New formulations

Abstract

The present invention relates generally to injectable formulations for the sustained release of etonogestrel, pharmaceutical dosage forms and application devices containing said formulations, methods for their preparation, and their use for contraception.

Description

[Technical field]

[0001] The present invention relates generally to injectable formulations for the sustained release of etonogestrel, pharmaceutical dosage forms and application devices containing said formulations, methods for their preparation, and their use for contraception. [Background technology]

[0002] To date, approximately 214 million women in developing countries have an unmet need for modern contraception. This is the result of a combination of limited access to contraceptive products and lack of family planning education and information on how contraceptive methods work. As a result, empowering women to act on their reproductive choices has become a high priority on the global shared development agenda. There is a particular need to develop new contraceptive technologies, including long-acting injectable (LAI) methods.

[0003] LAIs are one of the most convenient, effective, and safe contraceptive products and are justifiably popular with many women. Currently, existing birth control implants can provide reliable contraception by releasing progestin for 3-5 years. For example, Nexplanon® is a progestin-only implant for subcutaneous use. The implant is a 4 cm long, 2 mm diameter non-biodegradable rod consisting of an ethylene vinyl acetate (EVA) copolymer core containing etonogestrel, barium sulfate (a radiopaque component), and may contain magnesium stearate, surrounded by an EVA copolymer skin.

[0004] While they often provide long-term contraceptive effects, they fail to meet the needs and preferences of women who wish to utilize family planning tools and interventions. Solid rod implants may require surgical implantation and may cause inconvenience or damage within the patient's body. Furthermore, rod implants are expensive and not biodegradable. As a result, implant removal surgery (explantation) by specially trained doctors or nurses is essential.

[0005] Thus, there remains an unmet need for contraceptives that provide reliable contraception for a moderate period (months) and require low handling, in order to allow women more flexible access to family planning methods, address barriers to non-use, and accelerate contraceptive acceptance and uptake among women. That is, on the one hand, the contraceptive must provide adequate contraceptive efficacy for months, but on the other hand, for an overall shorter period compared to existing implants, and provide the flexibility to discontinue contraception (i.e., planning flexibility) if the woman wishes to become pregnant, reasonably quickly and easily (i.e., without the need for surgical implant removal). Furthermore, given that the need for contraception is particularly unmet in many developing countries, many of which have warm climates, there is a need for contraceptives that are stable enough to be transported or stored at high temperatures. There is also a need for contraceptives that can be obtained by robust and scalable manufacturing methods. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US6,350,812 [Non-patent literature]

[0007] [Non-Patent Document 1] Rautio, J. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255–270 (2008) Summary of the Invention [Problem to be solved by the invention]

[0008] In view of the above background, the present invention aims to provide improved contraceptive preparations or pharmaceutical dosage forms that act over several months and require less handling; application devices that allow easy administration of the preparations or dosage forms to a subject; robust and scalable methods of manufacturing the preparations; and their use as contraception that allows for greater planning flexibility. [Means for solving the problem]

[0009] As a solution, the present invention provides an injectable formulation for sustained release of etonogestrel, comprising: - Formula AB-A' (in the formula, Blocks A and A' are formed of poly(D,L-lactic acid) and contain m and n lactic acid (LA) repeat units, respectively; Block B is formed of poly(ethylene glycol) containing p ethylene oxide (EO) repeat units; a triblock copolymer (TB) having a molar ratio R(TB) of LA repeat units to EO repeat units ((m+n) / p) is 1.5-9); - a compound of the formula CD, Block C is formed by methoxypoly(ethylene glycol) containing r EO repeat units; Block D is formed of poly(D,L-lactic acid) containing q LA repeat units; a diblock copolymer (DB) having a molar ratio R(DB) of LA repeat units to EO repeat units (q / r) of 1.5 to 15); - with a water-miscible, pharma- ceutically acceptable organic solvent, including DMSO; - An injectable formulation comprising etonogestrel, a prodrug or a salt thereof.

[0010] The present invention further provides a pharmaceutical dosage form comprising the above formulation.

[0011] The present invention also relates to a method for preparing the above formulations and / or dosage forms, comprising the steps of: (i) - a triblock copolymer (TB) having the formula AB-A', in which blocks A and A' are formed of poly(D,L-lactic acid) and contain m and n lactic acid (LA) repeat units, respectively; block B is formed of poly(ethylene glycol) containing p ethylene oxide (EO) repeat units; the molar ratio R(TB)(m+n) / p of LA repeat units to EO repeat units is between 1.5 and 9; a diblock copolymer (DB) having the formula CD, in which the block C is formed by a methoxypoly(ethylene glycol) containing r EO repeat units; the block D is formed by a poly(D,L-lactic acid) containing q LA repeat units; the molar ratio R(DB) of the LA repeat units to the EO repeat units (q / r) is between 1.5 and 12; and - a water-miscible pharma- tically acceptable organic solvent, including DMSO, obtaining a vehicle by mixing until the polymer is dissolved; (ii) mixing the vehicle with etonogestrel to obtain a formulation; (iii) optionally sterilizing the formulation; (iv) providing a predetermined amount of the formulation, and optionally packaging, to obtain the dosage form.

[0012] The present invention further provides an application device comprising the above formulation and / or dosage form, the application device being adapted for administering the formulation or dosage form to a subject by injection.The present invention further provides the use of the above formulation, dosage form or device for contraception in a female subject. [Brief description of the drawings]

[0013] [Figure 1A] Figure 1 shows the in vitro release rate of etonogestrel over time from different formulations at a 10 mg dose. The formulations consist of 1.5-10% w / w etonogestrel, 30-50% w / w polymer, and 45-60% DMSO. Different diblock and triblock copolymers were used. The formulation compositions are detailed in Table 1. In vitro release studies were performed as described in Example 2. [Figure 1B] Figure 1 shows the in vitro cumulative etonogestrel release profiles obtained from different formulations at a 10 mg dose. The formulations consist of 1.5-10% w / w etonogestrel, 30-50% w / w polymer, and 45-60% DMSO. Different diblock and triblock copolymers were used. The formulation compositions are detailed in Table 1. In vitro release studies were performed as described in Example 2. [Figure 2A] Figure 1 shows the in vitro release rate of etonogestrel over time from different formulations at a dose of 15 mg. The formulations consisted of 7.5-10% w / w etonogestrel, 34-42% w / w polymer, and 50-56% DMSO. The diblock and triblock were fixed as were their relative ratios. The formulation compositions are detailed in Table 1. In vitro release studies were performed as described in Example 2. [Figure 2B] Figure 1 shows the in vitro cumulative etonogestrel release profiles obtained from different formulations at a 15 mg dose. The formulations consisted of 7.5-10% w / w etonogestrel, 34-42% w / w polymer, and 50-56% DMSO. The diblock and triblock were fixed as were their relative ratios. The formulation compositions are detailed in Table 1. In vitro release studies were performed as described in Example 2. [Figure 3A] Figure 1 shows the in vitro release rate of etonogestrel over time from the same formulation at various different doses ranging from 10 mg to 40 mg. The formulation compositions are detailed in Table 1. The in vitro release studies were performed as described in Example 2. [Figure 3B]Figure 1 shows the in vitro cumulative etonogestrel release profiles obtained from the same formulation at various different doses ranging from 10 mg to 40 mg. The formulation compositions are detailed in Table 1. In vitro release studies were performed as described in Example 2. [Figure 4] Figure 1 shows the mean kinetic profile of etonogestrel obtained after a single subcutaneous injection of Formulations #3, #7, or #9. The three test articles produced distinct sustained release profiles, with quantifiable levels of etonogestrel for up to 180 days at the 15 mg dose tested. Formulation compositions are detailed in Table 1. Pharmacokinetic studies were performed as described in Example 3. [Diagram 5] Figure 1 shows the mean kinetic profile of etonogestrel obtained after a single subcutaneous injection of formulations #15, #16, #17 or #18. The four test articles produced different sustained release profiles, with #18 providing quantifiable levels of etonogestrel for up to 224 days. The formulation compositions are detailed in Table 1, with the diblock and triblock being fixed as well as their relative ratios. Pharmacokinetic studies were performed as described in Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The contraceptive preparations, dosage forms, preparation methods, application devices and uses according to the invention provide several advantageous effects.

[0015] Due to its particular combination of components, the formulation is capable of releasing etonogestrel in a sustained and controlled manner, providing contraceptive efficacy characterized by a low initial burst and / or a long-term controlled release of etonogestrel over several months (e.g., at least 120 days).

[0016] The formulation of the present invention is an injectable liquid. That is, the formulation has a sufficiently low viscosity to allow easy administration by injection. Therefore, administration can be performed without the need for the involvement of a doctor or nurse. Therefore, handling and application are less laborious. Therefore, the application device adapted for injection allows easy administration of the formulation or dosage form to a subject.

[0017] The formulations of the present invention, upon injection, form a depot in situ and deliver etonogestrel to the subject.

[0018] The formulations of the present invention are biodegradable, in contrast to solid, non-biodegradable implants, which eliminates the need for implant removal surgery (explantation) by specially trained doctors, nurses, or medical professionals, further contributing to improved ease of application for subjects.

[0019] The formulation is liquid. It can be filtered, for example, by sterile filtration. This allows for robust and scalable purification during manufacturing, particularly sterilization by filtration. The formulation shows good filtration stability.

[0020] The formulations also exhibit good storage stability. For example, the formulations can exhibit good stability under long-term stability conditions in an oven set at 30°C ± 3°C and / or under accelerated stability conditions in an ICH climate chamber (40°C ± 2°C / 75% RH ± 5% RH), as determined, for example, by appearance, active ingredient assay, and related substances (UV-UPLC), water content (Karl Fischer volumetric titration), injectability (syringe injection force), copolymer integrity (dynamic viscosity, and molecular weight by GPC-RI), or in vitro release (e.g., repeatability over at least 30 days).

[0021] The formulation may also be compatible with dry heat sterilization. For example, the formulation may exhibit good stability as assessed through stability evaluation following dry heat sterilization cycles (e.g., +121°C / 35 min and +111°C / 60 min).

[0022] Specifically, the present invention provides the following aspects and embodiments:

[0023] 1. An injectable formulation for sustained release of etonogestrel, comprising: - Formula AB-A' (in the formula, Blocks A and A' are formed of poly(D,L-lactic acid) and contain m and n lactic acid (LA) repeat units, respectively; Block B is formed of poly(ethylene glycol) containing p ethylene oxide (EO) repeat units; a triblock copolymer (TB) having a molar ratio R(TB) of LA repeat units to EO repeat units ((m+n) / p) is 1.5-9); - a compound of the formula CD, Block C is formed by methoxypoly(ethylene glycol) containing r EO repeat units; Block D is formed of poly(D,L-lactic acid) containing q LA repeat units; a diblock copolymer (DB) having a molar ratio R(DB) of LA repeat units to EO repeat units (q / r) of 1.5 to 15); - with a water-miscible, pharma- ceutically acceptable organic solvent, including DMSO; - an injectable formulation comprising etonogestrel, a prodrug or a salt thereof.

[0024] 2. Block B has a number average molecular weight (M n (B)) and / or block C has a number average molecular weight (M n (C)) . The formulation of embodiment 1,

[0025] 3. The triblock copolymer (TB) has a number average molecular weight (M) of 1,700 to 48,000 g / mol, preferably 1,800 to 45,000 g / mol, more preferably 4,500 to 40,000 g / mol, more preferably 6,000 to 30,000 g / mol, more preferably 7,000 to 20,000 g / mol, more preferably 9,000 to 18,000 g / mol, more preferably 14,000 to 16,000 g / mol, and most preferably 11,000 to 15,000 g / mol. n (TB)); and / or The diblock copolymer (DB) has a number average molecular weight (M) of 650 to 77,000 g / mol, preferably 1,000 to 50,000 g / mol, more preferably 2,000 to 30,000 g / mol, more preferably 3,000 to 15,000 g / mol, more preferably 4,000 to 11,000 g / mol, more preferably 6,000 to 12,000 g / mol, more preferably 5,000 to 8,000 g / mol, more preferably 6,000 to 8,000 g / mol, or most preferably 5,500 to 7,500 g / mol. n (DB))

[0026] 4. The triblock copolymer (TB) has a mass average molecular weight (M) of 1,700 to 96,000 g / mol, preferably 1,800 to 90,000 g / mol, more preferably 4,500 to 80,000 g / mol, more preferably 6,000 to 60,000 g / mol, more preferably 7,000 to 40,000 g / mol, more preferably 9,000 to 36,000 g / mol, more preferably 14,000 to 32,000 g / mol; most preferably 11,000 to 30,000 g / mol. w (TB)); and / or The diblock copolymer (DB) has a mass average molecular weight (M) of 650 to 154,000 g / mol, preferably 1,000 to 100,000 g / mol, more preferably 2,000 to 60,000 g / mol, more preferably 3,000 to 30,000 g / mol, more preferably 4,000 to 22,000 g / mol, more preferably 6,000 to 24,000 g / mol, more preferably 5,000 to 16,000 g / mol, more preferably 6,000 to 16,000 g / mol, or most preferably 5,500 to 15,000 g / mol. w (DB))。 Formulation according to any one of the preceding aspects, having the following structure:

[0027] 5.M n The formulation according to any one of aspects 1 to 4, wherein (B) is 500 to 3,500, preferably 650 to 3,000, more preferably 650 to 2,500, more preferably 800 to 2,200, more preferably 800 to 2,000, more preferably 950 to 1,050, more preferably 1,000 to 2,000, and most preferably 1,000 to 1,500 or 1,500 to 2,000 g / mol; and / or R(TB) is 1.5 to 8.0, preferably 2.5 to 8.0, more preferably 2.5 to 7.5, more preferably 3.5 to 7.5, more preferably 3.5 to 7.0, and most preferably 4.5 to 7.5.

[0028] 6.M n The formulation according to any one of aspects 1 to 5, wherein (C) is 175 to 3,000, preferably 200 to 3,000, more preferably 200 to 2,500, more preferably 250 to 2,500, more preferably 350 to 2,000, more preferably 330 to 370, and most preferably 350 to 1,200 or 1,200 to 2,000 g / mol; and / or R(DB) is 1.8 to 12.0, preferably 1.8 to 11.0, more preferably 2.5 to 11.0, more preferably 2.5 to 10.0, more preferably 3.0 to 10.0, more preferably 3.0 to 9.5, and most preferably 6.5 to 10.5.

[0029] 7.(a)M n(B) is 500 to 2,000, preferably 600 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 6, preferably 2.5 to 6, more preferably 2.5 to 5, and most preferably 3.5 to 4.5; M n (C) is from 700 to 3,000, preferably from 700 to 2,500, more preferably from 1,500 to 2,500, and most preferably from 1,800 to 2,200 g / mol; R(DB) is from 2 to 12, preferably from 2.5 to 5, more preferably from 2.5 to 3.5, and most preferably from 2.7 to 3.3; or (b)M n (B) is 500 to 2,000, preferably 600 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 8, preferably 4 to 8, more preferably 4.5 to 7.5, and most preferably 5.5 to 6.5; M n (C) is from 200 to 3,000, preferably from 200 to 1,500, more preferably from 250 to 1,500, and most preferably from 250 to 500 g / mol; R(DB) is from 2.5 to 12, preferably from 2.5 to 11, more preferably from 6.5 to 10.5, and most preferably from 7.5 to 9.5; or (cm n (B) is 1,200 to 3,200, preferably 1,200 to 2,500, more preferably 1,500 to 2,500, and most preferably 1,800 to 2,200 g / mol; R(TB) is 1.5 to 8, preferably 5 to 8, more preferably 4 to 8, and most preferably 3.2 to 3.8; M n 7. The formulation according to any one of aspects 1 to 6, wherein (C) is from 175 to 2,500, preferably from 250 to 2,500, more preferably from 250 to 2,400, and most preferably from 300 to 2,400 g / mol; and R(DB) is from 2 to 12, preferably from 2.5 to 10, more preferably from 2.5 to 10, and most preferably from 2.7 to 9.

[0030] 8.M nThe formulation according to any one of the preceding aspects, wherein (B) is 500-1,800, preferably 650-1,800, more preferably 650-1,500, and most preferably 800-1,200 g / mol.

[0031] 9.M n The formulation according to any one of the preceding aspects, wherein (C) is from 200 to 1,500, preferably from 200 to 500, and most preferably from 250 to 500 g / mol.

[0032] 10. A formulation according to any one of aspects 1 to 9, wherein the etonogestrel content is 2.5% w / w or more or 15% w / w or less, preferably 2.5 to 15% w / w, more preferably 4 to 15% w / w, more preferably 4 to 12% w / w, more preferably 5 to 12% w / w, more preferably 5 to 10% w / w, more preferably 6 to 10% w / w, and most preferably 7 to 10% w / w, relative to the total mass of the formulation.

[0033] 11. The formulation according to any one of aspects 1 to 10, wherein the triblock copolymer (TB) content is 8% w / w or more or 40% w / w or less, preferably 8 to 40% w / w, more preferably 9 to 40% w / w, more preferably 9 to 35% w / w, more preferably 10 to 35% w / w, more preferably 10 to 30% w / w, more preferably 15 to 30% w / w, more preferably 15 to 25% w / w, and most preferably 17 to 21% w / w, relative to the total mass of the formulation.

[0034] 12. The formulation according to any one of aspects 1 to 11, wherein the diblock copolymer (DB) content is 6% w / w or more or 50% w / w or less, preferably 6 to 50% w / w, preferably 10 to 50% w / w, more preferably 10 to 45% w / w, more preferably 15 to 40% w / w, more preferably 15 to 40% w / w, more preferably 17 to 40% w / w, more preferably 17 to 30% w / w, and most preferably 17 to 21% w / w, relative to the total mass of the formulation.

[0035] 13. A formulation according to any one of aspects 1 to 12, wherein the total content of polymers TB and DB in the formulation is 14% w / w or more or 55% w / w or less, more preferably 18 to 55% w / w, more preferably 18 to 50% w / w, more preferably 30 to 55% w / w, more preferably 30 to 50% w / w, more preferably 32 to 50% w / w, more preferably 32 to 45% w / w, and most preferably 34 to 42% w / w, relative to the total mass of the formulation.

[0036] 14. The formulation according to any one of aspects 1 to 13, wherein the mass ratio of the triblock copolymer to the diblock copolymer (TB:DB) is 10:90 w / w or more or 70:30 w / w or less, preferably 10:90 to 70:30 w / w, more preferably 10:90 to 65:35 w / w, more preferably 15:85 to 65:35 w / w, more preferably 15:85 to 60:40 w / w, more preferably 20:80 to 60:40 w / w, more preferably 20:80 to 55:45 w / w, more preferably 42:58 to 58:42 w / w, and most preferably 47:53 to 53:47 w / w.

[0037] 15. The formulation according to any one of aspects 1 to 14, wherein the content of the water-miscible, pharma- ceutically acceptable organic solvent is 40% w / w or more or 82.5% w / w or less, preferably 45 to 82.5% w / w, more preferably 45 to 78% w / w, more preferably 40 to 78% w / w, more preferably 40 to 65% w / w, more preferably 45 to 65% w / w, more preferably 40 to 59% w / w, more preferably 46 to 57% w / w, and most preferably 50 to 56% w / w, based on the total mass of the formulation.

[0038] 16. The formulation according to any one of the preceding aspects, wherein the water-miscible, pharma- ceutically acceptable organic solvent consists essentially of DMSO or is a mixture of DMSO and one or more co-solvents, preferably N-methylpyrrolidone (NMP); more preferably the water-miscible, pharma- ceutically acceptable organic solvent is DMSO.

[0039] 17. The formulation of any one of the preceding aspects, further comprising one or more additional pharma- ceutically acceptable excipients, such as polylactic acid (PLA), polyethylene glycol, or poly(lactic-co-glycolic acid) (PLGA).

[0040] 18.M n (B) is 500 to 1,800, preferably 650 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 6, preferably 2.5 to 6, more preferably 2.5 to 5, and most preferably 3.5 to 4.5; M n 18. The formulation according to any one of aspects 1 to 17, wherein (C) is from 700 to 3,000, preferably from 700 to 2,500, more preferably from 1,500 to 2,500, and most preferably from 1,800 to 2,200 g / mol; R(DB) is from 2 to 12, preferably from 2.5 to 5, more preferably from 2.5 to 3.3, and most preferably from 2.7 to 3.3; and the etonogestrel content is 7% w / w or more, preferably 7.5% w / w or more, more preferably 8% w / w or more, more preferably 9% w / w or more, and more preferably 10% w / w or more, based on the total mass of the formulation.

[0041] 19.M n (B) is 500 to 1,800, preferably 650 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 8, preferably 2.5 to 8, more preferably 3.5 to 7.5, and most preferably 4.5 to 7.5; M n 19. The formulation according to any one of aspects 1 to 18, wherein (C) is from 175 to 3,000, preferably from 200 to 1,500, more preferably from 200 to 500, and most preferably from 250 to 500 g / mol; R(DB) is from 2.0 to 12.0, preferably from 3.0 to 10.0, more preferably from 3.0 to 9.5, and most preferably from 6.5 to 10.5; and the etonogestrel content is 7% w / w or more, preferably 7.5% w / w or more, more preferably 8% w / w or more, more preferably 9% w / w or more, and more preferably 10% w / w or more, based on the total mass of the formulation.

[0042] 20.M n (B) is 500 to 1,800, preferably 650 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 8, preferably 2.5 to 8, more preferably 3.5 to 7.5, and most preferably 4.5 to 7.5; M n 20. The formulation according to any one of aspects 1 to 19, wherein (C) is 175 to 3,000, preferably 200 to 1,500, more preferably 200 to 500, and most preferably 250 to 500 g / mol; R(DB) is 2.0 to 12.0, preferably 3.0 to 10.0, more preferably 3.0 to 9.5, and most preferably 6.5 to 10.5; and the etonogestrel content is 7% w / w or more and 10% w / w or less, preferably 7% w / w or more and 9% w / w or less, and most preferably 7.5% w / w or more and 8% w / w or less, based on the total mass of the formulation.

[0043] 21. The formulation according to any one of the preceding aspects, wherein the etonogestrel content is at least 7% w / w, preferably at least 7.5% w / w, preferably at least 8% w / w, more preferably at least 8% w / w, more preferably at least 9% w / w, more preferably at least 10% w / w, relative to the total weight of the formulation; and the content of water-miscible, pharma- ceutically acceptable organic solvent is at most 56% w / w, preferably at most 55% w / w, more preferably at most 54% w / w, relative to the total weight of the formulation.

[0044] 22. The formulation according to any one of the preceding aspects, wherein the etonogestrel content is equal to or greater than 7% w / w, preferably equal to or greater than 7.5% w / w, relative to the total weight of the formulation; and the content of water-miscible, pharma- ceutically acceptable organic solvent is equal to or less than 56% w / w, preferably equal to or less than 54% w / w, relative to the total weight of the formulation.

[0045] 23. The formulation according to any one of aspects 1 to 22, wherein the triblock copolymer (TB) content is at least 15% w / w, preferably at least 16% w / w, more preferably at least 17% w / w, relative to the total mass of the formulation; the diblock copolymer (DB) content is at most 35% w / w, preferably at most 30% w / w, more preferably at most 25% w / w, relative to the total mass of the formulation; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is at least 30:70 w / w, preferably at least 40:60 w / w, more preferably at least 50:50 w / w.

[0046] 24. The formulation according to any one of the preceding aspects, wherein the total content of polymers TB and DB in the formulation is at least 30% w / w, preferably at least 32% w / w, more preferably at least 34% w / w, relative to the total mass of the formulation.

[0047] 25. The formulation according to aspect 23 or 24, wherein the triblock copolymer (TB) content is equal to or less than 40% w / w, preferably equal to or less than 35% w / w, more preferably equal to or less than 30% w / w, relative to the total weight of the formulation; and the diblock copolymer (DB) content is equal to or more than 17% w / w, preferably equal to or more than 18.5% w / w, more preferably equal to or more than 20% w / w and equal to or less than 50% w / w, relative to the total weight of the formulation.

[0048] 26. A formulation according to any one of aspects 23 to 25, wherein the total content of polymers TB and DB in the formulation is 45% w / w or less, preferably 43% w / w or less, more preferably 40% w / w or less, and 35% w / w or more, preferably 38% w / w or more, more preferably 40% w / w or more, relative to the total weight of the formulation; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 45:55 w / w or more, preferably 47:53 w / w or more, more preferably 50:50 w / w or more.

[0049] 27. A formulation according to any one of the preceding aspects, wherein the total content of polymers TB and DB in the formulation is equal to or less than 48% w / w, preferably equal to or less than 45% w / w, preferably equal to or less than 43% w / w, more preferably equal to or less than 40% w / w, relative to the total mass of the formulation; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is equal to or greater than 45:55 w / w, preferably equal to or greater than 47:53 w / w, more preferably equal to or greater than 50:50 w / w.

[0050] 28.M n (B) is 650 to 3,200 g / mol; R(TB) is 2.5 to 7.5; M n (C) is 200 to 3,000 g / mol; R(DB) is 1.5 to 11, preferably (a)M n (B) is 650 to 2000 g / mol; R(TB) is 2.5 to 5.5; M n (C) is 1,000 to 3,000 g / mol; R(DB) is 1.5 to 4.5; the triblock copolymer (TB) content is 10 to 25% w / w, preferably 15 to 20% w / w, more preferably 15 to 18 or 18 to 20% w / w, based on the total mass of the formulation; the diblock copolymer (DB) content is 10 to 25% w / w, preferably 15 to 20% w / w, more preferably 15 to 18 or 18 to 20% w / w, based on the total mass of the formulation; the total content of polymers TB and DB is 20 to 50% w / w, preferably 30 to 40% w / w, more preferably 36 to 40% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60 to 60:40 w / w; or (b)M n (B) is 650 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n(C) is 200-800 g / mol; R(DB) is 6.5-11; the triblock copolymer (TB) content is 15-25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 15-25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 30-50% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w; or (cm n (B) is 1,500 to 3,200 g / mol; R(TB) is 2.5 to 5.5; M n (C) is 1,000-3,000 g / mol; R(DB) is 1.5-4.5; the triblock copolymer (TB) content is 15-25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 15-25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 30-50% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w; or (d)M n (B) is 650 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n (C) is 200-800 g / mol; R(DB) is 6.5-11; the triblock copolymer (TB) content is 15-25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 10-25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 25-50% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w; or (e)M n (B) is 500 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n(C) is 200-800 g / mol; R(DB) is 6.5-11; the triblock copolymer (TB) content is 10-25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 10-25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 20-50% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w; or (f)M n (B) is 500 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n 28. The formulation of any one of aspects 1 to 27, wherein (C) is 200-800 g / mol; R(DB) is 6.5-11; the triblock copolymer (TB) content is 10-25% w / w, based on the total weight of the formulation; the diblock copolymer (DB) content is 15-25% w / w, based on the total weight of the formulation; the total content of polymers TB and DB is 25-50% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w.

[0051] 29.(a)M n (B) is 800 to 1,800 g / mol; R(TB) is 3 to 5; M n (C) is 1,500 to 2,500 g / mol; R(DB) is 2 to 4; the triblock copolymer (TB) content is 12 to 22% w / w, preferably 15 to 20% w / w, more preferably 15 to 18 or 18 to 20% w / w, based on the total mass of the formulation; the diblock copolymer (DB) content is 12 to 22% w / w, preferably 15 to 20% w / w, more preferably 15 to 18 or 18 to 20% w / w, based on the total mass of the formulation; the total content of polymers TB and DB is 24 to 44% w / w, preferably 30 to 40% w / w, more preferably 36 to 40% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58 to 58:42 w / w; or (b)M n (B) is 800 to 1,800 g / mol; R(TB) is 5 to 7; Mn (C) is 250-650 g / mol; R(DB) is 7.5-10.5; the triblock copolymer (TB) content is 18-22% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 18-22% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 36-44% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w; or (cm n (B) is 1,800 to 3,200 g / mol; R(TB) is 3 to 5; M n (C) is 1,500-2,500 g / mol; R(DB) is 2-4; the triblock copolymer (TB) content is 18-22% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 18-22% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 36-44% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w; or (d)M n (B) is 800 to 1,800 g / mol; R(TB) is 5 to 7; M n (C) is 250-650 g / mol; R(DB) is 7.5-10.5; the triblock copolymer (TB) content is 18-22% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 15-19% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 33-41% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w; or (e)M n (B) is 800 to 1,800 g / mol; R(TB) is 5 to 7; M n(C) is 250-650 g / mol; R(DB) is 7.5-10.5; the triblock copolymer (TB) content is 15-19% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 17-21% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 32-40% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w; or (f)M n (B) is 800 to 1,800 g / mol; R(TB) is 5 to 7; M n 29. The formulation of any one of aspects 1 to 28, wherein (C) is 250-650 g / mol; R(DB) is 7.5-10.5; the triblock copolymer (TB) content is 17-21% w / w, based on the total weight of the formulation; the diblock copolymer (DB) content is 19-23% w / w, based on the total weight of the formulation; the total content of polymers TB and DB is 36-44% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w.

[0052] 30. The formulation of any one of the preceding aspects, wherein the remainder to 100% w / w is said water-miscible, pharma- ceutically acceptable organic solvent, and optionally one or more additional pharma- ceutically acceptable excipients.

[0053] 31. The formulation according to any one of the preceding aspects, which is in the form of an injectable liquid and / or is capable of passing through a filter having a maximum pore size of 20 μm or less, preferably 20 μm or less and 0.2 μm or more, more preferably 0.2 μm.

[0054] 32. A pharmaceutical dosage form comprising a formulation according to any one of aspects 1 to 31.

[0055] 33. The dosage form according to aspect 32, wherein the total amount of etonogestrel per dosage unit is preferably 5 to 60 mg, more preferably 20 to 60 mg, and most preferably 20 to 50 mg of etonogestrel.

[0056] 34. The dosage form according to aspect 32 or 33, wherein the total amount of etonogestrel per dosage unit is 5 to 60 mg, preferably 10 to 60 mg, more preferably 15 to 60 mg, more preferably 20 to 60 mg, more preferably 35 to 60 mg, and most preferably 20 to 60 mg; and / or the volume of the formulation per dosage unit is 0.05 to 0.8 mL, preferably 0.1 to 0.8 mL, and more preferably 0.3 to 0.8 mL.

[0057] 35. The dosage form according to any one of aspects 32 to 34, wherein the volume of the formulation per dosage unit is preferably 0.05 to 0.8 mL, more preferably 0.2 to 0.8 mL, and most preferably 0.2 to 0.6 mL.

[0058] 36. The dosage form of any one of aspects 32 to 35, wherein the total amount of etonogestrel per dosage unit is ≧50 mg, preferably 50 to 60 mg, more preferably >50 mg and ≦60 mg; and / or the volume of the formulation per dosage unit is 0.5 to 1.5 mL, preferably 0.6 to 1.5 mL, more preferably 0.6 to 0.8 mL.

[0059] 37. The dosage form according to any one of aspects 32 to 36, preferably aspect 32, wherein the total amount of etonogestrel per dosage unit is 5 to 50 mg of etonogestrel, preferably 10 to 50 mg, more preferably 15 to 45 mg, more preferably 20 to 45 mg, more preferably 35 to 45 mg, and most preferably 20 to 40 mg; and / or the volume of the formulation per dosage unit is 0.05 to 1.5 mL, preferably 0.05 to 0.5 mL, more preferably 0.1 to 0.5 mL, more preferably 0.1 to 0.3 mL, more preferably 0.3 to 0.5 mL, or most preferably 0.1 to 0.2 mL.

[0060] 38. A formulation according to any one of aspects 1 to 31 and / or a dosage form according to any one of aspects 32 to 37, which is stable for at least 3 months, preferably 6 months, more preferably 12 months, even more preferably 18 months, and most preferably 24 months, when stored at 30°C or 40°C under 75% relative humidity.

[0061] 39. The formulation according to any one of aspects 1 to 31 and / or the dosage form according to any one of aspects 32 to 37, which is stable when stored at 30° C. for at least 3 months, preferably 6 months, more preferably 12 months, even more preferably 18 months, and most preferably 24 months.

[0062] 40. A formulation according to any one of aspects 1 to 31 and / or a dosage form according to any one of aspects 32 to 37 or 39, which is stable for at least 3 months, preferably 6 months, more preferably 12 months, when stored at 40° C. under a relative humidity of 75%.

[0063] 41. A method for preparing a formulation according to any one of aspects 1 to 31 and / or a dosage form according to any one of aspects 32 to 40, comprising: (i) a triblock copolymer (TB) having the formula AB-A', in which the blocks A and A' are formed of poly(D,L-lactic acid) and contain m and n lactic acid (LA) repeat units, respectively; the block B is formed of poly(ethylene glycol) containing p ethylene oxide (EO) repeat units; the molar ratio R(TB)(m+n) / p of the LA repeat units to the EO repeat units is between 1.5 and 9; a diblock copolymer (DB) having the formula CD, in which the block C is formed by a methoxypoly(ethylene glycol) containing r EO repeat units; the block D is formed by a poly(D,L-lactic acid) containing q LA repeat units; the molar ratio R(DB) of the LA repeat units to the EO repeat units (q / r) is between 1.5 and 12; and - a water-miscible pharma- tically acceptable organic solvent, including DMSO, obtaining a vehicle by mixing until the polymer is dissolved; (ii) mixing the vehicle with etonogestrel to obtain a formulation; (iii) optionally sterilizing the formulation; (iv) providing a predetermined amount of the formulation, and optionally packaging, to obtain a dosage form.

[0064] 42. - the sterilization step of step (iii) comprises filtering the vehicle obtained in step (i) and / or the formulation obtained in step (ii) through a filter having a maximum pore size of 20 μm or less, preferably 20 μm or less and 0.2 μm or more; more preferably 0.2 μm; and / or - the sterilization step (iii) comprises subjecting the vehicle obtained in step (i) and / or the formulation obtained in step (ii) to dry heat; and / or - the mixing steps (i) and / or (ii) are carried out using a roller mixer; and / or - the mixing steps (i) and / or (ii) are carried out using an impeller reactor; and / or The method according to embodiment 41, wherein the method further comprises the step of adding one or more additional pharma- ceutically acceptable excipients before, during or after steps (i) and / or (ii).

[0065] 43. An application device comprising a formulation or dosage form according to any one of aspects 1 to 40, wherein the application device is adapted for administering the formulation or dosage form to a subject by injection, preferably subcutaneous or intramuscular injection, most preferably subcutaneous injection.

[0066] 44. An application device according to aspect 43, which is a self-administered drug delivery device or syringe, preferably a ready-to-use syringe.

[0067] 45. An application device according to aspect 43 or 44, adapted to provide an injection volume of 0.05 to 1.5 mL, preferably 0.05 to 0.5 mL, more preferably 0.1 to 0.5 mL, more preferably 0.1 to 0.3 mL, more preferably 0.3 to 0.5 mL, most preferably 0.1 to 0.2 mL of the formulation or dosage form.

[0068] 46. ​​An application device according to aspect 43 or 44, adapted to provide an injection volume of between 0.05 and 0.8 mL, more preferably between 0.2 and 0.8 mL, most preferably between 0.2 and 0.6 mL.

[0069] 47. Use of a formulation or dosage form according to any one of aspects 1 to 40, or a device according to any one of aspects 43 to 46, for contraception in a female subject.

[0070] 48. The use according to aspect 47, comprising administration to a subject of a total amount of etonogestrel, preferably between 5 and 60 mg, more preferably between 20 and 60 mg, and most preferably between 20 and 50 mg per administration.

[0071] 49. The use of aspect 47 or 48, comprising administration to a subject of a total amount of 15 to 45 mg of etonogestrel per administration.

[0072] 50. The use according to aspect 47 or 48, comprising administration to a subject of a total amount of etonogestrel of ≧45 mg, preferably ≧50 mg, more preferably 45-60 mg, even more preferably 50-60 mg, and most preferably >50 mg and ≦60 mg per administration.

[0073] 51. The use according to any one of aspects 47 to 50, comprising administration to the subject by injection, preferably subcutaneous or intramuscular injection, most preferably subcutaneous injection.

[0074] 52. The use according to any one of aspects 47 to 51, wherein the time interval between administration of two subsequent doses is at least 90 days, preferably at least 120 days, more preferably at least 160 days.

[0075] 53. The use according to any one of aspects 47 to 52, wherein the time interval between administration of two subsequent doses is less than or equal to 220 days, more preferably between 160 and 220 days.

[0076] 54. The use according to any one of aspects 47 to 53, wherein the contraceptive effect is provided for a period of less than 3 years, preferably less than 2 years, more preferably less than 1 year after administration.

[0077] The present invention provides the above formulations.

[0078] In one embodiment, block B has a number average molecular weight (M n (B)) and / or block C has a number average molecular weight (M n (C)) The number average molecular weight can be determined by methods established in the art (described further below).

[0079] In one embodiment, the triblock copolymer (TB) has a number average molecular weight (M) of 1,700 to 48,000 g / mol, preferably 1,800 to 45,000 g / mol, more preferably 4,500 to 40,000 g / mol, more preferably 6,000 to 30,000 g / mol, more preferably 7,000 to 20,000 g / mol, more preferably 9,000 to 18,000 g / mol, more preferably 14,000 to 16,000 g / mol, and most preferably 11,000 to 15,000 g / mol. n (TB)).

[0080] In one embodiment, the diblock copolymer (DB) has a number average molecular weight (M) of 650 to 77,000 g / mol, preferably 1,000 to 50,000 g / mol, more preferably 2,000 to 30,000 g / mol, more preferably 3,000 to 15,000 g / mol, more preferably 4,000 to 11,000 g / mol, more preferably 6,000 to 12,000 g / mol, more preferably 5,000 to 8,000 g / mol, more preferably 6,000 to 8,000 g / mol, or most preferably 5,500 to 7,500 g / mol. n (DB)).

[0081] In one embodiment, the triblock copolymer (TB) has a mass average molecular weight (M) of 1,700 to 96,000 g / mol, preferably 1,800 to 90,000 g / mol, more preferably 4,500 to 80,000 g / mol, more preferably 6,000 to 60,000 g / mol, more preferably 7,000 to 40,000 g / mol, more preferably 9,000 to 36,000 g / mol, more preferably 14,000 to 32,000 g / mol; most preferably 11,000 to 30,000 g / mol. w (TB)).

[0082] In one embodiment, the diblock copolymer (DB) has a mass average molecular weight (M) of 650 to 154,000 g / mol, preferably 1,000 to 100,000 g / mol, more preferably 2,000 to 60,000 g / mol, more preferably 3,000 to 30,000 g / mol, more preferably 4,000 to 22,000 g / mol, more preferably 6,000 to 24,000 g / mol, more preferably 5,000 to 16,000 g / mol, more preferably 6,000 to 16,000 g / mol, or most preferably 5,500 to 15,000 g / mol. w (DB)).

[0083] In one embodiment, M n(B) is 500 to 3,500, preferably 650 to 3,000, more preferably 650 to 2,500, more preferably 800 to 2,200, more preferably 800 to 2,000, more preferably 950 to 1,050, more preferably 1,000 to 2,000, and most preferably 1,000 to 1,500 or 1,500 to 2,000 g / mol; and / or R(TB) is 1.5 to 8.0, preferably 2.5 to 8.0, more preferably 2.5 to 7.5, more preferably 3.5 to 7.5, more preferably 3.5 to 7.0, and most preferably 4.5 to 7.5.

[0084] In one embodiment, M n (C) is 175 to 3,000, preferably 200 to 3,000, more preferably 200 to 2,500, more preferably 250 to 2,500, more preferably 350 to 2,000, more preferably 330 to 370, and most preferably 350 to 1,200 or 1,200 to 2,000 g / mol; and / or R(DB) is 1.8 to 12.0, preferably 1.8 to 11.0, more preferably 2.5 to 11.0, more preferably 2.5 to 10.0, more preferably 3.0 to 10.0, more preferably 3.0 to 9.5, and most preferably 6.5 to 10.5.

[0085] In one embodiment, M n (B) is 500 to 2,000, preferably 600 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 6, preferably 2.5 to 6, more preferably 2.5 to 5, and most preferably 3.5 to 4.5; M n (C) is from 700 to 3,000, preferably from 700 to 2,500, more preferably from 1,500 to 2,500, and most preferably from 1,800 to 2,200 g / mol; R(DB) is from 2 to 12, preferably from 2.5 to 5, more preferably from 2.5 to 3.5, and most preferably from 2.7 to 3.3.

[0086] In one embodiment, M n(B) is 500 to 2,000, preferably 600 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 8, preferably 4 to 8, more preferably 4.5 to 7.5, and most preferably 5.5 to 6.5; M n (C) is from 200 to 3,000, preferably from 200 to 1,500, more preferably from 250 to 1,500, and most preferably from 250 to 500 g / mol; R(DB) is from 2.5 to 12, preferably from 2.5 to 11, more preferably from 6.5 to 10.5, and most preferably from 7.5 to 9.5.

[0087] In one embodiment, M n (B) is 1,200 to 3,200, preferably 1,200 to 2,500, more preferably 1,500 to 2,500, and most preferably 1,800 to 2,200 g / mol; R(TB) is 1.5 to 8, preferably 5 to 8, more preferably 4 to 8, and most preferably 3.2 to 3.8; M n (C) is 175-2,500, preferably 250-2,500, more preferably 250-2,400, and most preferably 300-2,400 g / mol; R(DB) is 2-12, preferably 2.5-10, more preferably 2.5-10, and most preferably 2.7-9.

[0088] In one embodiment, M n (B) is 500 to 1,800, preferably 650 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol.

[0089] In one embodiment, M n (C) is from 200 to 1,500, preferably from 200 to 500, and most preferably from 250 to 500 g / mol.

[0090] In one embodiment, the etonogestrel content is 2.5% w / w or more, or 15% w / w or less, preferably 2.5 to 15% w / w, more preferably 4 to 15% w / w, more preferably 4 to 12% w / w, more preferably 5 to 12% w / w, more preferably 5 to 10% w / w, more preferably 6 to 10% w / w, and most preferably 7 to 10% w / w, relative to the total mass of the formulation.

[0091] In one embodiment, the triblock copolymer (TB) content is 8% w / w or more, or 40% w / w or less, preferably 8 to 40% w / w, more preferably 9 to 40% w / w, more preferably 9 to 35% w / w, more preferably 10 to 35% w / w, more preferably 10 to 30% w / w, more preferably 15 to 30% w / w, more preferably 15 to 25% w / w, and most preferably 17 to 21% w / w, based on the total mass of the formulation.

[0092] In one embodiment, the diblock copolymer (DB) content is 6% w / w or more, or 50% w / w or less, preferably 6 to 50% w / w, preferably 10 to 50% w / w, more preferably 10 to 45% w / w, more preferably 15 to 40% w / w, more preferably 15 to 40% w / w, more preferably 17 to 40% w / w, more preferably 17 to 30% w / w, and most preferably 17 to 21% w / w, relative to the total mass of the formulation.

[0093] In one embodiment, the total content of polymers TB and DB in the formulation is 14% w / w or more or 55% w / w or less, preferably 14 to 55% w / w, more preferably 18 to 55% w / w, more preferably 18 to 50% w / w, more preferably 30 to 55% w / w, more preferably 30 to 50% w / w, more preferably 32 to 50% w / w, more preferably 32 to 45% w / w, and most preferably 34 to 42% w / w, relative to the total mass of the formulation. Alternatively, the total content of all polymers (i.e., including TB and DB) in the formulation is 14% w / w or more or 55% w / w or less, preferably 14 to 55% w / w, more preferably 18 to 55% w / w, more preferably 18 to 50% w / w, more preferably 30 to 55% w / w, more preferably 30 to 50% w / w, more preferably 32 to 50% w / w, more preferably 32 to 45% w / w, and most preferably 34 to 42% w / w, relative to the total mass of the formulation.

[0094] In one embodiment, the mass ratio of the triblock copolymer to the diblock copolymer (TB:DB) is 10:90 w / w or more, or 70:30 w / w or less, preferably 10:90 to 70:30 w / w, more preferably 10:90 to 65:35 w / w, more preferably 15:85 to 65:35 w / w, more preferably 15:85 to 60:40 w / w, more preferably 20:80 to 60:40 w / w, more preferably 20:80 to 55:45 w / w, more preferably 42:58 to 58:42 w / w, and most preferably 47:53 to 53:47 w / w.

[0095] In one embodiment, the content of the water-miscible, pharma- ceutically acceptable organic solvent is 40% w / w or more, or 82.5% w / w or less, preferably 45 to 82.5% w / w, more preferably 45 to 78% w / w, more preferably 40 to 78% w / w, more preferably 40 to 65% w / w, more preferably 45 to 65% w / w, more preferably 40 to 59% w / w, more preferably 46 to 57% w / w, and most preferably 50 to 56% w / w, relative to the total mass of the formulation.

[0096] In one embodiment, the water-miscible, pharma- ceutically acceptable organic solvent consists essentially of DMSO or is a mixture of DMSO and one or more co-solvents, preferably N-methylpyrrolidone (NMP); more preferably the water-miscible, pharma-ceutically acceptable organic solvent is DMSO.

[0097] In one embodiment, the formulation further comprises one or more additional pharma- ceutically acceptable excipients, such as polylactic acid (PLA), polyethylene glycol, or poly(lactic-co-glycolic acid) (PLGA).

[0098] In one embodiment, M n (B) is 500 to 1,800, preferably 650 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 6, preferably 2.5 to 6, more preferably 2.5 to 5, and most preferably 3.5 to 4.5; M n (C) is from 700 to 3,000, preferably from 700 to 2,500, more preferably from 1,500 to 2,500, and most preferably from 1,800 to 2,200 g / mol; and R(DB) is from 2 to 12, preferably from 2.5 to 5, more preferably from 2.5 to 3.3, and most preferably from 2.7 to 3.3.

[0099] In one embodiment, M n (B) is 500 to 1,800, preferably 650 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 8, preferably 2.5 to 8, more preferably 3.5 to 7.5, and most preferably 4.5 to 7.5; M n (C) is from 175 to 3,000, preferably from 200 to 1,500, more preferably from 200 to 500, and most preferably from 250 to 500 g / mol; R(DB) is from 2.0 to 12.0, preferably from 3.0 to 10.0, more preferably from 3.0 to 9.5, and most preferably from 6.5 to 10.5.

[0100] In one embodiment, M n(B) is 500 to 1,800, preferably 650 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 8, preferably 2.5 to 8, more preferably 3.5 to 7.5, and most preferably 4.5 to 7.5; M n (C) is 175 to 3,000, preferably 200 to 1,500, more preferably 200 to 500, and most preferably 250 to 500 g / mol; R(DB) is 2.0 to 12.0, preferably 3.0 to 10.0, more preferably 3.0 to 9.5, and most preferably 6.5 to 10.5; and the etonogestrel content is 7% w / w or more, preferably 7.5% w / w or more, more preferably 8% w / w or more, more preferably 9% w / w or more, and more preferably 10% w / w or more, based on the total mass of the formulation.

[0101] In one embodiment, M n (B) is 500 to 1,800, preferably 650 to 1,800, more preferably 650 to 1,500, and most preferably 800 to 1,200 g / mol; R(TB) is 1.5 to 8, preferably 2.5 to 8, more preferably 3.5 to 7.5, and most preferably 4.5 to 7.5; M n (C) is 175 to 3,000, preferably 200 to 1,500, more preferably 200 to 500, and most preferably 250 to 500 g / mol; R(DB) is 2.0 to 12.0, preferably 3.0 to 10.0, more preferably 3.0 to 9.5, and most preferably 6.5 to 10.5; and the etonogestrel content is 7% w / w or more and 10% w / w or less, preferably 7% w / w or more and 9% w / w or less, and most preferably 7.5% w / w or more and 8% w / w or less, based on the total mass of the formulation.

[0102] In one embodiment, the etonogestrel content is at least 7% w / w, preferably at least 7.5% w / w, more preferably at least 8% w / w, more preferably at least 9% w / w, more preferably at least 10% w / w, relative to the total mass of the formulation.

[0103] In one embodiment, the etonogestrel content is 7% w / w or more, preferably 7.5% w / w or more, preferably 8% w / w or more, more preferably 8% w / w or more, more preferably 9% w / w or more, more preferably 10% w / w or more, based on the total mass of the formulation; and the content of water-miscible, pharma- ceutically acceptable organic solvent is 56% w / w or less, preferably 55% w / w or less, more preferably 54% w / w or less, based on the total mass of the formulation.

[0104] In one embodiment, the etonogestrel content is 7% w / w or more, preferably 7.5% w / w or more, based on the total mass of the formulation; the content of water-miscible, pharma- ceutically acceptable organic solvent is 56% w / w or less, preferably 54% w / w or less, based on the total mass of the formulation.

[0105] In one embodiment, the triblock copolymer (TB) content is 15% w / w or more, preferably 16% w / w or more, more preferably 17% w / w or more, based on the total mass of the formulation; the diblock copolymer (DB) content is 35% w / w or less, preferably 30% w / w or less, more preferably 25% w / w or less, based on the total mass of the formulation; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 30:70 w / w or more, preferably 40:60 w / w or more, more preferably 50:50 w / w or more.

[0106] In one embodiment, the total content of polymers TB and DB in the formulation is at least 30% w / w, preferably at least 32% w / w, more preferably at least 34% w / w, based on the total mass of the formulation.

[0107] In one embodiment, the triblock copolymer (TB) content is 40% w / w or less, preferably 35% w / w or less, more preferably 30% w / w or less, based on the total mass of the formulation; and the diblock copolymer (DB) content is 17% w / w or more, preferably 18.5% w / w or more, more preferably 20% w / w or more and 50% w / w or less, based on the total mass of the formulation.

[0108] In one embodiment, the total content of polymers TB and DB in the formulation is 48% w / w or less, preferably 45% w / w or less, preferably 42% w / w or less, more preferably 40% w / w or less, relative to the total mass of the formulation; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 45:55 w / w or more, preferably 47:53 w / w or more, more preferably 50:50 w / w or more.

[0109] In one embodiment, the total content of polymers TB and DB in the formulation is 48% w / w or less, preferably 45% w / w or less, more preferably 40% w / w or less, relative to the total mass of the formulation; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 45:55 w / w or more, preferably 47:53 w / w or more, more preferably 50:50 w / w or more.

[0110] In one embodiment, M n (B) is 650 to 3,200 g / mol; R(TB) is 2.5 to 7.5; M n (C) is 200-3,000 g / mol; R(DB) is 1.5-11.

[0111] In one embodiment, M n (B) is 650 to 2,000 g / mol; R(TB) is 2.5 to 5.5; M n (C) is 1,000 to 3,000 g / mol; R(DB) is 1.5 to 4.5; the triblock copolymer (TB) content is 10 to 25% w / w, preferably 15 to 20% w / w, more preferably 15 to 18 or 18 to 20% w / w, based on the total mass of the formulation; the diblock copolymer (DB) content is 10 to 25% w / w, preferably 15 to 20% w / w, more preferably 15 to 18 or 18 to 20% w / w, based on the total mass of the formulation; the total content of polymers TB and DB is 20 to 50% w / w, preferably 30 to 40% w / w, more preferably 36 to 40% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60 to 60:40 w / w.

[0112] In one embodiment, M n (B) is 650 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n (C) is 200-800 g / mol; R(DB) is 6.5-11; the triblock copolymer (TB) content is 15-25% w / w based on the total mass of the formulation; the diblock copolymer (DB) content is 15-25% w / w based on the total mass of the formulation; the total content of polymers TB and DB is 30-50% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w.

[0113] In one embodiment, M n (B) is 1,500 to 3,200 g / mol; R(TB) is 2.5 to 5.5; M n (C) is 1,000-3,000 g / mol; R(DB) is 1.5-4.5; the triblock copolymer (TB) content is 15-25% w / w based on the total mass of the formulation; the diblock copolymer (DB) content is 15-25% w / w based on the total mass of the formulation; the total content of polymers TB and DB is 30-50% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w.

[0114] In one embodiment, M n (B) is 650 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n (C) is 200-800 g / mol; R(DB) is 6.5-11; the triblock copolymer (TB) content is 15-25% w / w based on the total mass of the formulation; the diblock copolymer (DB) content is 10-25% w / w based on the total mass of the formulation; the total content of polymers TB and DB is 25-50% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w.

[0115] In one embodiment, M n(B) is 500 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n (C) is 200-800 g / mol; R(DB) is 6.5-11; the triblock copolymer (TB) content is 10-25% w / w based on the total mass of the formulation; the diblock copolymer (DB) content is 10-25% w / w based on the total mass of the formulation; the total content of polymers TB and DB is 20-50% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w.

[0116] In one embodiment, M n (B) is 500 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n (C) is 200-800 g / mol; R(DB) is 6.5-11; the triblock copolymer (TB) content is 10-25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 15-25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 25-50% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w.

[0117] In one embodiment, M n (B) is 800 to 1,800 g / mol; R(TB) is 3 to 5; M n (C) is 1,500 to 2,500 g / mol; R(DB) is 2 to 4; the triblock copolymer (TB) content is 12 to 22% w / w, preferably 15 to 20% w / w, more preferably 15 to 18 or 18 to 20% w / w, based on the total mass of the formulation; the diblock copolymer (DB) content is 12 to 22% w / w, preferably 15 to 20% w / w, more preferably 15 to 18 or 18 to 20% w / w, based on the total mass of the formulation; the total content of polymers TB and DB is 24 to 44% w / w, preferably 30 to 40% w / w, more preferably 36 to 40% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58 to 58:42 w / w.

[0118] In one embodiment, M n (B) is 800-1,800 g / mol; R(TB) is 5-7; M n (C) is 250-650 g / mol; R(DB) is 7.5-10.5; the triblock copolymer (TB) content is 18-22% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 18-22% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 36-44% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w.

[0119] In one embodiment, M n (B) is 1,800 to 3,200 g / mol; R(TB) is 3 to 5; M n (C) is 1,500-2,500 g / mol; R(DB) is 2-4; the triblock copolymer (TB) content is 18-22% w / w based on the total mass of the formulation; the diblock copolymer (DB) content is 18-22% w / w based on the total mass of the formulation; the total content of polymers TB and DB is 36-44% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w.

[0120] In one embodiment, M n (B) is 800-1,800 g / mol; R(TB) is 5-7; M n (C) is 250-650 g / mol; R(DB) is 7.5-10.5; the triblock copolymer (TB) content is 18-22% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 15-19% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 33-41% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w.

[0121] In one embodiment, M n(B) is 800-1,800 g / mol; R(TB) is 5-7; M n (C) is 250-650 g / mol; R(DB) is 7.5-10.5; the triblock copolymer (TB) content is 15-19% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 17-21% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 32-40% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w.

[0122] In one embodiment, M n (B) is 800-1,800 g / mol; R(TB) is 5-7; M n (C) is 250-650 g / mol; R(DB) is 7.5-10.5; the triblock copolymer (TB) content is 17-21% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 19-23% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 36-44% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 42:58-58:42 w / w.

[0123] In one embodiment, the formulation is configured as described in any of the preceding aspects or embodiments, with the remainder to 100% w / w being said water-miscible, pharma- ceutically acceptable organic solvent, and optionally one or more additional pharma- ceutically acceptable excipients.

[0124] In one embodiment, the formulation is in the form of an injectable liquid.The formulation can pass through a filter, for example, with a maximum pore size of 20 μm or less, preferably 20 μm or less and 0.2 μm or more, more preferably 0.2 μm.Filtration can remove particles such as impurities or microorganisms.0.2 μm is generally considered to be a suitable pore size for obtaining a sterile filtrate.

[0125] The present invention also provides a pharmaceutical dosage form comprising the above-mentioned formulation.As used herein, "dosage form" or "dosage unit" generally refers to an article that comprises or consists of a predetermined amount of formulation, so that a predetermined amount of etonogestrel (dose) is contained therein.The dosage form can be, for example, an injection liquid that comprises or consists of a predetermined amount of formulation; or a package (e.g., a container such as an injection vial) that contains a predetermined amount of formulation.

[0126] In one embodiment, the total amount of etonogestrel per dosage unit is preferably 5 to 60 mg, more preferably 20 to 60 mg, and most preferably 20 to 50 mg.

[0127] In one embodiment, the total amount of etonogestrel per dosage unit is 5 to 60 mg, preferably 10 to 60 mg, more preferably 15 to 60 mg, more preferably 20 to 60 mg, more preferably 35 to 60 mg, and most preferably 20 to 60 mg; and / or the volume of the formulation per dosage unit is 0.05 to 0.8 mL, preferably 0.1 to 0.8 mL, and more preferably 0.3 to 0.8 mL.

[0128] In one embodiment, the total amount of etonogestrel per dosage unit is 5 to 50 mg, preferably 10 to 50 mg, more preferably 15 to 45 mg, more preferably 20 to 45 mg, more preferably 35 to 45 mg, and most preferably 20 to 40 mg. Alternatively, the total amount of etonogestrel per dosage unit is ≧50 mg, preferably 50 to 60 mg, and more preferably >50 mg and ≦60 mg.

[0129] In one embodiment, the volume of the formulation per dosage unit is 0.05 to 1.5 mL, preferably 0.05 to 0.5 mL, more preferably 0.1 to 0.5 mL, more preferably 0.1 to 0.3 mL, more preferably 0.3 to 0.5 mL, or most preferably 0.1 to 0.2 mL. For example, in the case of a formulation suitable for loading 7.5% etonogestrel, preferably 530 mg of the formulation should be injected to reach a target dose of 40 mg, which corresponds to approximately 450 to 500 μL (e.g., 460 μL). Alternatively, the volume of the formulation per dosage unit is 0.5 to 1.5 mL, preferably 0.6 to 1.5 mL, more preferably 0.6 to 0.8 mL. For example, in the case of a formulation suitable for loading 7.5% etonogestrel, preferably 795 mg of the formulation should be injected to reach a target dose of 60 mg, which corresponds to approximately 720 μL.

[0130] In one embodiment, the formulation or dosage form is stable for at least 3 months, preferably 6 months, more preferably 12 months, even more preferably 18 months, and most preferably 24 months when stored at 30°C or 40°C at 75% relative humidity. Stability can be determined by various methods common in the art. For example, the formulation or dosage form can be stable for at least 3 months, preferably 6 months, more preferably 12 months, even more preferably 18 months, and most preferably 24 months when stored at 30°C. For example, the formulation or dosage form can be stable for at least 3 months, preferably 6 months, and more preferably 12 months when stored at 40°C at 75% relative humidity. Preferably, the formulation or dosage form may be considered stable over a period of time if it meets or substantially meets one or more of the following criteria: etonogestrel assay (%): 100+ / -5%; total related impurities (% area): ≦2%; dynamic viscosity (mPa·s): t0 viscosity + / - 25%; injectability force (N): <25N.

[0131] The present invention also provides a method for preparing the above-mentioned formulations and / or dosage forms, where the method is carried out up to and including step (ii) to obtain a formulation, up to and including step (iii) to obtain a sterile formulation, and up to and including step (iv) to obtain a dosage form.

[0132] In one embodiment, the sterilization method in step (iii) is filtration through a filter having a maximum pore size of 20 μm or less, preferably 20 μm or less and 0.2 μm or more; more preferably 0.2 μm.

[0133] In one embodiment, the sterilizing step (iii) comprises subjecting the vehicle obtained in step (i) and / or the formulation obtained in step (ii) to dry heat.

[0134] In one embodiment, the mixing steps of (i) and / or (ii) are carried out using a roller mixer.

[0135] In one embodiment, the mixing steps of steps (i) and / or (ii) are carried out using an impeller reactor.

[0136] In one embodiment, the method further comprises the step of adding one or more additional pharma- ceutically acceptable excipients as described above before, during or after steps (i) and / or (ii).

[0137] The present invention also provides an application device comprising the above-mentioned formulation or dosage form, wherein the application device is adapted to administer the formulation or dosage form to a subject by injection, preferably subcutaneous or intramuscular injection, most preferably subcutaneous injection.

[0138] In one embodiment, the application device is a self-administered drug delivery device or syringe, preferably a ready-to-use syringe.

[0139] In one embodiment, the application device is adapted to provide an injection volume of 0.05-1.5 mL, preferably 0.05-0.5 mL, more preferably 0.1-0.5 mL, more preferably 0.1-0.3 mL, more preferably 0.3-0.5 mL, most preferably 0.1-0.2 mL of the formulation or dosage form. The application device may also be adapted to provide an injection volume of preferably 0.05-0.8 mL or 0.8-1.5 mL, more preferably 0.2-0.8 mL, most preferably 0.2-0.6 mL. In this context, "adapted to" means that, upon actuation, the application device is capable of providing the predefined injection volume mentioned above. If the device has no or essentially no dead volume, the device is considered to be adapted to provide as an injection volume the entire or essentially the entire volume of the formulation or dosage form stored therein. Otherwise, the device is considered to be adapted to provide an injection volume equal to the entire volume of the formulation or dosage form stored therein minus the dead volume of the device.

[0140] The present invention also provides the use of a formulation, dosage form, or device described herein for contraception in a female subject. As used herein, "subject" refers generally to a mammal, preferably a human.

[0141] In one embodiment, the use includes administration to a subject of a total amount of etonogestrel of preferably 5 to 60 mg, more preferably 20 to 60 mg, and most preferably 20 to 50 mg. In one embodiment, the use includes administration to a subject of a total amount of etonogestrel of 15 to 45 mg per administration. That is, the total amount of etonogestrel contained in the formulation / dosage form administered to a subject per single administration is 15 to 45 mg.

[0142] In one embodiment, the use comprises administering to a subject by injection, preferably subcutaneous or intramuscular injection, most preferably subcutaneous injection. In one embodiment, the time interval between administration of two subsequent doses is 90 days or more, preferably 120 days or more, more preferably 160 days or more and / or 220 days or less, more preferably 160-220 days.

[0143] In one embodiment, contraceptive benefit is provided for a period of less than 3 years, preferably less than 2 years, and more preferably less than 1 year after administration.

[0144] Also disclosed is a method of contraception in a female subject, comprising administering to a subject in need thereof an effective amount of a formulation or dosage form, preferably using a device as described herein. In one embodiment, the method comprises administering to the subject a total amount of etonogestrel of preferably 5-60 mg, more preferably 20-60 mg, most preferably 20-50 mg per dose. In one embodiment, the method comprises administering to the subject a total amount of etonogestrel of 15-45 mg per dose; in an alternative embodiment, the method comprises administering to the subject a total amount of etonogestrel of ≧45 mg, preferably ≧50 mg, more preferably 45-60 mg, even more preferably 50-60 mg, most preferably >50 mg and ≦60 mg per dose. In one embodiment, the method comprises administering to the subject by injection, preferably subcutaneous or intramuscular injection. In one embodiment, the time interval between administration of two subsequent doses is 120 days or more, preferably 160 days or more. In one embodiment, the contraceptive effect is provided for a period of less than 3 years, preferably less than 2 years, more preferably less than 1 year after administration.

[0145] As used herein, the term "prodrug" refers to a pharma- ceutically acceptable compound that can be converted to etonogestrel under physiological conditions (i.e., upon administration to a mammalian subject) or by solvolysis. Prodrugs are bioreversible derivatives of drug molecules that undergo enzymatic and / or chemical transformations in vivo to release the active parent drug, which can then exert a desired pharmacological effect (see, e.g., Rautio, J. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255-270 (2008)). The term "prodrug" is also meant to include any covalently bonded carrier that releases etonogestrel in vivo when administered to a mammalian subject. Preferably, the prodrug is converted to etonogestrel in vivo, for example, by hydrolysis or oxidation reactions. Prodrugs can include compounds in which the hydroxy group of etonogestrel is bonded to any group that cleaves to form the free hydroxy group when the prodrug is administered to a mammalian subject, such as ester derivatives (e.g., alkyl esters, fatty esters, phenoxyacetate esters, or sulfate esters) or acetal derivatives (e.g., glucuronides) of the hydroxy functional group; and compounds (e.g., desogestrel) that are converted to etonogestrel by oxidation when administered to a mammalian subject.

[0146] Etonogestrel content / amount, as used herein, always refers to the amount of the parent drug molecule (C 22 H 28 O2; M=324.5 g / mol). If prodrugs or salts are present or used, their actual content / amount is recalculated according to the ratio of their respective molar mass to the molar mass of pure etonogestrel.

[0147] In general, M n (B) can be calculated as follows: M n (B)=M n (TB) / (1+R(TB) *72 / 44), where 72 and 44 correspond to the unit molar masses of the LA and EO units, respectively; R(TB) is the molar ratio of LA repeat units to EO repeat units in the triblock copolymer, as determined, for example, by NMR (described below); M n (TB) is the number average molecular weight of the triblock copolymer, determined, for example, by GPC (described below). n (B), as used herein, is preferably defined in this manner.

[0148] Or, M. n (TB) can be calculated as follows: M n (TB)=M n (B) * (1+R(TB) * 72 / 44) (in the formula, M n (B) is the number average molecular weight of the PEG monoblock polymer (i.e., poly(ethylene glycol)) used as a starting material in the synthesis of the triblock copolymer (TB), determined, for example, by GPCC (described below); R(TB) is the molar ratio of LA repeat units to EO repeat units in the triblock copolymer, determined, for example, by NMR (described below).

[0149] In general, M n (C) can be calculated as follows: M n (C)=M n (DB) / (1+R(DB) * 72 / 44), where 72 and 44 correspond to the unit molar masses of the LA and EO units, respectively; R(DB) is the molar ratio of LA repeat units to EO repeat units in the diblock copolymer, as determined, for example, by NMR (described below); M n (DB) is the number average molecular weight of the diblock copolymer, as determined, for example, by GPC C (described below); M n (C), as used herein, is preferably defined in this manner.

[0150] Or, M.n (DB) can be calculated as follows: M n (DB)=M n (C) * (1+R(DB) * 72 / 44) (in the formula, M n (C) is the number average molecular weight of the mPEG monoblock polymer (i.e., methoxypoly(ethylene glycol)) used as a starting material in the synthesis of the diblock copolymer (DB), as determined, for example, by GPC (described below); R(DB) is the molar ratio of LA repeat units to EO repeat units in the diblock copolymer, as determined, for example, by NMR (described below).

[0151] As used herein, number average molecular weight (M n ) can be determined by methods known in the art, for example, by GPC in THF at 25 or 35° C. As used herein, weight average molecular weight (M w ) can be determined by methods known in the art, for example, by GPC in THF at 25 or 35° C.

[0152] Preferably, the GPC analysis can be carried out using a Waters Alliance HPLC e2695 instrument equipped with a refractive index detector. The instrument can be equipped with a series of Waters styragel columns HR4, HR3, and HR2 maintained at 35° C. Samples are run at a constant flow rate of 1 mL / min in THF stabilized with BHT. Molecular weight distribution is determined by conventional calibration using polystyrene calibration standards obtained from Waters.

[0153] As used herein, the R ratio, which represents the ratio of lactic acid units to ethylene oxide units (LA / EO), is the chemical shift referenced to the solvent value of CDCl3, δ=7.26 ppm. 1It can be determined by H NMR spectroscopy (e.g., on a 300 MHz spectrometer). For this, all peaks are integrated separately. The intensity of the signal (integral) is directly proportional to the number of hydrogens that compose the signal. To determine the R ratio (LA / EO ratio), the integrals must be homogenous and represent the same number of protons (e.g., all signal values ​​are 1 H). Then, one characteristic peak for PLA and one characteristic peak for PEG are used to determine the LA / EO ratio. EXAMPLES

[0154] Example 1 Synthesis of copolymers and preparation of formulations Linear block copolymer synthesis The copolymers were synthesized according to the method described in US 6,350,812 with some modifications. Typically, the required amount of PEG (to give triblock copolymers) or methoxy-PEG (to give diblock copolymers) was heated to 65°C and dried in a reactor under vacuum for 2 hours. DL-lactide (corresponding to the targeted LA / EO molar ratio) and zinc lactate (1 / 1000 the amount of lactide) were added. The reaction mixture was first dehydrated by three short vacuum / N2 cycles. The reaction mixture was heated at 140°C and rapidly degassed under vacuum. The reaction was carried out at 140°C under a constant nitrogen flow (0.2 bar) for 4 days. The reaction was cooled to room temperature and its contents were dissolved in acetone, followed by precipitation with ethanol. The resulting product was subsequently dried under reduced pressure.

[0155] The resulting product has its M n and by GPC for the determination of its dispersity (D), and by HPLC for the determination of its residual lactide content and R ratio. 1 Characterized by 1 H NMR.

[0156] 1 H NMR spectroscopy was performed using a Brucker Advance 300 MHz spectrometer. All 1For H NMR spectrograms, TopSpin software was used for peak integration and analysis, and chemical shifts were referenced to the solvent value of CDCl3, δ=7.26 ppm.

[0157] For the determination of the R ratio, which represents the ratio of lactic acid units to ethylene oxide units (LA / EO), all peaks were integrated separately. The intensity of the signal (integral value) is directly proportional to the number of hydrogens that compose the signal. To determine the R ratio (LA / EO ratio), the integrals must be homogenous and represent the same number of protons (e.g., all signal values ​​are 1 H). Then, one characteristic peak of PLA and one characteristic peak of PEG are used to determine the LA / EO ratio. This method is particularly suitable for molecular weights of PEG above 1000 g / mol, where the signals obtained at the end-functions of the polymer are negligible.

[0158] GPC analysis was performed using a Waters Alliance HPLC e2695 instrument equipped with a refractive index detector. The instrument was equipped with a series of Waters styragel columns HR4, HR3, and HR2 maintained at 35° C. Samples were run at a constant flow rate of 1 mL / min in THF stabilized with BHT. Molecular weight distributions were determined by conventional calibration using polystyrene calibration standards obtained from Waters.

[0159] Formulation preparation Typically, the sustained release formulations were prepared as follows: The amount of copolymer required was weighed into an empty, tared glass vial. The glass vial was re-tared. The exact mass of DMSO was added. The vehicle (copolymer + solvent) was then placed on a roller mixer overnight at room temperature (RT) until the copolymer was completely dissolved. The amount of etonogestrel required was weighed into another glass vial and the vehicle was carefully transferred onto it. The vials were then placed on a roller mixer at RT for at least 24 hours. The headspace of each vial was flushed with a constant nitrogen flush for 30 seconds.

[0160] The formulations shown in Table 1 were prepared according to the general procedure above. The indicated dose indicates that the amount of each formulation containing the dose shown in the table was used as the dosage form in subsequent in vitro release or pharmacokinetic studies.

[0161] [Table 1]

[0162] Example 2 In vitro release (IVR) testing Typically, formulation masses corresponding to a dose of 10-50 mg etonogestrel were injected into 150 mL Erlenmeyer flasks containing 50 mL of phosphate buffer pH 7.4 (PBS) + 0.5% (w / V) hydroxypropyl-β-cyclodextrin (HPBCD). The Erlenmeyer flasks were then placed on an orbital shaker at 65 rpm in a 37°C climate chamber. At predefined time intervals, approximately 2 mL of medium was collected, filtered through a 0.2 μm hydrophilic filter and transferred to a 1.5 mL HPLC glass vial before analysis by UPLC; the remaining medium was discarded and fresh buffer was added to the Erlenmeyer flask, which was then placed back on the orbital shaker at 37°C. Sink conditions were maintained for the entire duration of the study.

[0163] The amount of API released from the depot was determined using a Waters Acquity UPLC system equipped with a UV detector set at 244 nm and a C18 analytical column (BEH C18, Waters). The column temperature was maintained at 48°C and the flow rate was fixed at 0.3 mL / min. Water / formic acid (100:0.1 V / V; solvent A) and acetonitrile / formic acid (100:0.1 V / V; solvent B) were used as mobile phases with an initial composition of 50 / 50. The proportion of solvent B was increased to 95% for 1-1.5 min, followed by a 0.5 min wash step and a 2.5 min re-equilibration period to 50 / 50.

[0164] The results are shown in Figures 1 to 3.

[0165] As shown in Figures 1A and 1B, a wide range of release profiles can be obtained in vitro by varying the formulation components and their contents while keeping the etonogestrel dose constant. In particular, after an initial burst, a plateau can be reached over several weeks, at which point the amount of API released per day can remain constant.

[0166] 2A and 2B show that by maintaining the etonogestrel dose and fixing the components of the formulation, adjustment of etonogestrel release can still be obtained when the component contents are changed.

[0167] The effect of etonogestrel dose is shown in Figures 3A and 3B. It can be observed that with a fixed composition, different release profiles of etonogestrel can still be obtained by varying the formulation volume, i.e., API dose.

[0168] Example 3 Pharmacokinetic (PK) studies in dogs Detailed in vivo setup procedures Three etonogestrel formulations (#3, #7, and #9) were tested in a pharmacokinetic study in female beagle dogs aged 10-12 months and weighing approximately 7-12 kg. Drug products containing 10 mg (#3 and #7) or 15 mg (#9) of etonogestrel were administered subcutaneously in the interscapular region of the dogs using a syringe and a 21G 5 / 8 inch needle. The injection formulation volume was fixed at 90 μL, 170 μL, or 180 μL depending on the initial etonogestrel content in the formulation. The number of dogs per group was fixed at 5.

[0169] Animal observations were recorded at least once daily after dosing and throughout the study, and injection sites were observed at each PK time point. Blood samples were collected in K2-EDTA anticoagulant tubes before dosing and at different time points after dosing, namely T0.5h, T1h, T2h, T3h, T6h, T10h, D1 (day 1), D2, D4, D7, D14, D21, D28 (1 month), D42, D56 (2 months), D70, D84 (3 months), D98, D112 (4 months), D126, D140 (5 months), D154, D168 (6 months), D182, D196 (7 months), and D210. Blood samples were centrifuged and plasma was separated and analyzed using a qualified analytical procedure to determine plasma concentrations of etonogestrel.

[0170] The results are shown in Figure 4 and the main PK parameters are summarized in Table 2.

[0171] [Table 2]

[0172] The data show that quantifiable etonogestrel levels can be measured for up to 182 days. The release period is dependent on the formulation composition and dose. For the three test formulations, C max The plasma concentration of #3 was rapidly reached 3 hours after injection of the formulation, after which the plasma concentration declined. For #3 and #9, a re-increase in API plasma levels was observed from day 42 to day 84, while #7 caused a continuous decline in levels.

[0173] Similarly, other etonogestrel formulations (#15, #16, #17, and #18) were tested in a pharmacokinetic study in female beagle dogs at least 7 months old and weighing approximately 6-9 kg. Drug products containing 40 mg of etonogestrel were administered subcutaneously in the interscapular region of the dogs using a syringe and a 21G 5 / 8 inch needle. Injection formulation volumes varied between 350 μL and 480 μL per dog depending on the initial etonogestrel concentration in each formulation. The number of dogs per group was fixed at 5.

[0174] Animal observations were recorded at least once daily after dosing and during the study period, and injection sites were observed twice weekly for the first month and at each PK time point thereafter.Blood samples were collected in K2-EDTA anticoagulant tubes before dosing and at different time points after dosing selected from T0.5h, T1h, T2h, T3h, T6h, T10h, 24h (D1; day 1), D2, D4, D7, D14, D21, D28 (1 month), D42, D56 (2 months), D70, D84 (3 months), D98, D112 (4 months), D126, D140 (5 months), D154, D168 (6 months), D182, D196 (7 months), D210, and D224. Blood samples were centrifuged, plasma separated and analyzed using a qualified analytical procedure to determine plasma concentrations of etonogestrel.

[0175] The results are shown in Figure 5 and the main PK parameters are summarized in Table 3.

[0176] [Table 3]

[0177] Interim results over 28 days were used to compare peak levels of the four test articles. Results showed similar plasma profiles across test articles, with #15 having a slightly lower Cmax.

[0178] The entire data set showed that etonogestrel levels in individual animals could be quantified over 154-210 days and 126-224 days for #15 and #18, respectively. The behavior of #15 and #18 during the first 3 hours was very similar, with a rapid increase in concentration (up to Cmax) followed by a decrease in plasma concentration. Two spikes (i.e., re-increase in plasma levels) were then observed for each formulation.

[0179] Comparing #18, tested at 40 mg in this final study, with #9, tested at 15 mg in the previous study, in dogs, the highest dose of 40 mg increased overall plasma exposure (AUC), but peak etonogestrel levels were not higher compared to 15 mg, which may be important for safety purposes.

[0180] Example 4 stability studies The stability of 800 mg aliquots of the composition in formulation #3 was evaluated in 3 mL vials under long term stability conditions in an oven at 30° C.±3° C. and accelerated stability conditions in an ICH climate chamber at 40° C. with 75% relative humidity. The study was completed with a stability evaluation of a second composition (in formulation #8) under the same conditions in an ICH climate chamber at 25° C. with 60% relative humidity and under storage conditions of +2-8° C. The formulations were prepared as detailed in Example 2 and aliquoted into different nitrogen flushed vials.

[0181] At the beginning of the study and at different selected time points up to 24 months, etonogestrel and related substances content is monitored by UPLC; the water content in the formulation is measured using Karl Fischer volumetric titration; copolymer integrity is confirmed by tracing molecular weight by GPC-RI and measuring sample dynamic viscosity, and formulation injectability is determined. The detailed setup is described below. Further time points are also evaluated.

[0182] The amount of etonogestrel and related substances was determined using a Waters Acquity UPLC system equipped with a UV detector set at 245 nm and a C18 analytical column (BEH C18, Waters). The column temperature was maintained at 30° C. and the flow rate was fixed at 0.5 mL / min. The mobile phases were water / formic acid (100:0.1 V / V; solvent A) and acetonitrile / formic acid (100:0.1 V / V; solvent B), with an initial composition of 81 / 19. The proportion of solvent B was increased to 37% in 4 min, kept constant for 3 min, increased to 75% in 3 min, and increased again to 95% in 0.5 min, followed by a 1 min wash step and a 3.5 min re-equilibration period to 50 / 50.

[0183] For GPC-RI analysis, the amount of formulation required to reach a copolymer concentration of 10 mg / mL was weighed into a 10 mL glass vial. The vial was then filled with THF stabilized with BHT and left under orbital stirring. 1 mL of the solution was then filtered through a 0.45 μm PTFE filter and transferred to an HPLC glass vial. The sample was then analyzed using the method described in Example 1.

[0184] Dynamic viscosity analysis was performed using an Anton Paar rheometer equipped with a cone-plate measuring system with a diameter of 50 mm and a cone angle of 2 degrees. The temperature was fixed at 25 °C. Before analysis, the formulations were vortexed for 30 seconds. 800 μL of the formulation was placed in the center of the thermoregulated measuring plate using a spatula. The measuring system was lowered leaving a gap of 0.104 mm between the measuring system and the measuring plate. 21 viscosity measurement points (10 per decade) were determined over shear rates from 10 to 1000 s-1.

[0185] Injectability analysis was performed using a Lloyd Instruments FT plus texturometer equipped with Nexygen plus software. 500 μL of formulation was removed from the previously vortexed vial using a 1 mL Soft-ject syringe with a 19 G 1 inch needle. Air bubbles were removed to avoid interference during injectability measurement. The 19 G needle was then replaced with a 21 G 5 / 8 inch Terumo needle. The syringe was placed on the texturometer. The flow rate was fixed at 2 mL / min. Injection of the formulation was started at a fixed rate. The average force in Newtons (N) required to inject each replicate was calculated using the texturometer software. Injectability analysis was performed in triplicate.

[0186] Moisture content determinations were performed using a V-30 titrator equipped with a Karl Fischer kit and interchangeable burette and sensor. A 1 mL syringe fitted with an 18G 1 inch needle was used to withdraw 900 μL of formulation and inject approximately 300 μL of formulation into the titration cell. The exact formulation injection volume was determined by indirect weighing.

[0187] The results are shown in Tables 4 and 5.

[0188] All the parameters remained consistent over the study period at the different storage conditions tested, indicating that the formulation is stable over time under different storage conditions.

[0189] Example 5 Sterilization research Similar to the stability study detailed in Example 4, the suitability of the dry heat sterilization method was evaluated through stability evaluation of 800 mg aliquots of the composition in formulation #8 in 3 mL vials after dry heat cycles (+121° C. / 35 min and +111° C. / 60 min). The results are shown in Table 6.

[0190] All parameters remained consistent after dry heat cycling and after 7 months of storage at 40°C / 75% RH, confirming the stability of the formulation after dry heat cycling and suggesting its compatibility with dry heat sterilization.

[0191] Alternatively, sterilization by filtration of etonogestrel formulations was also evaluated for formulation batches up to 5 L. Results showed that filtration through 0.2 μm filters was feasible for the formulations of the present invention.

[0192] [Table 4]

[0193] [Table 5]

[0194] [Table 6]

[0195] Example 6 Toxicity studies in rats The low systemic and local toxicity of the selected etonogestrel formulations and the corresponding polymeric vehicles is confirmed by evaluations carried out in female rats (20 rats per group) at least 13 weeks old and weighing 200-300 g after 26 weeks of repeated subcutaneous administration (4 doses at 6-week intervals). This exposure period is followed by a recovery period of about 4 weeks or more until the estrous cycle returns to normal in at least half of the animals in the high dose group (10 rats per group).

[0196] Briefly, on D1, D43 (6 weeks), D85 (12 weeks), and D127 (18 weeks), each animal is injected with a fixed dose (in mg / kg based on most recent body weight) of either control saline, control polymer vehicle, or etonogestrel formulation as detailed in Table 7. Injections are performed subcutaneously at four different sites for each animal. General in-life evaluations (including mortality / morbidity, clinical observations, injection site observations, body weight measurements, and food consumption monitoring) are performed at predefined time points throughout the study. Additionally, estrous cycles are monitored by vaginal smear sampling to determine the number and duration of cycles.

[0197] After 11, 25, and 30 weeks (or more if applicable), blood and urine samples were collected from each animal for clinical pathology (hematology, coagulation, clinical chemistry, and urinalysis).

[0198] Additionally, the toxicokinetics of etonogestrel formulations are evaluated by dedicated animal studies. For the determination of etonogestrel serum levels, blood samples are collected pre-dose and then at T0.5h, T2h, T3h, T24h, T168h, and T672h after each dose in the groups treated with etonogestrel formulations (9 rats per group), and only up to T2h after dose in the control treatment groups (3 saline and 6 control polymer vehicle). Additional blood samples are collected once a week during the 4-week recovery period in the groups treated with etonogestrel formulations. DMSO serum levels are also measured, and blood samples are collected pre-dose and then at T0.5h, T2h, T3h, T12h, and T24h after the first and last dose in the groups treated with etonogestrel formulations and polymer vehicle, and only up to T2h after dose in the control saline treatment group.

[0199] All blood samples are processed by centrifugation for serum collection. Serum samples are then stored at -80°C until analysis to determine etonogestrel and / or DMSO concentrations using a validated bioanalytical method. Toxicokinetic evaluations are performed using the measured concentrations. Time and dose effects are evaluated based on etonogestrel serum concentrations, with AUC tau , C max , C last Dose proportionality was determined by calculating the accumulation ratio of AUC tau and C max is determined by comparing with the corresponding dose ratio.

[0200] After 26 or 30 weeks (or more if applicable), the animals are euthanized and necropsy procedures, histological processing, and microscopic evaluation are performed.

[0201] [Table 7]

[0202] Given this toxicity study in rats, the low dose level of 4 mg / kg in rats is considered equivalent to a clinically relevant human dose (e.g., 40 mg / human) based on body surface area, and the high dose level of 120 mg / kg represents a 30-fold higher dose and is considered to provide a sufficient margin of safety.

Claims

1. 1. An injectable formulation for sustained release of etonogestrel, comprising: - Formula ABA' (In the formula, Blocks A and A' are formed of poly(D,L-lactic acid) and contain m and n lactic acid (LA) repeat units, respectively; Block B is formed of poly(ethylene glycol) containing p ethylene oxide (EO) repeat units; The molar ratio R(TB) of LA repeat units to EO repeat units ((m+n) / p) is 1.5 to 9. A triblock copolymer (TB) having the following structure: - Formula CD (In the formula, Block C is formed by methoxypoly(ethylene glycol) containing r EO repeat units; Block D is formed of poly(D,L-lactic acid) containing q LA repeat units; The molar ratio R(DB)(q / r) of LA repeat units to EO repeat units is 1.5 to 15. A diblock copolymer (DB) having the following structure: - with a water-miscible, pharma- ceutically acceptable organic solvent, including DMSO; - etonogestrel, a prodrug or a salt thereof 13. An injectable formulation comprising:

2. Block B has a number average molecular weight (M n (B)) and block C has a number average molecular weight (M n The formulation of claim 1, having (C).

3. 2. The formulation of claim 1, wherein the etonogestrel content is from 2.5% w / w to 15% w / w, based on the total mass of the formulation.

4. 2. The formulation of claim 1, wherein the triblock copolymer (TB) content is from 8% w / w to 40% w / w, based on the total mass of the formulation; and the diblock copolymer (DB) content is from 6% w / w to 50% w / w, based on the total mass of the formulation.

5. The formulation according to claim 1, wherein the total content of polymers TB and DB in the formulation is from 14% w / w to 55% w / w, based on the total mass of the formulation.

6. 2. The formulation according to claim 1, wherein the mass ratio of the triblock copolymer to the diblock copolymer (TB:DB) is 10:90 w / w or more and 70:30 w / w or less.

7. 2. The formulation of claim 1, wherein the content of the water-miscible, pharma- ceutically acceptable organic solvent is 40% w / w or more and 82.5% w / w or less, based on the total mass of the formulation; the water-miscible, pharma- ceutically acceptable organic solvent consists essentially of DMSO or is a mixture of DMSO with one or more co-solvents.

8. 2. The formulation of claim 1, which is in the form of an injectable liquid and / or is capable of passing through a filter having a maximum pore size of 20 μm or less.

9. M n (B) is 650 to 3,200 g / mol; R(TB) is 2.5 to 7.5; M n 2. The formulation of claim 1, wherein (C) is 200 to 3,000 g / mol; and R(DB) is 1.5 to 11.

10. (a)M n (B) is 650 to 2,000 g / mol; R(TB) is 2.5 to 5.5; M n (C) is between 1,000 and 3,000 g / mol; R(DB) is between 1.5 and 4.5; the triblock copolymer (TB) content is between 10 and 25% w / w, preferably between 15 and 20% w / w, more preferably between 15 and 18 or between 18 and 20% w / w, based on the total weight of the formulation; the diblock copolymer (DB) content is between 10 and 25% w / w, preferably between 15 and 20% w / w, more preferably between 15 and 18 or between 18 and 20% w / w, based on the total weight of the formulation; the total content of polymers TB and DB is between 20 and 50% w / w, preferably between 30 and 40% w / w, more preferably between 36 and 40% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is between 40:60 and 60:40 w / w; or (b)M n (B) is 650 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n (C) is between 200 and 800 g / mol; R(DB) is between 6.5 and 11; the triblock copolymer (TB) content is between 15 and 25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is between 15 and 25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is between 30 and 50% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is between 40:60 and 60:40 w / w; or (cm n (B) is 1,500 to 3,200 g / mol; R(TB) is 2.5 to 5.5; M n (C) is between 1,000 and 3,000 g / mol; R(DB) is between 1.5 and 4.5; the triblock copolymer (TB) content is between 15 and 25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is between 15 and 25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is between 30 and 50% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is between 40:60 and 60:40 w / w; or (d)M n (B) is 650 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n (C) is between 200 and 800 g / mol; R(DB) is between 6.5 and 11; the triblock copolymer (TB) content is between 15 and 25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is between 10 and 25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is between 25 and 50% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is between 40:60 and 60:40 w / w; or (e)M n (B) is 500 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n (C) is between 200 and 800 g / mol; R(DB) is between 6.5 and 11; the triblock copolymer (TB) content is between 10 and 25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is between 10 and 25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is between 20 and 50% w / w; the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is between 40:60 and 60:40 w / w; or (f)M n (B) is 500 to 2,000 g / mol; R(TB) is 4.5 to 7.5; M n 2. The formulation of claim 1, wherein (C) is 200-800 g / mol; R(DB) is 6.5-11; the triblock copolymer (TB) content is 10-25% w / w based on the total weight of the formulation; the diblock copolymer (DB) content is 15-25% w / w based on the total weight of the formulation; the total content of polymers TB and DB is 25-50% w / w; and the mass ratio of triblock copolymer to diblock copolymer (TB:DB) is 40:60-60:40 w / w.

11. A pharmaceutical comprising the formulation according to claim 1, wherein the total amount of etonogestrel per dosage unit is preferably 5 to 60 mg and / or the volume of the formulation per dosage unit is 0.05 to 1.5 mL.

12. 12. The formulation of claim 1 or the medicament of claim 11, which is stable for at least 3 months when stored at 30°C or 40°C at a relative humidity of 75%.

13. A method for preparing a formulation according to claim 1 and / or a medicament according to claim 11, comprising the steps of: (i)- Formula ABA' (wherein blocks A and A' are formed of poly(D,L-lactic acid) and contain m and n lactic acid (LA) repeat units, respectively; block B is formed of poly(ethylene glycol) containing p ethylene oxide (EO) repeat units; and the molar ratio R(TB)(m+n) / p of LA repeat units to EO repeat units is 1.5 to 9.) A triblock copolymer (TB) having - Formula CD (wherein block C is formed of methoxypoly(ethylene glycol) containing r EO repeat units; block D is formed of poly(D,L-lactic acid) containing q LA repeat units; the molar ratio R(DB) of LA repeat units to EO repeat units (q / r) is 1.5 to 12.) A diblock copolymer (DB) having the formula: - a water-miscible pharma- tically acceptable organic solvent, including DMSO, obtaining a vehicle by mixing until the polymer is dissolved; (ii) mixing the vehicle with etonogestrel to obtain a formulation; (iii) optionally sterilizing the formulation; (iv) providing a quantity of the formulation, and optionally packaging, to obtain the medicament.

14. 12. An application device comprising the formulation according to claim 1 or the medicament according to claim 11, the application device being adapted for administering the formulation or medicament to a subject by injection; Preferably a self-administration drug delivery device or syringe, preferably a ready-to-use syringe; and / or an application device preferably adapted to provide an injection volume of the formulation or medicament of between 0.05 and 1.5 mL.

15. A formulation according to claim 1, a medicament according to claim 11 or a device according to claim 14 for contraception in a female subject.

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