Controlled release progesterone compositions and uses thereof

Abstract

The present invention relates to a composition comprising 35-55% by weight, relative to the total weight of the composition, of a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20-100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40-200° C., and 30-55% by weight of progesterone. The present invention further relates to the use of such a composition for synchronizing the estrus phase of a herd of non-human mammals, preferably a herd of cattle.

Description

[Technical field]

[0001] The present invention relates to the field of polymeric compositions for the controllable release of drugs, more specifically progesterone, in mammals. [Background technology]

[0002] Progesterone is a naturally occurring steroid hormone secreted by the cells of the corpus luteum of the ovary and the corpus luteum of the placenta. It is involved in pregnancy, embryogenesis, and the menstrual cycle in many species of mammals.

[0003] Progesterone is also commonly administered to mammals, especially cattle, to synchronize estrus and thus control and harmonize the sexual cycle of females. Estrous synchronization facilitates artificial insemination by freeing the inseminator from certain constraints related to estrous detection, and therefore has many advantages in terms of time and cost savings. More specifically, the advantages of estrous synchronization are in particular the elimination of the monitoring of the estrous phase of females and the construction of homogenous batches of animals, which makes it possible to carry out artificial insemination in several females on fixed and planned days. This artificial insemination day makes it possible to group parturitions and therefore facilitates their monitoring.

[0004] Thus, various polymer compositions have been developed to control the release of progesterone in non-human mammals. For example, JUROX PTY LTD in WO 2017 / 117627 describes polymer compositions containing 5-15% by weight of progesterone, relative to the total weight of the composition. These polymer compositions are more specifically used in intravaginal devices. Ceva Sante Animale also developed a 170 cm 2 The researchers have developed bovine vaginal diffusion systems for progesterone, such as the Prid Delta system, which comprises a polymer composition having a surface area of ​​9.12 mg / cm. The progesterone is present in an amount of 11% by weight relative to the total weight of the composition, thus resulting in a weight ratio of progesterone on the polymer matrix of 0.12 and a surface area of ​​9.12 mg / cm. 2This corresponds to an areal density of progesterone in the polymer matrix of 100 μm.

[0005] However, these polymer compositions containing a relatively small amount of progesterone (less than 15% by weight, based on the total weight of the composition) need to contact a large mucosal surface to obtain an effective diffusion profile. Therefore, these polymer compositions with less concentrated progesterone are more suitable for large devices with a large surface area in contact with the mucosa. In fact, polymer compositions with less concentrated progesterone are less suitable for small-sized compact devices with a minimum contact surface with the mucosa, as the amount of progesterone may be insufficient for an effective biological effect.

[0006] Therefore, there is currently a need to develop and provide new progesterone-enriched polymeric compositions that provide effective, continuous, sustained release. Summary of the Invention

[0007] In this context, the inventors have developed a composition with controlled release of progesterone, comprising a polymer matrix impregnated with a relatively concentrated amount of progesterone, at least 30% by weight, relative to the total weight of the composition. Such a polymer composition has a satisfactory progesterone diffusion profile, comparable to that observed in compositions containing smaller amounts of progesterone, at a concentration of 5-15% by weight, relative to the total weight of the composition. Thus, the polymer composition according to the invention allows for the release of an effective amount of progesterone over time, in a controlled and prolonged manner, on small mucosal surfaces. The polymer composition according to the invention also has a certain degree of flexibility. Considering their properties and advantages, the polymer composition according to the invention can be used in compact and small devices, which are more comfortable for mammals and therefore improve their health.

[0008] Thus, the present invention preferably provides a composition with controlled release of progesterone, comprising, relative to the total weight of the composition: 35 to 55% by weight of a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20 to 100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40 to 200 ° C; and 30% to 55% by weight, preferably 35% to 55% by weight, of progesterone.

[0009] The present invention further comprises: a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20 to 100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40 to 200 ° C; progesterone, The weight ratio of progesterone to the polymer matrix is ​​from 0.5 to 2, preferably from 0.54 to 1.57, and even more preferably 1.00 or 1.28.

[0010] The present invention also provides a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20 to 100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40 to 200 ° C; progesterone, The surface density of progesterone in the polymer matrix is ​​20 to 100 mg / cm 2 , preferably 25 to 80 mg / cm 2 The present invention relates to a composition,

[0011] In particular, the thermoplastic polymer is chosen from EVA type thermoplastic polymers and thermoplastic elastomer polymers (TPE).

[0012] Preferably, the EVA type thermoplastic polymer is an ethylene-vinyl acetate copolymer containing 18%, 28% or 40% by weight of vinyl acetate monomer relative to the total weight of the ethylene-vinyl acetate copolymer, preferably 40% by weight.

[0013] Preferably, the thermoplastic elastomer polymer (TPE) is selected from styrene block-based thermoplastic elastomer polymer (TPE-S) and polyurethane thermoplastic elastomer polymer (TPE-U).

[0014] According to a more preferred embodiment, the thermoplastic elastomeric polymer (TPE) is a block copolymer of polystyrene-polybutadiene-polystyrene (SBS), a block copolymer of polystyrene-polyene-polystyrene (SIS), a block copolymer of polystyrene-polyisobutylene-polystyrene (SIBS), a block copolymer of polystyrene-poly(ethylene-propylene)-polystyrene (SEP The styrenic block thermoplastic elastomer polymer (TPE-S) is selected from block copolymers of polystyrene-poly(ethylene-propylene) (SEP), block copolymers of polystyrene-poly(ethylene-butylene)-polystyrene (SEBS), block copolymers of poly-α-methylstyrene-poly(butadiene-isoprene)-α-methylstyrene, block copolymers of polydimethylsiloxane-styrene, graft block copolymers of polystyrene-polybutadiene, graft block copolymers of polystyrene-poly(ethylene oxide), block copolymers of poly[styrene-per-dimethylsiloxane], and block copolymers of polyisobutylene-polystyrene (PIB-PS). According to an even more preferred embodiment, the thermoplastic elastomeric polymer (TPE) is a blend comprising a block copolymer of polystyrene-poly(ethylene-butylene)-polystyrene (SEBS), paraffin oil, and polypropylene.

[0015] A particular object of the invention is a composition as defined above, further comprising from 5 to 35% by weight, relative to the total weight of the composition, of a pore-forming agent and / or a swelling agent.

[0016] According to a particular embodiment, the pore former is a polyethylene glycol, preferably with a molecular weight of 1500 to 8000 g / mol, 2000 to 6000 g / mol, even more preferably 4000 g / mol.

[0017] According to another particular embodiment, the swelling agent is polyethylene oxide.

[0018] A preferred composition of the present invention comprises, based on the total weight of the composition: - 35 to 55% by weight, preferably 35% by weight, of an ethylene-vinyl acetate copolymer, - 10 to 30% by weight, preferably 20% by weight, of polyethylene glycol, -35 to 55% by weight, preferably 45% by weight, of progesterone.

[0019] Another preferred composition of the present invention comprises, based on the total weight of the composition: - 35 to 55% by weight, preferably 50% by weight, of a blend comprising a polystyrene-poly(ethylene-butylene)-polystyrene block copolymer, paraffin oil, and polypropylene; -30 to 55% by weight, preferably 35 to 55% by weight, and even more preferably 50% by weight of progesterone.

[0020] According to a preferred embodiment of the present invention, the composition described in the present application is a veterinary composition. Preferably, the composition is applied to cattle, goats, sheep and pigs, and even more preferably to cattle.

[0021] Another object of the invention relates to the composition described in the present application for use in synchronizing the estrous phase of a herd of non-human mammals, preferably of cattle, goats, sheep or pigs.

[0022] According to a particular embodiment of the invention, the compositions are administered mucosally, preferably intranasally or intravaginally.

[0023] A further object of the present invention relates to a device for the controlled release of an active ingredient comprising the composition defined in the present application. Preferably, the device is a nasal or intravaginal device. [Brief description of the drawings]

[0024] [Figure 1] Amount of progesterone released per unit area (mg / cm2) using composition #8 according to the invention and composition Prid Delta. [Diagram 2] Effect of Pore-Forming or Swelling Agents Progesterone diffusion profile (%) with compositions #14, #11, #15, and #12 according to the invention (Figure 2). Progesterone diffusion profile (%) with compositions #8 and #10 according to the invention (Figure 3). Progesterone diffusion profile (%) with compositions #18, #10, #8, and #9 according to the invention (Figure 4). [Diagram 3] Effect of Pore-Forming or Swelling Agents Progesterone diffusion profile (%) with compositions #14, #11, #15, and #12 according to the invention (Figure 2). Progesterone diffusion profile (%) with compositions #8 and #10 according to the invention (Figure 3). Progesterone diffusion profile (%) with compositions #18, #10, #8, and #9 according to the invention (Figure 4). [Figure 4] Effect of Pore-Forming or Swelling Agents Progesterone diffusion profile (%) with compositions #14, #11, #15, and #12 according to the invention (Figure 2). Progesterone diffusion profile (%) with compositions #8 and #10 according to the invention (Figure 3). Progesterone diffusion profile (%) with compositions #18, #10, #8, and #9 according to the invention (Figure 4). [Figure 5A] 1 is a depiction of a device comprising a composition according to the present invention. [Figure 5B] 1 is a depiction of a device comprising a composition according to the present invention. [Figure 5C] 1 is a depiction of a device comprising a composition according to the present invention. [Figure 5D] 1 is a depiction of a device comprising a composition according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The present invention provides a polymer composition enriched with progesterone, which ensures a controlled release of this medicament active ingredient in the mammal to which the composition is applied. More specifically, the polymer composition according to the present invention has a weight ratio of progesterone to polymer matrix that is significantly greater (5-15 times) than the weight ratios of commonly used controlled release compositions of progesterone.

[0026] "Controlled release of an active ingredient" refers to continuous release over an extended period of time. More specifically, a controlled release active ingredient diffuses more slowly and for longer in the body for better absorption and therefore better biological effect.

[0027] Therefore, the present invention provides a composition comprising, based on the total weight of the composition: 35 to 55% by weight of a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20 to 100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40 to 200 ° C; and 30% to 55% by weight, preferably 35% to 55% by weight, of progesterone.

[0028] The present invention further comprises: a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20 to 100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40 to 200 ° C; progesterone, The weight ratio of progesterone to the polymer matrix is ​​from 0.5 to 2, preferably from 0.54 to 1.57, and even more preferably 1.00 or 1.28.

[0029] According to a particular embodiment, the weight ratio of progesterone to the polymer matrix is ​​between 0.5 and 1.6, preferably between 0.54 and 1.57, between 0.60 and 1.50, between 0.70 and 1.40, between 0.80 and 1.30, between 0.90 and 1.30, between 0.95 and 1.30. According to a preferred embodiment, the weight ratio of progesterone to the polymer matrix is ​​1.00 or 1.28.

[0030] The present invention further comprises: a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20 to 100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40 to 200 ° C; progesterone, The surface density of progesterone in the polymer matrix is ​​20 to 100 mg / cm 2 , preferably 25 to 80 mg / cm 2 The composition includes a composition,

[0031] According to certain embodiments, the areal density of progesterone in the polymer matrix is ​​between 20 and 100 mg / cm. 2 , preferably 25 to 80 mg / cm 2 , 50-67mg / cm 2 and even more preferably about 29.85, about 43.48, about 50.00, about 56.25 mg / cm 2 , and about 66 or 67 mg / cm 2 It is.

[0032] The term "about" is understood by those of skill in the art and can vary to some extent depending on the context in which it is used. If some uses of the term are not clear to a person of ordinary skill in the art based on the context, "about" means 20% more or less than the particular term, preferably 10% more or less than the particular term.

[0033] As used herein, the terms "comprises," "comprise," or "comprising" (and other equivalent terms, such as "containing" and "including") are "open ended" and may be generally interpreted to include all features mentioned as well as all optional features, additional features and characteristics not specified. According to certain embodiments, unless otherwise indicated, they may also be interpreted as "consisting essentially of" when the specified features and optional additional unspecified features that do not materially affect the basic and novel characteristics of the claimed invention are included, or as "consisting of" when only the specified features are included.

[0034] More specifically, according to the present invention, the progesterone is impregnated into a polymer matrix. In the context of the present invention, the term "impregnated" also includes the terms "mixed", "integrated", "embedded", "combined", "fused" and "amalgamated". Thus, the composition comprises a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20-100 measured by a Type A durometer according to the ASTM D2240 standard and a melting point of 40-200°C, and the progesterone is impregnated into the polymer matrix.

[0035] A "thermoplastic" material is understood to mean a material that can be repeatedly softened by heating and hardened by cooling. In the case of polymers, the polymerization of a thermoplastic material is said to be reversible.

[0036] According to the invention, the polymer matrix comprises a thermoplastic polymer having a Shore A hardness measured by a Type A durometer according to standard ASTM D2240 of 20 to 100. Preferably, the thermoplastic polymer has a Shore A hardness of 20 to 90, 25 to 100, 30 to 100, 40 to 100, even more preferably the thermoplastic polymer has a Shore A hardness of 40.

[0037] The Shore hardness tester makes it possible to measure the hardness of a material. There are more than 12 existing Shore measurement scales, the most common being the A scale for soft materials and the D scale for hard materials. The hardness measurement method established by the ASTM D2240 standard makes it possible to measure the depth of the indentation made in the material to be characterized, using established forces and standardized indentation heads. The depth is proportional to the hardness and ductility of the material and to the geometric shape of the indentation head used. The ASTM D2240 standard consists of pressing an indentation head into the material to be characterized, and the hardness is read directly on the scale of the device, such as a type A durometer for soft thermoplastic polymers.

[0038] According to the invention, the polymer matrix comprises a thermoplastic polymer having a melting point between 40 and 200° C. Preferably, the thermoplastic polymer has a melting point between 40 and 135° C., even more preferably below 44° C.

[0039] The melting point or melting temperature of a polymer is the temperature at which it changes from a rubbery state to a liquid or viscous state. The melting point of a polymer can be determined by various techniques known to those skilled in the art, such as direct detection by visual observation using a capillary tube, detection using a polarized light microscope, and thermal analysis techniques such as, for example, thermomechanical analysis, differential thermal analysis, and differential scanning calorimetry. More specifically, the thermoplastic polymer is selected from EVA type thermoplastic polymers and thermoplastic elastomeric polymers (TPEs).

[0040] Thermoplastic polymers of the EVA type are derived from copolymers of ethylene and vinyl acetate. There are several types of thermoplastic EVA polymers that differ in the weight ratio of vinyl acetate monomer to the total weight of the polymer (ethylene-vinyl acetate copolymer). For example, EVA 18 contains 18% by weight of vinyl acetate monomer relative to the total weight of the ethylene-vinyl acetate copolymer. EVA 28 contains 28% by weight of vinyl acetate monomer relative to the total weight of the ethylene-vinyl acetate copolymer. EVA 40 contains 40% by weight of vinyl acetate monomer relative to the total weight of the ethylene-vinyl acetate copolymer. Thermoplastic polymers of the EVA type are generally hydrophobic and transparent. They have good chemical resistance and good impact resistance. They also have a high coefficient of friction and good adhesion properties.

[0041] In a preferred embodiment, the thermoplastic polymer of the EVA type is an ethylene-vinyl acetate copolymer comprising 18%, 28% or 40% by weight of vinyl acetate monomer relative to the total weight of the ethylene-vinyl acetate copolymer. In an even more preferred embodiment, the thermoplastic polymer of the EVA type is an ethylene-vinyl acetate copolymer comprising 40% by weight of vinyl acetate monomer relative to the total weight of the ethylene-vinyl acetate copolymer. Thus, preferred thermoplastic polymers of the EVA type are EVA18, EVA28 or EVA40 polymers. An even more preferred thermoplastic polymer of the EVA type is EVA40 polymer.

[0042] Thermoplastic elastomeric polymers (TPEs) are a family of (often block) copolymers that combine the elastic properties of elastomers with thermoplasticity.

[0043] An "elastomeric" polymer is understood to mean a polymer that is able to recover its shape after deformation. A thermoplastic elastomer is therefore a heterogeneous polymer composed of regions of thermoplastic polymeric material and regions of elastomeric polymeric material. The term "regions" is used to describe zones of material that contain polymer chains of elastomeric or thermoplastic nature. Preferably, the thermoplastic elastomeric polymer (TPE) according to the invention comprises monomers or blocks of monomers of thermoplastic nature and blocks of monomers of elastomeric nature.

[0044] Thermoplastic elastomers (TPEs) or block copolymers of thermoplastic and elastomeric monomers can be classified into different categories depending on the nature and proportion of the monomers. Thermoplastic elastomeric polymers include, but are not limited to, thermoplastic polymers based on styrene blocks (TPE-S), thermoplastic elastomeric polymers based on polyester blocks (TPE-E), polyurethane elastomer thermoplastic polymers (TPE-U), thermoplastic elastomeric polymers based on amide blocks (TPE-A), vulcanized thermoplastic polymers (TPE-V), and thermoplastic olefins (TPE-O).

[0045] Examples of styrene block-based thermoplastic elastomer polymers (TPE-S) include block copolymers of polystyrene-polybutadiene-polystyrene (SBS), block copolymers of polystyrene-polyene-polystyrene (SIS), block copolymers of polystyrene-polyisobutylene-polystyrene (SIBS), block copolymers of polystyrene-poly(ethylene-propylene)-polystyrene (SEPS), block copolymers of polystyrene-poly(ethylene-propylene) (SEP), block copolymers of polystyrene-poly(ethylene- In one embodiment, the block copolymer is selected from block copolymers of poly(styrene-butadiene-isoprene)-polystyrene (SEBS), block copolymers of poly-α-methylstyrene-poly(butadiene-isoprene)-α-methylstyrene, block copolymers of polydimethylsiloxane-styrene, graft block copolymers of polystyrene-polybutadiene, graft block copolymers of polystyrene-poly(ethylene oxide), block copolymers of poly[styrene-per-dimethylsiloxane], and block copolymers of polyisobutylene-polystyrene (PIB-PS).

[0046] Polyurethane thermoplastic elastomeric polymers (TPE-U) are thermoplastic elastomeric polymers based on isocyanate blocks.

[0047] Preferably, the thermoplastic elastomer polymer (TPE) is a styrene block-based thermoplastic elastomer polymer (TPE-S) and a polyurethane thermoplastic elastomer polymer (TPE-U).

[0048] Preferably, the thermoplastic elastomer polymer is a styrene block-based thermoplastic elastomer polymer (TPE-S). More specifically, the styrene block-based thermoplastic elastomer polymer (TPE-S) is a block copolymer of polystyrene-polybutadiene-polystyrene (SBS), a block copolymer of polystyrene-polyene-polystyrene (SIS), a block copolymer of polystyrene-polyisobutylene-polystyrene (SIBS), a block copolymer of polystyrene-poly(ethylene-propylene)-polystyrene (SEPS), a block copolymer of polystyrene-poly(ethylene-propylene) (SEP), a block copolymer of polystyrene-poly(ethylene According to an even more preferred embodiment, the styrene block based thermoplastic elastomer polymer (TPE-S) is selected from the block copolymers of polystyrene-poly(ethylene-butylene)-polystyrene (SEBS), block copolymers of poly-α-methylstyrene-poly(butadiene-isoprene)-α-methylstyrene, block copolymers of polydimethylsiloxane-styrene, graft block copolymers of polystyrene-polybutadiene, graft block copolymers of polystyrene-poly(ethylene oxide), block copolymers of poly[styrene-per-dimethylsiloxane], and block copolymers of polyisobutylene-polystyrene (PIB-PS). According to an even more preferred embodiment, the styrene block based thermoplastic elastomer polymer (TPE-S) is a block copolymer of polystyrene-poly(ethylene-butylene)-polystyrene (SEBS).

[0049] The above thermoplastic elastomers (TPEs) may be in the form of a mixture in the composition of the present invention.The above thermoplastic elastomers (TPEs) can also be blended in the presence of other types of polymers, such as polyethylene or polypropylene, and in the presence of excipients.A suitable polymer blend for the composition of the present invention is the blend medioprene®, available from HEXPOL TPE, which includes a block copolymer of polystyrene-poly(ethylene-butylene)-polystyrene (SEBS), paraffin oil, and polypropylene.

[0050] According to an even more advantageous embodiment, the styrenic block based thermoplastic elastomeric polymer (TPE-S) is a blend comprising a block copolymer of polystyrene-poly(ethylene-butylene)-polystyrene (SEBS), paraffin oil, and polypropylene.

[0051] A preferred composition of the present invention comprises - 35 to 55% by weight, preferably 50% by weight, based on the total weight of the composition, of a blend comprising a polystyrene-poly(ethylene-butylene)-polystyrene block copolymer, paraffin oil, and polypropylene; -30 to 55% by weight, preferably 35 to 55% by weight, and even more preferably 50% by weight of progesterone.

[0052] According to one particular embodiment of the invention, the composition further comprises a pore-forming agent and / or a swelling agent, preferably in a proportion of 5-35% by weight relative to the total weight of the composition, which agents make it possible to better control the release of progesterone from the polymer matrix and to improve the progesterone diffusion profile in order to obtain an improved biological effect.

[0053] The pore former may be a polyethylene glycol, preferably having a molecular weight of 1500-8000 g / mol, 2000-6000 g / mol, even more preferably 4000 g / mol, a polyvinyl alcohol, a polyvinylpyrrolidone, preferably having a low molecular weight such as polyvinylpyrrolidone K12-K30, a sugar such as sucrose or lactose, or a surfactant, preferably a non-ionic surfactant.

[0054] The swelling agent may be polyethylene oxide, polyvinylpyrrolidone, preferably with a high molecular weight such as polyvinylpyrrolidone K90, crospovidone, carbomer, cellulose derivatives such as sodium carboxymethylcellulose, sodium starch glycolate, hydroxypropylmethylcellulose and methylcellulose, or hydrocolloids such as alginates, chitosan or pectin.

[0055] A preferred subject matter according to the present invention is a composition as defined above, which further comprises from 5 to 35% by weight, relative to the total weight of the composition, of a pore-forming agent and / or a swelling agent.

[0056] According to a preferred embodiment, the pore former is polyethylene glycol, in particular having a molecular weight of 1500 to 8000 g / mol, preferably 2000 to 6000 g / mol, even more preferably 4000 g / mol.

[0057] According to another preferred embodiment, the pore former is polyvinylpyrrolidone, in particular having a low molecular weight and preferably having grades K12 to K30, with grades K12, K17 and K25 being particularly preferred.

[0058] According to another preferred embodiment, the pore-forming agent is a surfactant, preferably non-ionic, in particular a surfactant selected from the group consisting of docusate sodium, docusate potassium, esters of fatty acids and esters of polyoxyethylene sorbitan (polysorbates), polyoxygenated hydrogenated castor oil and derivatives thereof.

[0059] According to another preferred embodiment, the swelling agent is polyethylene oxide.

[0060] Of course, one skilled in the art can incorporate one or more additional excipients into the polymer matrix of the composition according to the invention, if desired. For example, these excipients can be antioxidants, antimicrobial preservatives, colorants, plasticizers, lubricants, and / or mold release agents in the polymer matrix.

[0061] A preferred composition of the present invention comprises, based on the total weight of the composition: - 35 to 55% by weight, preferably 35% by weight, of an ethylene-vinyl acetate copolymer, - 10 to 30% by weight, preferably 20% by weight, of polyethylene glycol, -30 to 55% by weight, preferably 35 to 55% by weight, and even more preferably 45% by weight of progesterone.

[0062] An even more preferred composition of the present invention comprises, based on the total weight of the composition: 35% by weight of EVA 40 polymer; 20% by weight of polyethylene glycol having a molecular weight of 4000 g / mol; -45% by weight of progesterone.

[0063] Another preferred composition of the present invention comprises, based on the total weight of the composition: - 35 to 55% by weight, preferably 55% by weight, of an ethylene-vinyl acetate copolymer, - 10 to 30% by weight, preferably 15% by weight, of polyvinylpyrrolidone, -30 to 55% by weight, preferably 30% by weight, of progesterone.

[0064] The composition of the present invention may further comprise at least one manufacturing aid, such as a lubricant and a plasticizer. The lubricants may include, non-exhaustively, magnesium stearate, talc, colloidal silica, glyceryl behenate, and the like. Among the plasticizers, non-exhaustively, may be mentioned glycerol, triethyl citrate, tributyl citrate, acetyl triethyl citrate, dibutyl sebacate, dibutyl phthalate, tributyl sebacate, glycerol tricaprylate, triacetin, vegetable oils such as castor oil and coconut oil, medium chain triglycerides, medium chain polyethylene glycols such as PEG400, and acetylated monoglycerides. Preferably, the plasticizer may be selected from glycerol, triethyl citrate, tributyl citrate, acetyl triethyl citrate, dibutyl sebacate, triacetin, vegetable oils such as castor oil and coconut oil, medium chain triglycerides, and acetylated monoglycerides.

[0065] The compositions of the invention as defined in the present application can be applied to any type of mammal, preferably non-human mammals such as cows, sheep, goats, horses, dogs, cats and pigs, even more preferably cows, goats, sheep and pigs, advantageously cows.

[0066] According to a particular embodiment of the present invention, the composition is a veterinary composition. Preferably, it is applied to cattle, even more preferably to cows or heifers. According to another particular embodiment, the composition is applied to goats, preferably goats and ewes, or pigs, preferably sows.

[0067] According to another particular embodiment of the invention, the composition is applied for several days, preferably for at least 3, 4, 5, 6, 7, 14, 18, 21 days, even more preferably for at least 7, 14 or 18 days.

[0068] The composition according to the invention is specific for the release of progesterone, an active ingredient commonly used in the veterinary field to synchronize estrus in non-human mammals, as indicated in the introduction. Preferably, the polymer composition according to the invention releases progesterone transmucosally, in particular intranasally or intravaginally.

[0069] Another subject of the invention therefore relates to the use of the composition according to the invention for synchronizing the estrus of a herd of non-human mammals, preferably of cattle, goats, sheep or pigs. Preferably, the composition according to the invention is administered mucosally, more preferably intranasally or intravaginally. Thus, the invention also relates to the composition according to the invention for use in synchronizing the estrus of a herd of non-human mammals, preferably of cattle, goats, sheep or pigs.

[0070] The present invention also relates to a method for synchronizing the estrous phase of a herd of non-human mammals, preferably of cattle, goats, sheep or pigs, which comprises applying a composition according to the invention to said non-human mammals, preferably to the mucous membranes, more particularly nasally or intravaginally.

[0071] A further object relates to a device with controlled release of progesterone comprising a composition according to the invention. Preferably, the device is a nasal or intravaginal device. Such a device has a diameter of 5 to 100 cm. 2 , 7.5~90cm 2 , 10~90cm 2 , preferably 15 to 70 cm 2 , and even more preferably 16 cm 2 , 20cm 2 , 23cm 2 , 25cm 2 , 30cm 2 , 35cm 2 , 40cm 2 , 45cm 2 , 50cm 2 , 60cm 2 , 67cm 2 The composition according to the present invention has a surface area of

[0072] Examples of intravaginal devices include devices shaped like a hedgehog, a Christmas tree, or an arrow. One particular intravaginal device is 10-20 cm 2 , preferably 16cm 2 A particular device is a hedgehog shaped device as shown in FIG. 5C containing a composition according to the invention having a surface area of ​​50-80 cm. 2 , preferably 67cm 2 A particular device is a Christmas tree shaped device containing a composition according to the present invention having a surface area of ​​30-50 cm, as shown in FIG. 2 , preferably 40cm 2 Such a device is particularly suitable for application in sows.

[0073] An example of a nasal device may be a nose ring. An example of a particular nasal device is a 60 cm 2A nose ring comprising a composition according to the invention, having a surface area of ​​60 cm. Preferentially, the composition according to the invention is placed on both ends of the nose ring, in particular on the front surface of a support plate intended to abut the nasal septum separating the nostrils of a ruminant. According to a preferred embodiment, the nose ring is a nose ring comprising a composition according to the invention, having a surface area of ​​60 cm. 2 According to this preferred embodiment, each end of the nose ring comprises a composition of the present invention having a total surface area of ​​30 cm 2 Such a device is particularly suitable for application to ruminants, preferably cattle.

[0074] Further aspects and advantages of this invention will become apparent from consideration of the following examples, which must be considered as illustrative and non-limiting. EXAMPLES

[0075] A-Composition The compositions of the present invention were generally prepared by extrusion followed by injection molding. More specifically, the various components were weighed, premixed by hand, then mixed in a mixer of the Turbula T2F type for 30 minutes. The extrusion process was then carried out using an extruder ThermoFisher Pharma 11 Twin-screw. The granules obtained at the end of the extrusion process were injection molded to obtain rod-shaped parts, which were then cut into pieces of approximately 16 cm. 2 A part was produced with a weight of 2 g and dimensions of 47×13×3 mm, corresponding to a surface area of ​​1.0 mm.

[0076] Specific compositions according to the present invention are set forth below in Table 1. A comparative composition of the product Prid Delta from CEVA Health is also provided for illustration.

[0077] [Table 1] %: Percentages are expressed by weight relative to the total weight of the composition. EVA: Ethylene vinyl acetate TPE-U: Polyurethane thermoplastic elastomer polymer PEG: Polyethylene glycol PEO: Polyethylene oxide

[0078] B-The amount of progesterone released by the composition of the present invention The amount of progesterone released by the compositions of the present invention is measured according to the DISSOLUTEST method using a Type 2 apparatus (paddle apparatus) as described in the European Pharmacopoeia, the United States Pharmacopoeia, and the Japanese Pharmacopoeia.

[0079] The results are shown in Table 2 below.

[0080] [Table 2] Q: Amount of progesterone released (mg) ND: Not measured

[0081] The amount of progesterone released per unit surface area by Composition #8 compared with Prid delta is shown in FIG.

[0082] C-Progesterone Diffusion Profile The progesterone diffusivity obtained using the compositions of the present invention is calculated according to the following formula: Diffusion rate (%) = (Q of progesterone in the composition .放出 (mg) / Q of progesterone in medium .初期 ) x 100

[0083] The progesterone diffusivity obtained using the compositions of the present invention is determined according to the method described above.

[0084] The results are shown in Table 3 below and illustrated in FIGS.

[0085] [Table 3] Diffusion rate: Progesterone diffusion rate (%) ND: Not measured

[0086] D-Hardness of the composition of the present invention The hardness of the compositions of the present invention is measured by a Type A Durometer according to standard ASTM D2240. The results are shown in Table 4 below.

[0087] [Table 4]

[0088] E-Conclusion The results show that the polymer compositions according to the invention enriched in progesterone (30-55% by weight, preferably 35-55% by weight, relative to the total weight of the composition) have progesterone diffusivities substantially comparable to the polymer composition Prid Delta, even though they are less enriched in progesterone (11% by weight), especially for the compositions according to the invention further comprising polyethylene glycol.

[0089] The results in Table 4 demonstrate a degree of flexibility for the polymer compositions of the present invention, especially those compositions of the present invention further comprising polyethylene glycol.

[0090] In conclusion, the inventors have demonstrated that the progesterone-enriched polymeric composition of the present invention (30-55% by weight, based on the total weight of the composition) allows for the release and delivery in a long-term continuous manner of sufficient amounts of progesterone to achieve the desired therapeutic objectives. The progesterone-enriched polymeric composition of the present invention is relatively flexible and therefore can be used in smaller, more compact administration devices, and therefore more comfortable for the mammal.

Claims

1. A composition comprising, based on the total weight of the composition: - 35 to 55% by weight of a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20 to 100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40 to 200°C; - 30 to 55% by weight of progesterone.

2. 1. A composition comprising: a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20 to 100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40 to 200°C; - progesterone, A composition, wherein the weight ratio of progesterone to said polymer matrix is ​​between 0.5 and 2, preferably between 0.54 and 1.57, even more preferably 1 or 1.

28.

3. 1. A composition comprising: a polymer matrix comprising a thermoplastic polymer having a Shore A hardness of 20 to 100, measured by a Type A durometer according to the ASTM D2240 standard, and a melting point of 40 to 200°C; - progesterone, A composition, wherein the areal density of progesterone in said polymer matrix is ​​between 20 and 100 mg / cm2, preferably between 25 and 80 mg / cm2.

4. The composition according to any one of claims 1 to 3, wherein the thermoplastic polymer is chosen from EVA type thermoplastic polymers and thermoplastic elastomeric polymers (TPE).

5. 5. The composition according to claim 4, wherein the EVA type thermoplastic polymer is an ethylene-vinyl acetate copolymer comprising 18%, 28% or 40% by weight of vinyl acetate monomer relative to the total weight of the ethylene-vinyl acetate copolymer, preferably 40% by weight.

6. The composition of claim 4, wherein the thermoplastic elastomeric polymer (TPE) is selected from styrene block-based thermoplastic elastomeric polymers (TPE-S) and polyurethane thermoplastic elastomeric polymers (TPE-U).

7. The thermoplastic elastomeric polymer (TPE) may be a block copolymer of polystyrene-polybutadiene-polystyrene (SBS), a block copolymer of polystyrene-polyisoprene-polystyrene (SIS), a block copolymer of polystyrene-polyisobutylene-polystyrene (SIBS), a block copolymer of polystyrene-poly(ethylene-propylene)-polystyrene (SEPS), a block copolymer of polystyrene-poly(ethylene-propylene) (SEP), a block copolymer of polystyrene-poly(ethylene-butylene)-polystyrene (SEBS), 5. The styrenic block based thermoplastic elastomer polymer (TPE-S) according to claim 4, which is selected from the group consisting of block copolymers of poly-α-methylstyrene-poly(butadiene-isoprene)-α-methylstyrene, block copolymers of polydimethylsiloxane-styrene, graft block copolymers of polystyrene-polybutadiene, graft block copolymers of polystyrene-poly(ethylene oxide), block copolymers of poly[styrene-per-dimethylsiloxane], and block copolymers of polyisobutylene-polystyrene (PIB-PS). Composition of.

8. 5. The composition of claim 4, wherein the thermoplastic elastomeric polymer (TPE) is a blend comprising a block copolymer of polystyrene-poly(ethylene-butylene)-polystyrene (SEBS), paraffin oil, and polypropylene.

9. The composition according to any one of claims 1 to 3, further comprising from 5 to 35% by weight, based on the total weight of the composition, of a pore-forming agent and / or a swelling agent.

10. The composition according to claim 9, wherein the pore former is a polyethylene glycol, preferably having a molecular weight of 1500 to 8000 g / mol, 2000 to 6000 g / mol, even more preferably 4000 g / mol.

11. The composition of claim 9, wherein the swelling agent is polyethylene oxide.

12. The composition comprises, based on the total weight of the composition: - 35 to 55% by weight, preferably 35% by weight, of an ethylene-vinyl acetate copolymer; - 10 to 30% by weight, preferably 20% by weight, of polyethylene glycol, A composition according to any one of claims 1 to 3, comprising 30 to 55% by weight, preferably 35 to 55% by weight, even more preferably 45% by weight of progesterone.

13. The composition comprises, based on the total weight of the composition: - 35-55% by weight, preferably 50% by weight, of a blend comprising polystyrene-poly(ethylene-butylene)-polystyrene block copolymer, paraffin oil, and polypropylene; A composition according to any one of claims 1 to 3, comprising 30 to 55% by weight, preferably 35 to 55% by weight, even more preferably 50% by weight of progesterone.

14. The composition according to any one of claims 1 to 3, wherein said composition is a veterinary composition and is preferably applied to cattle, goats, sheep and pigs, preferably cattle.

15. A composition according to any one of claims 1 to 3 for use in synchronising the estrous phase of a herd of non-human mammals, preferably of cattle, goats, sheep and pigs.

16. The composition for use according to claim 15, wherein the composition is administered mucosally, preferably intranasally or intravaginally.

17. A device with controlled release of progesterone comprising a composition according to any one of claims 1 to 3, preferably a nasal or intravaginal device.

Images