or 3D printing. The system according to the invention then comprises: - impregnating / swelling the polymer matrices (copolymers (a) and homopolymers (b)) with a solution or suspension containing at least one active ingredient; - coating the polymer matrix (copolymer (a) and homopolymer (b)) with a solution or suspension comprising at least one active ingredient and, optionally, water-soluble excipients to form a coating on the surface of the polymer matrix, or - by depositing a powder containing the active ingredient and water-soluble excipients on the surface of the polymer matrix (copolymer (a) and homopolymer (b)), followed by hot pressing the polymer matrix and the powder, and coating the surface of the polymer matrix with a solvent such as acetone, ethanol or dichloromethane to facilitate the adhesion of the powder to the polymer matrix, and incorporating the active ingredient into the polymer matrix after formation by one of the following means.

[0074] Thus, according to the present invention, the active ingredient can be incorporated into the very structure of the polymer matrix comprising copolymer (a) and homopolymer (b) and / or can form at least a partial coating on the outer surface of the polymer matrix comprising copolymer (a) and homopolymer (b) after formation.

[0075] Generally, the thickness of the systems achieved in the present invention will depend on the amount of polymer matrix used and the surface of the support or mold used to form it.

[0076] The system of the present invention can be in any type of dosage form suitable for the morphology of the uterine cavity.Therefore, the system of the present invention can be in the form of a film, a tube, a powder, a porous structure, such as a 2D or 3D matrix, a complex 3D structure, a gel, or a porous or non-porous hydrogel.

[0077] Film is understood to mean, for example, a two-dimensional material obtained on a flat surface from the evaporation of the solvent that solubilized the A and B block copolymers (a) and the homopolymers (b) according to the invention. The thickness of such a film is advantageously between a few microns and a few hundred microns, in particular between 10 μm and 1000 μm. In a particular embodiment, the film has a thickness between 200 μm and 600 μm. The thickness is understood to be "dry" in the sense that it is measured under anhydrous conditions (for example by optical microscopy) after formation and, optionally, after complete evaporation of the solvent used to solubilize the copolymers.

[0078] The dimensions of the film can be adapted according to requirements, inter alia, by cutting a larger dimension film to the desired dimensions.

[0079] The film can be folded to form a tube or sleeve, optionally closed with a suture or adhesive joint, or folded in an accordion shape, or the tube can be formed around a cylinder or directly by extrusion.

[0080] In the context of the present invention, a tube denotes a hollow or solid three-dimensional cylindrical object, the walls of which are formed from a film of the A and B block copolymer (a) and the homopolymer (b) according to the invention. Preferentially, the diameter of such a tube is several hundred microns, in particular between 500 μm and 5000 μm. In a particular embodiment, the tube has a wall thickness of 1000 μm and a diameter of 3000 μm. For example, the degradable uterine system can have the shape of a cylinder, the diameter of which can be between 0.1 mm and 9 mm, preferably between 2 mm and 6 mm. The length of the cylinder can be between 0.5 cm and 20 cm, preferably between 3 cm and 10 cm. The cylinder can be straight or curved, U-shaped, V-shaped or L-shaped, serpentine or can be wound around a core.

[0081] In one particular embodiment, the system according to the invention is obtained by forming it on a support intended to form part of said system, for example the material is dried on a woven or knitted fabric of another polymer, thus forming the assembly of a composite material.

[0082] Advantageously, the system according to the invention comprises or consists only of the copolymer (a), the homopolymer (b), at least one active ingredient and, optionally, trace amounts of solvent.

[0083] In certain cases, the system of the present invention may further comprise an excipient or additive. This excipient or additive can be added to the copolymer-based composition before or during the formation of the material, for example, to be dispersed in the copolymer (a) and homopolymer (b). In other words, it is possible to impregnate or coat the material with this excipient or additive after formation.

[0084] The system of the present invention exhibits swelling and expansion properties that are particularly suitable for intrauterine use. In particular, the specific properties of the intrauterine system of the present invention allow for easy administration in the uterine cavity, followed by its expansion by swelling and sustained release of the active ingredient in the vicinity of the uterine wall. In a particular embodiment, the specific properties of the intrauterine system of the present invention allow the system to come into contact with the uterine wall after swelling and expansion. Such contact with the uterine wall allows, among other things, a more localized and rapid treatment.

[0085] Advantageously, the material according to the invention has a swelling ratio in an aqueous or wet medium having the same osmotic pressure as biological fluids, between 1 and 20, preferably between 3 and 15. The swelling ratio is measured in the following way: after weighing a strip of dry material, it is immersed in a saline medium (PBS 1X) with stirring at 37° C. for 24 hours. After 24 hours, the excess PBS is removed with blotting paper and the strip is weighed again. The swelling ratio corresponds to the ratio weight of the wet strip of material / weight of the dry strip of material. The swelling ratio of a material is proportional to its percentage water absorption, which corresponds to the ratio [(weight of the wet strip of material-weight of the dry strip of material) / weight of the dry strip of material]×100.

[0086] Swelling of the material is accompanied by an increase in surface area and volume (the "hydrated" surface area or volume), which is particularly advantageous in medical uses for local administration of active ingredients, since it facilitates the deployment of the material in the uterine cavity, in particular so as to get as close as possible to the uterine wall.

[0087] The increase in surface area is rapid and can reach 200% to 300% within minutes to hours, especially in aqueous or wet media. In particular, the increase in surface area can reach up to 100% within 30 minutes and / or up to 300% within 24 hours. The increase in surface area is accompanied by an increase in the volume of the material and is measured visually, under the same conditions as when measuring the swelling ratio, by only changing the residence time in the saline solution. The increase in surface area corresponds to the ratio [(surface area of ​​the "hydrated" strip after immersion time t - surface area of ​​the "dry" strip) / surface area of ​​the "dry" strip] x 100.

[0088] Thus, the particular swelling properties of the intrauterine system according to the invention allow it to unfold within the cavity and advantageously come into contact with the uterine wall in order to locally release the active ingredient without the risk of expulsion.

[0089] According to a preferred embodiment, the intrauterine system according to the invention allows for a sustained release of the active ingredient in the uterine cavity for at least 10 days, such as 10 days, 12 days, 15 days, 21 days, 28 days, 30 days, 2 months, 3 months, 4 months, 5 months or 6 months. Advantageously, the sustained release of the active ingredient is carried out for 10 days to 12 months, in particular 10 days to 9 months, in particular 10 days to 6 months, in particular 10 days to 3 months, in particular 10 days to 2 months, in particular 10 days to 30 days. Advantageously, the sustained release of the active ingredient is a continuous sustained release. Within the context of the present invention, the amount of active ingredient released at each release time can be measured by HPLC with a UV detector, a fluorescence detector or a mass spectrometer.

[0090] A further particularly advantageous feature of the system according to the invention is that it is degradable in an aqueous or moist medium. In particular, the system according to the invention degrades in an aqueous or moist medium after a residence time of 10 days to 12 months, preferentially 10 days to 9 months, preferentially 10 days to 6 months, in particular 10 days to 3 months, in particular 10 days to 70 days. The degradation time in an aqueous or moist medium is determined in vitro, in particular in a uterine model. The degradation of the material is due to the progressive hydrolysis of the ester bonds of the polyester blocks, followed by the solubilization of the blocks containing PEO. The loss of mechanical properties of the material is directly related to its degradation. The degradation can also be evaluated by measuring the decrease in the molecular weight of a strip of the material over time, for example by size exclusion chromatography, after immersion in a saline medium (PBS 1X) at 37° C. with stirring. The solubilization of the PEO blocks and the hydrolysis of the polyester blocks in the uterine cavity are slow and adjusted to allow the material to be excreted at the desired time. Thus, the degradation characteristics of the system of the present invention enable it to remain intact in the uterine cavity for a sufficient period of time to sustainably release the active ingredient at the uterine wall, and then to degrade sufficiently to allow its natural excretion.

[0091] Advantageously, the degradable intrauterine system according to the invention is in the form of a film having a triangular or trapezoidal shape so that it swells, hydrates and unfolds to contact the walls of the uterine cavity.

[0092] The film may have a dry thickness of, for example, 300 to 600 microns.

[0093] In a particular embodiment, as shown in Figure 1, the film 1 has a trapezoid shape with a height h of approximately 1-4 cm, a larger width L of approximately 1-2.5 cm, and a smaller width l of approximately 0.5-1.5 cm. For example, the trapezoid has a height of approximately 2.5 cm, a larger width L of approximately 2 cm, and a smaller width l of approximately 1 cm. These dimensions can be easily adapted by the skilled artisan depending on the type of patient to be treated, whether the patient is primiparous or multiparous, the patient's age, the anatomical structure of the uterus, the reasons for fear of adhesion development, etc., especially within the above-mentioned ranges.

[0094] The intrauterine system of the present invention is particularly suitable for use in the treatment of gynecological disorders such as uterine fibroids, endometrial cancer, endometrial sub-implantation ability, thin endometrium, infections, bleeding (menorrhagia, uterine bleeding), side effects of cancer, aging, menopause, or vaginal dryness, or pelvic pain such as dysmenorrhea, endometriosis, or adenomyosis, in female mammals, more particularly in women.

[0095] kit The present invention also relates to a kit comprising an intrauterine system according to the invention and means for inserting said system into the uterine cavity. The kit according to the invention advantageously comprises means for inserting and positioning the material in the uterine cavity.

[0096] For example, as shown in FIG. 2, the kit 10 according to the invention may include a hollow cylindrical inserter 11, in whose bore 12 a film 2 having an inverted trapezoidal shape is accommodated. Advantageously, in order to minimize the dimensions of the inserter 11, the film is accommodated in the bore 12 in a compressed form. For example, the film is folded in an accordion shape and held closed by the inner wall of the bore 12. The accordion unfolds only after it is released in the uterine cavity. Moreover, this unfolding is facilitated by the polymer of the film swelling with moisture on contact with the intrauterine fluid, with an almost simultaneous increase in the volume of the film.

[0097] The kit 10 advantageously includes a plunger 13 mounted for translational sliding at the inserter's distal end 14, the opposite proximal end 15 being the end at which the inserter 11 is intended to be introduced into the uterine cavity. The plunger 13 consists of a rod 16 which, when pressed towards the proximal end 15 and into the bore 12 of the inserter 11, moves the film 2 translationally out of the inserter 11.

[0098] Advantageously, the plunger 13 includes a stop means 17 at the proximal end of the rod 16 which is intended to abut against the wall of the inserter adjacent its proximal end 15, to indicate to the person handling the kit 10 that the film 2 has been fully expelled from the inserter 11 and is in place in the uterine cavity. The insertion means / inserter assembly may then be removed by simply withdrawing it, leaving the film 2 itself in place in the uterine cavity.

[0099] The kit of the present invention, and in particular the insertion means, allows for a reliable introduction and placement of the degradable intrauterine system of the present invention. Furthermore, the compressed configuration of the intrauterine system of the present invention in the dry form (before swelling) allows for a small size of the kit, which facilitates its introduction through the patient's cervix.

[0100] The kit of the present invention may be used especially for patients suffering from gynecological disorders such as uterine fibroids, endometrial cancer, endometrial hypo-implantation, thin endometrium, infections, bleeding (menorrhagia, uterine bleeding), side effects of cancer, aging, menopause, or vaginal dryness, or pelvic pain such as dysmenorrhea, endometriosis, or adenomyosis. The compressed form of the material and the use of the small size applicator facilitate its placement in the often sensitive uterine cavity of these patients. Moreover, its natural expulsion during the menstrual cycle allows the patient to avoid further intervention by medical personnel to remove the above-mentioned device.

[0101] The present invention will now be illustrated by means of examples which are given by way of illustration and are not intended to limit the invention in any way. EXAMPLES

[0102] Example 1 illustrates the preparation of a degradable intrauterine system for the sustained release of flurbiprofen in the uterine cavity. 1.Synthesis of ABA triblock copolymer a. Material Commercially available poly(ethylene oxide) (PEO): supplier is Sigma Aldrich, CAS number 25322-68-3. The commercial PEO was analyzed in the laboratory by size exclusion chromatography (SEC) to determine its weight-average molar mass (Mw). The analysis was carried out in analytical solvent (dimethylformamide) and Mw was determined via a standard range of poly(ethylene glycol). The weight-average molar mass Mw is 95000 Da and its inherent viscosity is 0.16 ml / mg.

[0103] Commercially available D,L-lactide: supplier is Corbion Purac, CAS number is 95-96-5.

[0104] b. Method The ABA triblock is synthesized in the following manner. PEO (Mw 95,000) (200 g) and D,L-lactide (458 g) are dried under vacuum at ambient temperature for 24 hours. The PEO and D,L-lactide are introduced into a round-bottom polymerization flask in the presence of stannous octoate (85 mg). Then, vacuum (10 -3The mixture is then heated at 140° C. and again subjected to 10 successive cycles of vacuum and argon. The mixture is allowed to return to ambient temperature and then placed in an ice bath. Upon crystallization, 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 at 140° C. for 3 days with mechanical rotation. The mixture is solubilized in dichloromethane and precipitated from an ether / ethanol mixture. The precipitate is collected and then dried under vacuum for 24 hours.

[0105] c. Characterization The ABA triblock was analyzed by size exclusion chromatography (SEC) in the laboratory to determine its weight average molar mass (Mw). The analysis was performed in analytical solvent (dimethylformamide) and Mw was determined via a standard range of poly(ethylene glycol). The weight average molar mass Mw is 113000 Da. The triblock was analyzed by falling ball viscosimetry at a concentration of 0.05 g / ml in chloroform at 25° C. The inherent viscosity of the ABA triblock is 0.051 ml / mg.

[0106] 2. Blend of ABA triblock copolymer, PCL homopolymer, and flurbiprofen a. Material The homopolymer added to the ABA triblock is commercial polycaprolactone (PCL), supplier Evonik Operations GmbH, CAS number 24980-41-4, analyzed in the laboratory by size exclusion chromatography (SEC) to determine its weight-average molar mass (Mw). The analysis was carried out in analytical solvent (dimethylformamide) and the Mw was determined via a standard range of poly(methyl methacrylate) (PMMA). The weight-average molar mass Mw is 140000 Da. The inherent viscosity is provided by the supplier. The inherent viscosity of PCL (25°C, 0.1%, chloroform) is 1.82 dl / g.

[0107] The active ingredient is flurbiprofen, the supplier is Sigma Aldrich, the CAS number is 5104-49-4.

[0108] b. Method 80% by weight of ABA triblock (3.2 g) and 20% by weight of PCL homopolymer (0.8 g) are solubilized in 40 ml of dichloromethane with stirring at ambient temperature. Flurbiprofen (0.4 g, corresponding to 10% of the total weight of the polymer, i.e. 9% by weight of the total weight of the system) is added to the mixture, and the mixture is stirred for 4 hours. The mixture is dried in a rotary evaporator at a given temperature under a vacuum of 100 mbar until the dichloromethane is removed. The dried mixture is collected.

[0109] 3. Preparation of the Flurbiprofen-releasing Intrauterine System of the Present Invention a. Formation A mixture containing the ABA triblock, homopolymer, and flurbiprofen is formed by hot pressing. The mixture is pressed between two heated platens at 85° C. for 8 minutes, with a pressure of 20 mPa between the two platens. The thickness of the film depends on the amount of polymer used and the surface area of ​​the support. The resulting polymer film has a thickness of 500 microns. The film is then cut using a punch into a trapezoid shape with a height h of 2.5 cm, a maximum width L of 2 cm, and a minimum width l of 1 cm. The film has a weight of about 200 mg, containing 9% flurbiprofen, i.e., 18 mg flurbiprofen.

[0110] 4. Evaluation of the characteristics of the intrauterine system of the present invention a. Method i. In vitro conditions for release testing The trapezoidal film is placed in a 50 ml closed glass flask containing 33 ml of phosphate buffered saline (pH 7.4). The flasks (n=3) are placed at 37°C under mechanical stirring (100 rpm). 1 ml of the solution is sampled 2 h, 4 h, 1 day, 2 days, 9 days, and 12 days after release. After each sampling, 1 ml of phosphate buffered saline is added to the medium, except for the 9th day sampling, where the entire medium is replaced by 33 ml of phosphate buffered saline. Each sample, i.e., n=3 samples per time, is analyzed by high performance liquid chromatography (HPLC). The amount of released flurbiprofen is calculated for each sample time from the calibration curve equation.

[0111] The concentration of flurbiprofen released at time t (μg / ml) is calculated as follows: Flurbiprofen concentration (t) (μg / ml) = area under the curve measured by HPLC / a, where a is the value of the calibration curve equation y=ax.

[0112] The amount of flurbiprofen (μg) released into the medium at time t is calculated as follows: Amount of flurbiprofen (t) (μg) = total volume of medium (ml) × concentration of flurbiprofen (t) (μg / ml)

[0113] The cumulative percentage of flurbiprofen released at time t is then calculated in the following manner: Cumulative percentage of flurbiprofen (t) (%) = (amount of flurbiprofen (t) (μg) / initial amount of flurbiprofen (μg)) × 100%

[0114] ii. Methods for measuring the increase in surface area of ​​a film The increase in surface area of ​​the film is measured after 24 hours of release under in vitro conditions. The film is removed and the surface area of ​​the film is measured using ImageJ software. The increase in surface area is measured as follows: Surface area increase rate (%) = ((surface area (t = 24 hours) - surface area (t = 0)) / surface area (t = 0)) x 100

[0115] iii. Evaluation of film degradation under in vitro degradation conditions The trapezoidal film is placed in a 50 ml closed glass flask containing 33 ml of phosphate buffered saline (pH 7.4). The flasks (n=3) are placed at 37° C. under mechanical stirring (100 rpm). The appearance of the film is evaluated after 24 hours, 15 days, and 70 days of in vitro degradation. After 15 days of degradation, the film is dried in a freeze dryer at −60° C. under 0.025 mbar for 24 hours to obtain a stable mass. The dried film is weighed to determine the mass loss of the film after 15 days of degradation. The mass loss of the film is calculated as follows: Mass reduction rate (%) = ((mass (t) - mass (t = 0)) / mass (t = 0)) × 100

[0116] iv. Method for quantifying flurbiprofen release by high performance liquid chromatography (HPLC) Separation by high performance liquid chromatography (HPLC) is performed using an HPLC system (Shimadzu) containing a Kinetex C18 column (2.6 μm, 100×4.6 mm, Phenomenex, California, USA) maintained at 30° C. The mobile phase consists of 60% water and 40% acetonitrile (60 / 40 v / v). The isocratic flow rate is 1.0 ml / min. The injection volume is 10 μl. Detection is performed at a wavelength of 247 nm.

[0117] A calibration curve is prepared by solubilizing 1 mg of pure active ingredient in 40 ml of phosphate buffered saline (PBS) in 50 ml closed glass flasks (n=3). From this stock solution, serial dilutions are made with PBS to obtain a concentration range of 2.5-25 μg / ml.

[0118] b.Results i. Increased surface area of ​​the film After 24 hours of exposure, the film had a surface area of ​​808 mm2, ie, a 115% increase in surface area relative to the initial surface area of ​​the film.

[0119] ii. Release kinetics Calibration curve The calibration curve was linear (r2=0.99968) in the concentration range of 2.5-25μg / ml.

[0120] Release kinetics Figure 3 shows the cumulative percentage of flurbiprofen released over time from films composed of a mixture of ABA triblock and PCL homopolymer. Under in vitro release conditions, flurbiprofen is released from the polymer film over time with a burst effect on day 1, followed by release through day 12. The intrauterine system allows for the release of flurbiprofen over 12 days under in vitro release conditions.

[0121] iii. Decomposition Figure 4 shows the appearance of a film composed of a mixture of ABA triblock and PCL homopolymer after 24 hours (Figure 4.a) and after 15 days (Figure 4.b) of degradation under in vitro degradation conditions. After 24 hours of degradation, the film becomes a flexible and elastic barrier. After 15 days of degradation, the film has lost its mechanical properties since it crumbles into several small pieces when handled. After 15 days of in vitro degradation, the film has lost 30% of its initial mass and can be easily removed by natural routes under clinical use conditions. After 70 days of in vitro degradation, the film is completely solubilized in the degradation medium.

[0122] Example 2 illustrates the preparation of a degradable intrauterine system for the sustained release of flurbiprofen in the uterine cavity. 1.Synthesis of ABA triblock copolymer The synthesis is similar to that of the ABA triblock copolymer in Section 1 of Example 1.

[0123] 2. Blend of ABA triblock copolymer, PCL homopolymer, and flurbiprofen a. Material Same as section 2a of Example 1.

[0124] b. Method 60 wt% triblock ABA (2.4 g) and 40 wt% homopolymer PCL (1.6 g) are solubilized in 40 ml of dichloromethane with stirring at room temperature. Flurbiprofen (0.4 g, corresponding to 9 wt% based on the total weight of the system) is added to the mixture and the mixture is stirred for 4 hours. The mixture is dried in a rotavapor at a given temperature under a vacuum of 100 mbar until the dichloromethane is removed. The dried mixture is collected. The formulation is named "ABA60 / 40PCL+9%F", where "F" is flurbiprofen.

[0125] 40 wt% triblock ABA (1.6 g) and 60 wt% homopolymer PCL (2.4 g) are solubilized in 40 ml of dichloromethane with stirring at room temperature. Flurbiprofen (0.4 g, corresponding to 9 wt% based on the total weight of the system) is added to the mixture and the mixture is stirred for 4 hours. The mixture is dried in a rotavapor at a given temperature under a vacuum of 100 mbar until the dichloromethane is removed. The formulation is named "ABA40 / 60PCL+9%F", where "F" is flurbiprofen.

[0126] 100 wt% triblock ABA (4 g) and 0 wt% homopolymer PCL (0 g) are solubilized in 40 ml of dichloromethane with stirring at room temperature. Flurbiprofen (0.4 g, corresponding to 9 wt% based on the total weight of the system) is added to the mixture, and the mixture is stirred for 4 hours. The mixture is dried in a rotavapor at a given temperature under a vacuum of 100 mbar until the dichloromethane is removed. The formulation is named "ABA100 / 0PCL+9%F", where "F" is flurbiprofen.

[0127] 3. Preparation of intrauterine delivery system of flurbiprofen according to the present invention Molding process The mixture containing the triblock ABA, optionally the homopolymer, and flurbiprofen is molded by hot pressing. The mixture is pressed between two heated platens at 85° C. for 8 minutes, with a pressure of 20 mPa between the two platens. The thickness of the film depends on the amount of polymer used and the surface of the substrate. The resulting polymer film has a thickness of 500 microns. The film is then cut with a punch into a trapezoidal shape with a height h of 2.5 cm, a maximum width L of 2 cm, and a minimum width l of 1 cm. The film has a mass of about 200 mg, with 9% flurbiprofen, i.e. 18 mg flurbiprofen.

[0128] 4. Evaluation of the characteristics of the intrauterine system of the present invention a. Method i. In vitro conditions for release testing The trapezoidal films are placed in 50 ml closed glass vials containing 33 ml of phosphate buffer (pH 7.4). The vials (n=3) are placed at 37°C under mechanical shaking (100 rpm). 1 ml of solution is taken 2 h, 4 h, 1 day, 2 days, 9 days, and 12 days after release. After each sampling, 1 ml of phosphate buffered saline is added to the medium, except for the 9th day sample, where the entire medium is replaced by 33 ml of phosphate buffered saline. Each sample, i.e., n=3 samples per time, is analyzed by high performance liquid chromatography (HPLC). The amount of released flurbiprofen is calculated for each sample time from the calibration curve equation.

[0129] The concentration of flurbiprofen released at time t (μg / ml) is calculated as follows: Flurbiprofen concentration (t) (μg / ml) = area under the curve measured by HPLC / a, where a is the value of the calibration curve equation y=ax.

[0130] The amount of flurbiprofen (μg) released into the medium at time t is calculated as follows: Amount of flurbiprofen (t) (μg) = total volume of medium (ml) × concentration of flurbiprofen (t) (μg / ml)

[0131] The cumulative percentage of flurbiprofen released at time t is then calculated as follows: Cumulative percentage of flurbiprofen (t) (%) = (amount of flurbiprofen (t) (μg) / initial amount of flurbiprofen (μg)) × 100%

[0132] ii. Method for quantifying flurbiprofen release by high performance liquid chromatography (HPLC) Quantification by high performance liquid chromatography (HPLC) is performed using an HPLC system (Shimadzu) containing a Kinetex C18 column (2.6 μm, 100×4.6 mm, Phenomenex, California, USA) maintained at 30° C. The mobile phase consists of 60% water and 40% acetonitrile (60 / 40 v / v). The isocratic flow rate is 1.0 ml / min. The injection volume is 10 μl. Detection is performed at a wavelength of 247 nm.

[0133] A calibration curve is prepared by solubilizing 1 mg of pure active ingredient in 40 ml of phosphate buffered saline (PBS) in 50 ml closed glass vials (n=3). From this stock solution, serial dilutions are made with PBS to obtain a concentration range of 2.5-25 μg / ml.

[0134] b.Results i. Release kinetics Calibration curve The calibration curve was linear (r2=0.99968) in the concentration range of 2.5-25μg / ml.

[0135] Release kinetics FIG. 5 shows the cumulative percentage of flurbiprofen released over time from ABA60 / 40PCL and ABA40 / 60PCL films composed of triblock ABA blends and homopolymer PCL, and ABA100 / 0PCL films composed of triblock ABA alone. Under in vitro release conditions, flurbiprofen was released from the polymer films over time with a burst effect on day 1 followed by release by day 12. The addition of PCL to the blend modulates the release kinetics of flurbiprofen during the first few days. The intrauterine system allows for the release of flurbiprofen for 12 days under in vitro release conditions. In the absence of PCL homopolymer, more than 50% of flurbiprofen was released in 4 hours, making this formulation unacceptable for sustained release.

[0136] Example 3 illustrates the preparation of a degradable intrauterine system for the sustained release of flurbiprofen in the uterine cavity. 1.Synthesis of ABA triblock copolymer The synthesis is similar to that of the ABA triblock copolymer in Section 1 of Example 1.

[0137] 2. Blend of ABA triblock copolymer, PCL homopolymer, and flurbiprofen a. Material Same as section 2a of Example 1.

[0138] b. Method 30 wt% ABA triblock (96 mg), 19 wt% PCL homopolymer (64 mg), 51 wt% PLA50 homopolymer (166.4 mg) are solubilized in 40 ml of dichloromethane with stirring at room temperature. Flurbiprofen (90 mg, corresponding to 22 wt% based on the total weight of the system) is added to the mixture and the mixture is stirred for 4 hours. The mixture is dried in a rotavapor at a given temperature under a vacuum of 100 mbar until the dichloromethane is removed. The formulation is named "ABA30 / 70PCL / PLA50+22%F", where "F" is flurbiprofen.

[0139] 20 wt% ABA triblock (64 mg), 29 wt% PCL homopolymer (96 mg), 51 wt% PLA50 homopolymer (166.4 mg) are solubilized in 40 ml of dichloromethane with stirring at room temperature. Flurbiprofen (90 mg, corresponding to 22 wt% based on the total weight of the system) is added to the mixture and the mixture is stirred for 4 hours. The mixture is dried in a rotavapor at a given temperature under a vacuum of 100 mbar until the dichloromethane is removed. The formulation is named "ABA20 / 80PCL / PLA50+22%F", where "F" is flurbiprofen.

[0140] 3. Preparation of intrauterine delivery system of flurbiprofen according to the present invention Molding process The mixture containing triblock ABA, homopolymer PCL, homopolymer PLA50, and flurbiprofen is molded by hot pressing. The mixture is pressed between two heated platens at 85° C. for 8 minutes, with a pressure of 20 mPa between the two platens. The thickness of the film depends on the amount of polymer used and the surface of the substrate. The resulting polymer film has a thickness of 1000 microns. The film is then cut with a punch into a trapezoidal shape with a height h of 2.5 cm, a maximum width L of 2 cm, and a minimum width l of 1 cm. The film has a mass of about 416 mg, with 22% being flurbiprofen, i.e. about 90 mg of flurbiprofen.

[0141] 4. Evaluation of the characteristics of the intrauterine system of the present invention c. Method i. In vitro conditions for release testing 50 mg samples of the trapezoidal film are cut and placed into 50 ml sealed glass vials containing 45 ml of phosphate buffered saline (pH 7.4). The vials (n=3) are placed at 37°C under mechanical stirring (100 rpm). 1 ml of solution is taken 2 hours, 4 hours, 1 day, 2 days, 7 days after release, and every 7 days up to day 56. After each sampling, 1 ml of phosphate buffer is added to the medium. Each sample, i.e., n=3 samples per time, is analyzed by high performance liquid chromatography (HPLC). The amount of flurbiprofen released is calculated for each sampling time from the calibration curve equation.

[0142] The concentration of flurbiprofen released at time t (μg / ml) is calculated as follows: Flurbiprofen concentration (t) (μg / ml) = area under the curve measured by HPLC / a, where a is the value of the calibration curve equation y=ax.

[0143] The amount of flurbiprofen (μg) released into the medium at time t is calculated as follows: Amount of flurbiprofen (t) (μg) = total volume of medium (ml) × concentration of flurbiprofen (t) (μg / ml)

[0144] The cumulative percentage of flurbiprofen released at time t is then calculated as follows: Cumulative percentage of flurbiprofen (t) (%) = (amount of flurbiprofen (t) (μg) / initial amount of flurbiprofen (μg)) × 100%

[0145] ii. Method for quantifying flurbiprofen release by high performance liquid chromatography (HPLC) Quantification by high performance liquid chromatography (HPLC) is performed using an HPLC system (Shimadzu) containing a Kinetex C18 column (2.6 μm, 100×4.6 mm, Phenomenex, California, USA) maintained at 30° C. The mobile phase consists of 60% water and 40% acetonitrile (60 / 40 v / v). The isocratic flow rate is 1.0 ml / min. The injection volume is 10 μl. Detection is performed at a wavelength of 247 nm.

[0146] A calibration curve is prepared by solubilizing 1 mg of pure active ingredient in 40 ml of phosphate buffered saline (PBS) in 50 ml closed glass vials (n=3). From this stock solution, serial dilutions are made with PBS to obtain a concentration range of 2.5-25 μg / ml.

[0147] d.Result i. Release kinetics Calibration curve The calibration curve was linear (r2=0.99968) in the concentration range of 2.5-25μg / ml.

[0148] Release kinetics FIG. 6 shows the cumulative percentage of flurbiprofen released over time from ABA30 / 70PCL / PLA50 and ABA20 / 80PCL / PLA50 films composed of triblock mixture ABA and homopolymers PCL and PLA50. Under in vitro release conditions, flurbiprofen is released from the polymer film over time with a burst effect on day 1 followed by release up to day 35. The addition of triblock ABA to the mixture modulates the release kinetics of flurbiprofen over time. The intrauterine system allows for the release of flurbiprofen for 35 days under in vitro release conditions. Increasing the percentage of PLA in the homopolymer fraction of the system retards the release of flurbiprofen.

[0149] Example 4 illustrates the preparation of a degradable intrauterine system for the sustained release of flurbiprofen in the uterine cavity. 1.Synthesis of ABA triblock copolymer The synthesis is similar to that of the ABA triblock copolymer in Section 1 of Example 1.

[0150] 2. Blend of ABA triblock copolymer, PCL homopolymer, and flurbiprofen a. Material Same as section 2a of Example 1.

[0151] a. Method 20 wt% ABA triblock (66.56 mg), 30 wt% PCL homopolymer (99.84 mg), 50 wt% PLA50 homopolymer (166.38 mg) are solubilized in 40 ml of dichloromethane with stirring at room temperature. Flurbiprofen (83.19 mg, corresponding to 20 wt% based on the total mass of the system) is added to the mixture and the mixture is stirred for 4 hours. The mixture is dried in a rotavapor at a given temperature under a vacuum of 100 mbar until the dichloromethane is removed. The formulation is named "ABA20 / 80PCL / PLA50+20%F", where "F" is flurbiprofen.

[0152] 6 wt% ABA triblock (52 mg), 9 wt% PCL homopolymer (78.67 mg), 85 wt% PLA50 homopolymer (748.3 mg) are solubilized in 40 ml of dichloromethane with stirring at room temperature. Flurbiprofen (374.83 mg, corresponding to 30 wt% based on the total weight of the system) is added to the mixture and the mixture is stirred for 4 hours. The mixture is dried in a rotavapor at a given temperature under a vacuum of 100 mbar until the dichloromethane is removed. The formulation is named "ABA6 / 94PCL / PLA50+30%F", where "F" is flurbiprofen.

[0153] 3. Preparation of intrauterine delivery system of flurbiprofen according to the present invention Molding process The mixture containing triblock ABA, homopolymer PCL, homopolymer PLA50, and flurbiprofen is molded by hot pressing. The mixture is pressed between two heated platens at 85° C. for 8 minutes, with a pressure of 20 mPa between the two platens. The thickness of the film depends on the amount of polymer used and the surface of the substrate. The resulting polymer films have a thickness of 1000 microns for “ABA20 / 80PCL / PLA50+20%F-1mm” and “ABA6 / 94PCL / PLA50+30%F-1mm” and 2000 microns for “ABA6 / 94PCL / PLA50+30%F-2mm”. The film is then cut into a trapezoid shape with a height h of 2.5 cm, a maximum width L of 2 cm, and a minimum width l of 1 cm. The "ABA20 / 80PCL / PLA50+20%F-1mm" and "ABA6 / 94PCL / PLA50+30%F-1mm" films have a mass of about 416 mg containing 20% ​​flurbiprofen, i.e., about 83 mg of flurbiprofen, and 30% flurbiprofen, i.e., about 124.8 mg of flurbiprofen, respectively. The "ABA6 / 94PCL / PLA50+30%F-2mm" film has a mass of about 832 mg containing 30% flurbiprofen, i.e., about 250 mg of flurbiprofen.

[0154] 4. Evaluation of the characteristics of the intrauterine system of the present invention e. Method i. In vitro conditions for release testing For the "ABA20 / 80PCL / PLA50+20%F-1mm" and "ABA6 / 94PCL / PLA50+30%F-1mm" formulation conditions, 14 mg samples of trapezoidal films were cut and placed in 50 ml sealed glass vials containing 14 ml of phosphate buffered saline (pH 7.4).

[0155] For the "ABA6 / 94PCL / PLA50+30%F-2mm" formulation condition, a 28 mg sample of the trapezoidal film is cut and placed in a 50 ml sealed glass vial containing 28 ml of phosphate buffer (pH 7.4).

[0156] The vials (n=3) are placed at 37° C. under mechanical stirring (100 rpm). After each day or at 3-day intervals until the 56th day of release, 1 ml of solution is taken. After each sampling, 1 ml of phosphate-buffered saline is added to the medium. Each sample, i.e., n=3 samples per time, is analyzed by high performance liquid chromatography (HPLC). The amount of flurbiprofen released is calculated for each sampling time from the calibration curve equation.

[0157] The concentration of flurbiprofen released at time t (μg / ml) is calculated as follows: Flurbiprofen concentration (t) (μg / ml) = area under the curve measured by HPLC / a, where a is the value of the calibration curve equation y=ax.

[0158] The amount of flurbiprofen (μg) released into the medium at time t is calculated as follows: Amount of flurbiprofen (t) (μg) = total volume of medium (ml) × concentration of flurbiprofen (t) (μg / ml)

[0159] The cumulative percentage of flurbiprofen released at time t is then calculated as follows: Cumulative percentage of flurbiprofen (t) (%) = (amount of flurbiprofen (t) (μg) / initial amount of flurbiprofen (μg)) × 100%

[0160] ii. Method for quantifying flurbiprofen release by high performance liquid chromatography (HPLC) Quantification by high performance liquid chromatography (HPLC) is performed using an HPLC system (Shimadzu) containing a Kinetex C18 column (2.6 μm, 100×4.6 mm, Phenomenex, California, USA) maintained at 30° C. The mobile phase consists of 60% water and 40% acetonitrile (60 / 40 v / v). The isocratic flow rate is 1.0 ml / min. The injection volume is 10 μl. Detection is performed at a wavelength of 247 nm.

[0161] A calibration curve is prepared by solubilizing 10 mg of pure active ingredient in 10 ml of phosphate buffered saline (PBS) in 50 ml closed glass vials (n=3). From this stock solution, serial dilutions are made with PBS to obtain a concentration range of 25-1000 μg / ml.

[0162] iii. In vivo testing A 1mm-thick film of "ABA20 / 80PCL / PLA50+20%F" was placed in the uterus of a female rat (Sprague Dawley, 8 weeks old). -Percentage of water absorption, - mass loss over time, The amount of flurbiprofen absorbed into uterine tissue was assessed.

[0163] Flurbiprofen was orally administered to female rats in another group to evaluate the amount of flurbiprofen absorbed into the uterine tissue, which served as the control group.

[0164] Surgical procedure Film placement technique The formulations were molded according to section 3.a. Approximately 15 mg samples of trapezoidal film were cut and placed in the uterus (also known as uterine horns) of rats after anesthesia with 2% isoflurane, laparotomy, and dissection of the uterine horns. Each rat has two rat uterine horns. Therefore, a test specimen was placed in each uterine horn. The horns were then sutured and a ligature was placed at the vaginal side to prevent the device from being removed from the vagina.

[0165] Oral Administration Technique Flurbiprofen was administered orally at 4 mg / kg twice daily. Flurbiprofen was first solubilized in a 0.5 mg / ml hydroxyethylcellulose solution (Cellosize).

[0166] Rats received 300 mg / kg paracetamol 24 hours prior to surgery and 0.05 mg / kg buprenorphine subcutaneously after anesthesia and before the start of surgery.

[0167] At each time of death, the uterine horns were incised longitudinally and film samples were taken. Groups were divided as follows (see Table 1):

[0168] [Table 1]

[0169] A method for measuring water absorption of films under in vivo conditions The water absorption rate of the films is measured 11 hours after placement in the uterine horn (Group 2A). The films are placed on absorbent paper and weighed. The percentage of water absorption is measured as follows: Moisture absorption rate (%) = ((mass (t = 11 hours) - mass (t = 0)) / mass (t = 0)) × 100

[0170] Evaluation of film degradation under in vivo degradation conditions At each death time, the film is taken and then dried by freeze-drying at -60°C under 0.025 mbar for 24 hours to obtain a stable mass. The dried film is weighed to measure the film mass loss. The film mass loss is calculated as follows: Mass reduction rate (%) = ((mass (t) - mass (t = 0)) / mass (t = 0)) × 100

[0171] Evaluation of the amount of flurbiprofen absorbed into uterine tissue under in vivo conditions. At each time of death, uterine horns were harvested and analyzed by liquid chromatography (LC30AD fitted with an Agilent C18 column) coupled to a mass spectrometer (Shimadzu TripleQuad 8060) (LC-MS).

[0172] The uterine horns are placed in an Eppendorf and ground in 0.5 mL of 1X PBS. 100 μL of the homogenate is taken. 20 μL of 1 mg / mL deuterium (D5)-labeled flurbiprofen is added to the homogenate. Then 430 μL of methanol:water mixture (8:1 ratio, -20°C) is added, mixed by end-over-end and stirred at 4°C for 20 minutes. The mixture is centrifuged at 16,000 g for 5 minutes at 4°C. The mixture is placed in a Captiva EMR-Lipids plate and conditioned with 200 μL of 0.1% ACN formic acid (FA). The plate is centrifuged at 1000 rpm for 2 minutes. 400 μL of the supernatant is transferred to the Captiva EMR-Lipids plate. The plate is centrifuged at 1000 rpm for 45 minutes and dried at 30°C for 3 hours. Add 60 μL of methanol and inject 20 μL. Samples were analyzed in positive mode.

[0173] A. Results i. Release kinetics Calibration curve The calibration curve was linear (r2=0.99968) in the concentration range of 2.5-25μg / ml.

[0174] Release kinetics Figure 7 shows the cumulative percentage of flurbiprofen released over time from 1,000 μm and 2,000 μm thick ABA6 / 94PCL / PLA50+30%F films composed of the triblock mixture ABA and the homopolymers PCL and PLA50. Under in vitro release conditions, flurbiprofen is released from the polymer films over time. The thickness of the film modulates the release kinetics of flurbiprofen.

[0175] 8 shows the cumulative percentage of flurbiprofen released over time from 1 mm thick films ABA20 / 80PCL / PLA50+20%F and ABA6 / 94PCL / PLA50+30%F, composed of the triblock mixture ABA and the homopolymers PCL and PLA50. Under in vitro release conditions, flurbiprofen is released from the polymer films over time with a burst effect on day 1, followed by release by day 22 for ABA20 / 80PCL / PLA50+20%F and by day 14 for ABA6 / 94PCL / PLA50+30%F.

[0176] ii. Measurement of water absorption of films under in vivo conditions An average water absorption rate of 65.34% (Sd 3,49%) was observed in the “ABA20 / 80PCL / PLA50+20%F” film.

[0177] iii. Measurement of mass loss of films under in vivo degradation conditions Figure 9 shows the mass loss of the ABA20 / 80PCL / PLA50+20%F film at various times after placement in the uterine horns of rats. The "ABA20 / 80PCL / PLA50+20%F" film lost 40% of its mass at 56 days after placement.

[0178] iv. Measurement of the amount of flurbiprofen absorbed into uterine tissue under in vivo conditions Figure 10 shows the amount of flurbiprofen absorbed into rat uterine tissue after placement of the "ABA6 / 94PCL / PLA50+30%F" film, and the amount of flurbiprofen absorbed into uterine tissue after oral administration of flurbiprofen. Comparable tissue concentrations of flurbiprofen (24-39 μg / g) were measured at 11 hours, 25 hours, and 15 days after oral administration or introduction of the intrauterine delivery system into the horn, suggesting that the intrauterine delivery system may achieve the same therapeutic effect. It is also noted that the "ABA6 / 94PCL / PLA50+30%F" film releases flurbiprofen for 56 days under in vivo conditions.

Claims

1. A degradable intrauterine system for sustained release of an active ingredient in the uterine cavity, comprising: (a) a degradable A and B block copolymer, the A block is polyester; the B block is poly(oxyethylene) (PEO) having a weight average molecular weight of 50 kDa or greater; and a degradable A and B block copolymer having an ethylene oxide unit / ester unit molar ratio of 0.05 to 5; (b) at least one polyester homopolymer; and (c) at least one active ingredient adapted for release in the uterine cavity; Intrauterine system.

2. the weight ratio of copolymer (a) / homopolymer (b) is from 99 / 1 to 1 / 99, preferably from 95 / 5 to 5 / 95, more preferably from 80 / 20 to 5 / 95; The intrauterine system of claim 1 .

3. The A and B block copolymers are selected from AB diblock copolymers, and ABA and BAB triblock copolymers, and mixtures thereof, preferably ABA and BAB triblock copolymers, and mixtures thereof; The intrauterine system of claim 1 .

4. the weight average molecular weight of the B block in the A and B block copolymer is between 75 kDa and 150 kDa, preferably between 80 kDa and 125 kDa, more preferentially between 90 kDa and 115 kDa, more preferably between 90 kDa and 110 kDa, The intrauterine system of claim 1 .

5. the ratio of ethylene oxide units to ester units of the A and B block copolymers is from 0.1 to 4, preferably from 0.1 to 3; The intrauterine system of claim 1 .

6. The A block is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polybutyrolactone (PBL), polyhydroxyalkanoate (PHA), and copolymers thereof; The intrauterine system of claim 1 .

7. the A block is polycaprolactone (PCL) or, advantageously, poly(lactic acid) (PLA) containing at least 50% L-lactic acid; The intrauterine system of claim 1 .

8. the homopolymer (b) is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polybutyrolactone (PBL), and polyhydroxyalkanoate (PHA), and mixtures thereof; advantageously, the homopolymer (b) is PLA and / or PCL; The intrauterine system of claim 1 .

9. the homopolymer (b) has a number average molar mass of 25,000 g / mol to 250,000 g / mol; The intrauterine system of claim 1 .

10. The active ingredient used for release in the uterine cavity is selected from anti-infective agents, such as antibiotics, antifungals or antivirals, steroidal or non-steroidal anti-inflammatory agents, vasoconstrictors, vasodilators, uterine relaxants, labor-inducing agents, hormones, hormone analogs, hormone agonists and hormone antagonists, and anti-cancer agents, or mixtures thereof, and is advantageously selected from NSAIDs, and hormones, hormone analogs, hormone agonists and hormone antagonists, or mixtures thereof. The intrauterine system of claim 1 .

11. The content of the active ingredient is 0.01% to 60% by weight, preferably 1% to 60% by weight, based on the total weight of the system. The intrauterine system of claim 1 .

12. the active ingredient is not covalently bound to the copolymer (a) or the homopolymer (b); The intrauterine system of claim 1 .

13. The system releases the active ingredient over a period of at least 10 days. The intrauterine system of claim 1 .

14. The system degrades after a residence time of 10 days to 12 months in an aqueous or moist environment. The intrauterine system of claim 1 .

15. A kit comprising at least one intrauterine system according to any one of claims 1 to 14 and means for inserting said system into the uterine cavity.

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