Veterinary antiprolactin composition for ruminants for use by intramammary administration - Patents.com

Abstract

The present invention relates to veterinary compositions and methods for reducing milk production in dairy ruminants in a more efficient and safe manner, particularly by administering the compositions by the intramammary route after cessation of milking at the start of the dry period.

Description

[Technical field]

[0001] The present invention relates to a veterinary composition and in particular to a method for reducing milk production in dairy ruminants, in a more efficient and safe manner, at the onset of the dry period (i.e. the sudden cessation of milking), which consists in administering said composition by the intramammary (IMM) route at the time of dry-off, i.e. after the last milking.

[0002] In dairy ruminants, lactation generally lasts for 5-20 months; in dairy cows, it is most often 10 months. After this lactation, milking is stopped, generally abruptly, and the dairy ruminant does not produce milk until calving, when the subsequent lactation begins. This period between the cessation of milking and the subsequent lactation, which is generally at parturition (or calving for cows), known as the "dry period," is generally set at about 2 months (i.e., 45-70 days) in dairy cows.

[0003] The dry period is necessary to ensure optimal milk production during the subsequent lactation, but the dry period requires several dietary changes and transitions to adapt to the physiological needs of the animal that is no longer producing milk. These dietary changes cause numerous physiological disruptions and stresses in the ruminant. The dry period results in a metabolism in dairy ruminants that is significantly different from that observed during lactation. The transition from lactation to the non-lactation state promotes the outcome of a primary disruption of homeostasis in the dairy cow.

[0004] During the dry period, and more specifically within the first 24 hours after dry-off, milk synthesis in the mammary gland continues, especially in lactating ruminants with high levels of milk production. As a result, the need for calcium transfer from the blood to the milk continues during these first 24 hours. In addition, in the implementation of the dry period, breeders very often reduce the feed, which further reduces the calcium supply and its level in the blood circulation. Furthermore, antiprolactin products, when administered by parenteral route, generally intramuscularly (IM), to aid in dry-off, also have the known effect of reducing the intestinal absorption of calcium obtained from the diet. All this contributes to increasing the risk of hypocalcemia during lactation dry-off.

[0005] At dry-off, some dairy cows that receive the veterinary composition by intramuscular route after the last milking may therefore experience hypocalcemia within 24 hours after treatment administration. In some cases, hypocalcemia may cause the cow to lie down, requiring appropriate therapy to be given by a veterinarian. The way to know if a dairy cow is experiencing hypocalcemia is to analyze the blood for calcium concentration within the first 1-2 days after the last milking. A dairy cow with a blood calcium concentration below 8.8 mg / dl (2.2 mmol / l) but showing no clinical signs is considered potentially hypocalcemic. This latter condition is also considered detrimental to the cow's health, which may further promote the outcome of different metabolic disorders in the cow.

[0006] On the other hand, there is a need for a treatment that efficiently reduces milk production so that the mammary gland quickly stops its milk synthesis without excessive udder engorgement due to milk accumulation and stasis. This will help prevent adverse effects on the health of dairy cows. In fact, less udder engorgement is associated with a reduction in galactorrhea, which is a high risk factor for new intramammary infections in dairy cows. It also reduces pain and discomfort of the cow during the day after dry-off. Finally, it promotes involution during the dry period, which is an important physiological process for the health and regeneration of the mammary gland for the next lactation.

[0007] In veterinary medicine, prolactin inhibitor-based compositions such as Galastop® (cabergoline, Ceva Sante Animale) can be administered as a treatment for lactation during pseudo-pregnancy in female dogs. They are also prescribed to stop milk production in ruminants. WO2010 / 040765 in the name of the present applicant describes the administration of anti-prolactin dopamine receptor agonist compounds, such as cabergoline, to pregnant ruminants to promote lactation dry-off and promote mammary involution, especially by intramuscular administration. However, such intramuscular administration of cabergoline may potentially induce hypocalcemia in dairy cows, especially during the first 24 hours after administration after dry-off, for reasons explained in the previous section.

[0008] The Applicant has now surprisingly discovered that administration of a veterinary composition comprising cabergoline to a ruminant via the intramammary route is able to reduce milk production more efficiently when dry-off is performed.

[0009] Surprisingly, the intramammary administration of the veterinary composition according to the invention improves the bioavailability of cabergoline in ruminants, thereby allowing more satisfactory efficacy results in terms of reduced milk production and / or reduced udder engorgement. In addition, it has also been surprisingly found that the intramammary administration of cabergoline allows the prevention and / or reduction of hypocalcemia, especially within the first 24 hours after cessation of milking, compared to cabergoline used by the intramuscular route. Summary of the Invention

[0010] The present invention relates to a veterinary composition comprising cabergoline for use in reducing lactation or milk production in dairy ruminants, said composition being administered via the intramammary route to the dairy ruminant, preferably at the time of performance of the dry period, i.e. at the time of drying off.

[0011] According to the present invention, the composition is administered by intramammary route in an effective therapeutic amount to induce a reduction in milk production in a dairy ruminant, preferably at the time of implementing the dry period of the dairy ruminant.

[0012] The composition is administered to the dairy ruminant by the intramammary route in a single treatment and / or repeated treatments, preferably in a single treatment.

[0013] Intramammary administration of the veterinary composition according to the invention further does not affect the milk production performance and / or milk quality of the ruminant animal during subsequent lactation.

[0014] The present invention also relates to a kit for reducing milk production in dairy ruminants comprising a veterinary composition as defined above and, optionally, means for the intramammary administration of cabergoline.

[0015] In one aspect there is provided the use of cabergoline for the manufacture of a veterinary composition for reducing milk production in a dairy ruminant, said composition being administered to the dairy ruminant by intramammary route, preferably at the time of performance of the dry period.

[0016] In another aspect, a method for reducing milk production in a dairy ruminant is provided, wherein a veterinary composition comprising cabergoline is administered to said ruminant in a therapeutically effective amount by intramammary route, preferably at the time of performing the dry period. [Brief description of the drawings]

[0017] [Figure 1] Milk production during the morning milking on D2-D9 (L) - cabergoline treatment during the evening milking on D4 (arrow). Group averages. [Diagram 2] : Inter-teatillary circumference (cm) from treatment day D0 to post-treatment day D9. Average per group (control: upper curve, treated cows: lower curve). [Diagram 3] : Delta inter-papillary circumference (ITP) (cm) from treatment day D0 to post-treatment day D9 (+216 h). Average per group (control: upper curve, treated cows: lower curve). [Figure 4]: Mean and sd plasma concentration (pg / mL)-time (hours) profiles of intramammary administration of cabergoline [Diagram 5] : Mean and sd plasma concentration (pg / mL)-time (hours) profiles of intramuscularly administered cabergoline (comparison study) [Figure 6A-6B] : Mean (sd) blood Ca concentration (mmol / L) (Graph A: control "ctrl" cows vs. cabergoline IMM treated "cab IMM" cows) and difference relative to baseline (0h) pretreatment with respect to time (hours) (Graph B: control "ctrl" cows vs. cabergoline IMM treated "cab IMM" cows). [Figure 7] Comparison of mean blood Ca concentration as a function of time between different studies: IMM study (upper curve) and IM study (two lower curves, IM study 1 and 2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The phrase "dry period" includes the period between the last milking of a lactation and the subsequent lactation of the subsequent lactation, which generally begins at calving. The dry period generally lasts about two months in dairy cows, more specifically, 56-70 days.

[0019] In the context of the present invention, the terms "last milking", "dry off" or "cessation of milking" can be used interchangeably. They correspond to the time when the dry period is carried out.

[0020] The present invention relates to a veterinary composition comprising cabergoline for use in reducing milk production, said composition being administered via the intramammary route to a dairy ruminant, preferably at the time of the dry period.

[0021] The present invention also relates to veterinary compositions comprising cabergoline administered via the intramammary route in single and / or repeated treatments for use in reducing milk production, preferably during the implementation of the dry period.

[0022] The compositions used according to the invention also make it possible to reduce milk production and induce mammary involution in ruminants, thereby avoiding intramammary infections or inflammations.

[0023] Also interestingly, such intramammary administration of the composition of the invention makes it possible to improve the bioavailability of cabergoline in ruminants, allowing, when compared with intramuscular administration, the administration of lower doses of cabergoline while obtaining similar results and / or efficacy, or the administration of doses of cabergoline similar to those administered intramuscularly while obtaining higher results and / or efficacy.

[0024] Furthermore, the inventors have surprisingly noticed that a veterinary composition comprising cabergoline administered via the intramammary route also makes it possible to prevent or reduce hypocalcemia in ruminants during the dry period, in particular within the first 24 hours after cessation of milking, compared to cabergoline when administered by the IM route.

[0025] When the compositions are administered intramammarially to ruminants during the implementation of the dry period, they make it possible to maintain a blood calcium concentration of 2.1 mmol / l, or preferably 2.2 mmol / l or more in ruminants, without any specific diet, and more particularly without any dietary regime aimed at maintaining a sufficient blood calcium concentration in ruminants (for example diets with sufficient amounts of magnesium and balancing these diets to provide DCAD). Thus, the compositions used according to the invention prevent from hypocalcemia or reduce the risk of developing hypocalcemia, especially within the first 24 hours after dry-off, i.e. when the risk of developing hypocalcemia is high when using cabergoline by the IM route.

[0026] The present invention also relates to a method of reducing milk production in dairy ruminants, comprising intramammary administration of an effective therapeutic regimen of a veterinary composition, preferably upon implementation of the dry period.

[0027] Preferably, the veterinary composition is administered to dairy cattle.

[0028] The veterinary compositions for use according to the invention are more particularly administered intramammarily after the last milking, at dry-off. In certain embodiments, the veterinary compositions are preferably administered intramammarily after the last milking, more preferably within the first 5 hours, the first 4 hours or the first 2 hours after the last milking, preferably within the first 30 minutes (e.g. 15-20 minutes) after the last milking.

[0029] The veterinary compositions and methods according to the invention are attractive to farmers because their use is simple to implement and allows for a rapid cessation of milk production in the mammary gland without inducing udder engorgement. They also allow for sufficient blood calcium levels to be maintained without worrying about a specific blood calcium level increase regimen, as compared to when cabergoline is used by the IM route. The treatment of the invention results in savings in terms of simplified herd management and disease treatment costs when lactation resumes. Thus, administration of the compositions according to the invention allows for better management of the feeding program during the dry period.

[0030] Cabergoline, whose chemical name is N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propenyl)-8g-ergoline-8-carboxamide, is an antiprolactin agonist compound specific for the D2 dopamine receptor. It is described in particular in US 4,526,892. Its chemical structure is: [ka]

[0031] Cabergoline is the active ingredient in human drugs marketed under the names Dostinex® and Cabaser®. It is also the main active ingredient in a veterinary composition marketed under the name Galastop® for female dogs prone to lactation with pseudopregnancy. None of these cabergoline-based compositions, Dostinex® or Galastop®, are administered by the intramammary route.

[0032] The effective or therapeutic dose of cabergoline administered according to the present invention is likely to vary according to the ruminant being treated. The dosage, also called the treatment regimen, can be easily determined by systematic testing based on the following examples and is within the capabilities of the skilled artisan. According to certain embodiments of the present invention, the effective therapeutic dose according to the present invention is 1-50 μg / kg, or 5-50 μg / kg, preferably about 5-11 μg / kg, more preferably about 6-9 μg / kg.

[0033] More preferably, the amount of cabergoline administered intramammarily is between 0.25 and 7 mg, preferably between 0.3 and 6 mg, more particularly between 1 and 6 mg per dairy ruminant.

[0034] More preferably, the amount of cabergoline administered intramammarily is 2-7 mg, preferably 3-6 mg, more particularly 5-6 mg per dairy cow.

[0035] According to a particular embodiment, the amount of cabergoline administered intramammarily is between 2 and 4 mg, preferably between 3 and 3.5 mg, per dairy ruminant, preferably per dairy cow.

[0036] According to the present invention, the term "ruminant" refers to herbivorous mammals, such as, for example, cows, sheep, goats, camelids, or bovids. The compositions according to the present invention are preferably administered to milk-producing (or dairy) ruminant mammals, such as dairy cows, sheep, and goats, more preferably dairy cows.

[0037] Advantageously, the veterinary compositions of the present invention may be administered in association with standard care for treating and / or preventing intramammary inflammation and infection (such as mastitis) in ruminants. Examples of standard care or preventative compositions for mastitis are topical disinfectants for the udder, antibiotics such as penicillins, cephalosporins, gentamicin, or teat sealants.

[0038] As mentioned above, hypocalcemia is caused by a temporary blood calcium deficiency that usually occurs around the time of parturition when lactation resumes, but can also develop in other periods, especially within the first 48 hours and more frequently within the first 24 hours after dry-off of milk-producing ruminants after administration of cabergoline by the IM route. According to certain embodiments of the present invention, preventing and / or reducing hypocalcemia in dairy ruminants refers to a treatment in which the ruminant presents or achieves a sufficient blood calcium concentration, which is equal to or greater than 2.1 mmol / l, preferably 2.2 mmol / L.

[0039] The veterinary compositions are administered by the intramammary route. For this purpose, the veterinary compositions are administered to one or more quarters of the mammary gland by introduction of the composition via infusion, implantation, injection, or a combination thereof. Administration is generally performed through the teat canal by intramammary infusion. The implantation may be in the form of a solid, paste, gel, or suspension. The infusion or injection described herein may be by bolus injection or continuous infusion. The formulations for injection may be presented in unit dosage form, for example in ampoules or in multi-dose containers, optionally with added preservatives. The composition may be a suspension, solution, or emulsion in an oily or aqueous vehicle.

[0040] Preferably, the composition is administered to one or more, preferably all, quadrants of the mammary gland of a ruminant animal, for example, in dairy cows, it is administered to one, two, three or four quadrants of the udder, preferably all four quadrants.

[0041] Depending on the formulation of the compositions used, they may further comprise ingredients conventionally used in pharmacy for the preparation of liquid or solid formulations for intramammary administration.

[0042] The composition according to the invention can also contain solvents, glidants, lubricants, and any excipients, such as lactose, cellulose, or starch, in appropriate amounts, according to the type of formulation. Stearic acid, magnesium stearate, L-leucine, or, for example, glycerol tribehenate can be used as lubricants. Sodium carboxymethylamidon, cross-linked sodium carboxymethylcellulose, or cross-linked polyvinylpyrrolidone can be used as disintegrants. Pure silica or colloidal silicon dioxide can be used as lubricants. The solid oral form can be in the form of tablets covered with a coating.

[0043] The injectable preparation is prepared by mixing an effective therapeutic amount of at least one antiprolactin compound as described above with a solvent, a pH adjusting agent, a buffering agent, a suspending agent, a solubilizing agent, a stabilizer, an isotonic agent, and / or a preservative, and converting the mixture into a subcutaneous or intramuscular injection according to conventional methods. As the solvent, mention may be made of dimethyl sulfoxide (DMSO), an oily solvent such as a medium chain triglyceride, or a mixture of capric acid, caprylic acid, and triglycerides, such as that marketed under the name Mygliol® 812. If necessary, the injectable preparation can be lyophilized according to conventional methods. Examples of suspending agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, xanthan gum, sodium carboxymethylcellulose, and polyethoxylated sorbitan monolaurate. Examples of solubilizing agents include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester. Additionally, stabilizers include sodium sulfite, sodium metal sulfite, and ethers, and preservatives include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, benzyl alcohol, phenol, cresol, and chlorocresol. An example of an isotonicity agent is mannitol.

[0044] The present invention further relates to a kit for veterinary use, more particularly for reducing milk production in dairy ruminants. The kit according to the invention comprises at least one compartment, optionally in a sterile package, containing an effective therapeutic amount of cabergoline as described above, for intramammary administration to ruminants. The kit may also comprise a means allowing administration of the composition by the intramammary route, and / or instructions relating to the mode and time of administration of the veterinary composition.

[0045] All embodiments described above for the compositions and uses of said compositions also apply to the kits and methods of the invention.

[0046] Described herein below are examples, which are illustrative and not limiting in any way. EXAMPLES

[0047] Example 1: Effect of cabergoline by intramammary (IMM) route on milk production in dairy cows (continuation of milking context) The cabergoline composition is a solution containing cabergoline with dimethylsulfoxide and medium chain triglycerides as excipients. It corresponds to the product called Velactis™ (cabergoline 1.12 mg / mL).

[0048] Five lactating prim Holstein cows were included in the study and had the following characteristics: -Multiparous: Birth order 2-4 -Daily milk yield (L): 17.4+ / -2.8 - Days milked (d): 251+ / -51 -Weight(kg):686+ / -29

[0049] Cabergoline was administered as an oily solution as above, and an intramammary cannula was inserted into the teat canal and attached to the tip of a syringe containing the solution. A volume of 10 mL was deposited directly into each quadrant of the udder cistern. Velactis™ (cabergoline 1.12 mg / mL) was diluted with its excipient according to the test dose immediately prior to administration.

[0050] Cows were milked twice daily, in the morning and in the evening, at approximately 7 am and 5 pm, respectively.

[0051] Milk production (morning milking) was measured before (baseline) and during the days after treatment. In the D0 study, 3 / 5 cows were treated with vehicle only, showing that the vehicle had no effect on milk production.

[0052] Five cows were treated after the evening milking (D4), i.e., 15–20 min after the end of milking, with a dose of 1.34 mg / fourth divided into all four quarters (total dose of 5.4 mg / cow), corresponding to approximately 7.5 μg / kg, expressed according to kg body weight.

[0053] All five cows showed a sharp drop in milk production with an average of -6 L at the next morning milking (D5), representing a mean decrease of -54% (sd=10, min -38%, max -62%) compared to milk production baseline values ​​(D2-D4). Milk production then gradually increased over the following days (approximately -15% of baseline, 3 days after treatment), see Figure 1.

[0054] These results by the IMM route compare favorably with those obtained by the IM (intramuscular) route from another previously performed study, in which different IM doses were tested to establish a dose-effect relationship of cabergoline on reducing milk production. The results obtained were as follows: [Table 1]

[0055] Extrapolation of the dose-effect relationship at the 7.5 μg / kg IM dose yielded the predicted effect of -43% reduction in milk production, a result confirmed by another study (field controlled study, n=106) which found a reduction in milk production of approximately -40% for treated cows versus negative control cows.

[0056] Thus, it is concluded that cabergoline administered by IMM route at a dose of 1.34 mg / fourths in all four quarters shows a better effect on milk production reduction compared to a similar total dose of 5.6 mg / cow (i.e., about 75 μg / kg) administered by IM route, which is the registered dose of Velactis®. This better effect was similar to that observed with a higher IM dose of cabergoline (12 μg / kg). However, this high dose (12 μg / kg) by IM route is not practically used in ruminants. This conclusion is also supported by the pharmacokinetic results obtained in the study detailed below, which show the effect proportionality on milk production reduction associated with systemic cabergoline exposure (see Example 2.2). Moreover, the milk production reduction obtained by IMM route appeared to be more reliable and reproducible, since the sd, minimum, and maximum values ​​were less dispersed compared to those by IM route.

[0057] Example 2. Pharmacokinetics of cabergoline by the IMM route and effects on udder engorgement and blood calcium concentrations at dry-off in dairy cows. The study included 10 lactating dairy cows (9 prim Holsteins and 1 Brown Swiss). The cows were assigned to two groups: - Negative control group (n=5): No treatment at D0 dry-off - Study group (n=5): Cabergoline IMM treatment at D0 dry-off after last milking (1.34 mg / 4 in all 4 of 4 fractions - same modality as in Example 1) [Table 2]

[0058] No feed restrictions were imposed within the 3 weeks before or after D0 dry-off. Animals had free access to water and hay throughout the study. Each cow was fed 7 kg / day of lactating cow antibiotic-free concentrate until D0 dry-off. After dry-off, each cow was fed 7 kg / day of heifer antibiotic-free concentrate. The composition of the concentrate is shown below: [Table 3]

[0059] Sudden cessation of milking was performed on D0 dry-off.

[0060] Internipple circumference (ITP), considered a proxy for breast volume and engorgement, was measured pre-treatment, both before and after milking, and then uniformly post-treatment up to 9 days after treatment.

[0061] Blood was collected and cabergoline and calcium concentrations were evaluated at different time points: before treatment and up to 6 days after treatment for cabergoline and up to 3 days after treatment for calcium.

[0062] 2.1 Effect on ITP (breast engorgement): ITP in treated cows increased less than controls during the first 48 hours after treatment and was always lower than controls during follow-up after dry-off, as shown in Figure 2.

[0063] The results are also empirical when expressed as the difference in ITP (ΔITP), i.e. calculated by subtracting the ITP value after milking on D0 from the ITP value at each time point after dry-off, as illustrated in Figure 3.

[0064] These delta ITP results obtained with the IMM route are within the same range of efficacy as with the IM route, or somewhat better.

[0065] In another study under similar experimental conditions, by IM route, at the same total dose, the delta ITP results obtained can be compared with the IMM results as follows: [Table 4]

[0066] 2.2 Cabergoline blood concentration Following intramammary (IMM) administration of 5.4 mg / breast of cabergoline, the mean and sd plasma concentration-time profiles of cabergoline were as shown in FIG.

[0067] In a comparative study, cabergoline (Velactis™, 1.12 mg / ml) administered by intramuscular route at an equivalent dose (5.6 mg / cow) showed the plasma concentration time profile shown in FIG. 5 (Comparative Study).

[0068] The pharmacokinetic parameters from both studies are compared in the following table: [Table 5]

[0069] At an equivalent dose of 5.4 mg / calf (approximately 7.5 μg / kg), the AUC IMM Pathway / AUC IM It can be concluded that blood cabergoline bioavailability, as assessed by the ratio of routes, is higher via the IMM route than via the IM route.

[0070] Interestingly, in a dose-effect study as described in Example 1, AUCo-inf was: [Table 6]

[0071] These PK results together showed good linear proportionality between cabergoline doses (ranging from 1.33 to 12 μg / kg) and their AUC, and consequently between AUC and cabergoline effect on milk production reduction. It also showed that the dose exposure at 7 to 8 μg / kg by the IMM route was equivalent to that at 12 μg / kg by the IM route, explaining the better observed effect compared to the IM route at 7 to 8 μg / kg.

[0072] It is concluded that the IMM route is a method to improve cabergoline efficacy compared to the parenteral route (IM).

[0073] 2.3 Blood calcium concentration Compared to control cows (i.e., no cabergoline treatment, see animal characteristics, Example 2), cows treated with the cabergoline IMM route showed a slight decrease in blood calcium concentration (mean value of -0.2 mmol / L), limited only at the +6 hour time point. No decrease was observed at the pre (+3h) and post (+12h, +24h and beyond) time points.

[0074] Figure 6 shows the time evolution of blood calcium concentrations in both groups. These results are surprising compared to blood calcium concentrations after IM cabergoline treatment at the same total dose (5.6 mg / calf), which besides the IMM route showed a higher systemic exposure than the IM route described above (e.g., 2.2).

[0075] From a previous study conducted using a dose of 5.6 mg / bovine cabergoline by the IM route, a more significant reduction in blood calcium was observed in time and magnitude. The study was conducted in comparison to a negative control group, and blood calcium reduction was monitored and well identified. Calcium reduction was observed as early as 2-3 hours after treatment, up to 6-12 hours, and returned to normal after 24 hours.

[0076] FIG. 7 shows the difference in mean blood calcium relative to pre-treatment baseline values ​​as a function of time between the IMM study detailed above (top curve) and the IM studies (the two bottom curves, named IM studies 1 and 2 in the legend of FIG. 7).

[0077] It is important to note that the trial of Example 2, when compared to IM trials 1 and 2, provided the advantage of a lesser decrease in blood calcium levels, despite the lower amount of calcium provided by the diet. In these last two IM trials, 150 g calcium / day / cow was provided through a complete or partial mixed ration, whereas in the IMM trial of Example 2, only 50 g calcium was provided via concentrate (7 kg / day / cow at 0.7% Ca), the remainder was provided ad libitum via hay. The exact amount of Ca provided by the hay was unknown, but it was certainly less than the two IM trials, for the following reasons: i) The calcium content in hay is generally lower than in concentrates, usually around 0.3%. ii) The actual hay dry matter intake can be estimated to be about 13-15 kg for the cows included in Example 2.

[0078] The amount of calcium provided can be estimated to be about 100 g / d / cow in Example 2, which is clearly less than the 150 g of calcium provided in the two IM studies (the two lower curves, IM studies 1 and 2 in Figure 7).

[0079] Cabergoline use via the IMM route has the surprising ability to disturb calcium homeostasis less in dairy cows compared to the IM route at the same dose, and even in the context of less stringent dietary calcium recommendations.

[0080] Thus, cabergoline use by the IMM route has a better safety profile with regard to the risk of bovine recumbency due to any hypocalcemia associated with cabergoline treatment, while maintaining the same or better efficacy compared to the IM route for dry-off of dairy cows (according to the IMM dose selected for administration).

[0081] In conclusion, the IMM route is a way to improve the safety and efficacy of cabergoline for dry-off in dairy cows compared to the known IM route for this indication. IMM cabergoline administration allows to reduce milk production more efficiently than the IM route, which is explained by the higher blood cabergoline bioavailability. IMM cabergoline administration also allows to prevent ruminants from hypocalcemia during the dry period, more specifically shortly after dry-off (especially within the first 24 hours after the last milking).

Claims

1. A veterinary composition for reducing milk production in a dairy ruminant, said composition comprising cabergoline and administered to said dairy ruminant by intramammary route.

2. 10. The veterinary composition of claim 1, wherein the composition is administered during the dry period.

3. 2. The veterinary composition of claim 1, wherein the composition is administered at dry-off after the last milking or within the first 5, 4 or 2 hours after the last milking.

4. 4. The veterinary composition according to any one of claims 1 to 3, wherein the therapeutic dose of cabergoline is 1 to 50 μg / kg, 5 to 50 μg / kg, about 5 to 11 μg / kg, or about 6 to 9 μg / kg.

5. The veterinary composition of any one of claims 1 to 4, wherein the composition is administered to one or more quadrants of the mammary gland by introduction of the composition via infusion, implantation, injection, or a combination thereof.

6. The veterinary composition according to any one of claims 1 to 5, wherein the composition is administered to all four quadrants of the mammary gland of the ruminant.

7. 7. The veterinary composition according to any one of claims 1 to 6, wherein the amount of cabergoline administered intramammarily is 0.25 to 7 mg, 0.3 to 6 mg, or 1 to 6 mg per dairy ruminant.

8. 7. The veterinary composition according to any one of claims 1 to 6, wherein the amount of cabergoline administered intramammarily is 2 to 7 mg, 3 to 6 mg, or 5 to 6 mg per cow.

9. A veterinary composition according to any one of claims 1 to 8, characterized in that the ruminant is a herbivorous mammal selected from cattle, sheep, goats, camelids or bovids.

10. A veterinary composition according to any one of claims 1 to 8, wherein the ruminant is a milk-producing ruminant mammal.

11. The veterinary composition of claim 10, wherein the milk-producing ruminant mammal is a dairy cow, sheep, or goat.

12. 1. A kit for reducing milk production in a dairy ruminant, said kit comprising at least one compartment for packaging containing an effective therapeutic amount of cabergoline for intramammary administration to the ruminant.

13. 13. The kit of claim 12, further comprising a means allowing administration of the cabergoline composition by the intramammary route and / or instructions relating to the mode and time of administration of said veterinary composition.

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