Treatment methods for foot rot

Abstract

The present invention is a novel use of an injectable pharmaceutical composition containing tildipirosin for the treatment and prevention of foot rot. The use of a single subcutaneous dose of tildipirosin has been shown to effectively treat naturally occurring foot rot.

Description

Background Art

[0001] Foot rot in cattle is a necrotic disease that affects the connective tissue in the interdigital area and is caused by bacteria, mainly Fusobacterium necrophorum. Foot rot disorders are also common in sheep, goats, and pigs. These disorders cause the feet of animals, specifically the area between the two toes of the affected animal, to rot. They are accompanied by severe pain and are infectious. Foot infections affect the productivity and reproductive ability of animals and cause significant economic losses, especially in animals raised in intensive feedlot systems.

[0002] Tildipirosin is a semi-synthetic macrolide antibiotic and the active ingredient of Zuprevo (registered trademark). The IUPAC name of tildipirosin is (4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-[(2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-5,9,13-trimethyl-7-(2-piperidin-1-yl ethyl)-15-(piperidin-1-ylmethyl)-1-oxacyclohexadeca-11,13-diene-2,10-dione, and its structure is as follows.

[0003]

Chemical formula

[0004] Zuprevo® is a ready-to-use sterile injection containing 18% tildipyrosine, a semi-synthetic macrolide antibiotic, for the treatment and prevention of bovine respiratory disease. Each 1 mL of Zuprevo® contains 180 mg of tildipyrosine as a free base, 82.5 mg of citrate monohydrate, 400 mg of propylene glycol, and an appropriate amount of water with citrate monohydrate added to adjust the pH. This pharmaceutical composition is used for the treatment and prevention of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni, which are susceptible to tildipyrosine. See Freedom of Information, NADA 141-334, May 14, 2012.

[0005] Zuprevo® 4% Tildipyrosine Injection is available for the treatment of porcine respiratory disease (SRD) associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, and Haemophilus parasuis. This solution contains tildipyrosine as a free base at a concentration of 40 mg / mL, propylene glycol, citrate monohydrate, and water. See EPAR Summary for the Public, EMA / 166222 / 2011, revised February 2015.

[0006] WO2008 / 012343 discloses a method for producing tildipyrosine. WO2009 / 013351 discloses solvated and unsolvated forms of tildipyrosine. U.S. Patent No. 6,514,946 discloses the structure of tildipyrosine and its use for the treatment of various diseases in livestock and poultry.

[0007] Recent studies have shown that tildipirosin is rapidly absorbed and slowly excreted after a single subcutaneous administration to healthy lambs. It has been suggested that tildipirosin may be useful for the treatment and prevention of respiratory bacterial infections in sheep (see Abu-Basha, EA, et al., Pharmacokinetics and bioavailability of tildipirosin following intravenous and subcutaneous administration in sheep. J vet Pharmacol Therap. 2020;00:1-7. https: / / doi.org / 10.1111 / jvp.12901). [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] WO2008 / 012343 [Patent Document 2] WO2009 / 013351 [Patent Document 3] U.S. Patent No. 6,514,946 [Non-patent literature]

[0009] [Non-Patent Document 1] Freedom of Information, NADA 141-334, May14, 2012. [Overview of the project] [Problems that the invention aims to solve]

[0010] None of these references disclose the use of tildipyrosine for the treatment or prevention of hoof rot. [Means for solving the problem]

[0011] One embodiment of the present invention is an injectable pharmaceutical composition for use in the treatment and / or prevention of hoof rot in animals, comprising tildipyrosine, a salt or solvate thereof, and a pharmaceutically acceptable carrier. [Brief explanation of the drawing]

[0012] [Figure 1] This figure provides data on claudication in the tildipyrosine group and the control group. [Figure 2] This figure provides disease data for the tildipyrosin group and the control group. [Modes for carrying out the invention]

[0013] This invention represents a novel use of an injectable pharmaceutical composition containing tildipyrosine for the treatment and prevention of hoof rot. The use of tildipyrosine injection at a single subcutaneous dose of 4 mg of tildipyrosine per kg of body weight (BW) has been demonstrated to effectively treat spontaneously occurring hoof rot.

[0014] Treatment for hoof rot is useful in beef cattle raised in concentrated conditions, such as cattle kept in confinement at fattening farms.

[0015] The treatment is intended to reduce hoof lesions and lameness, mitigate infections, and prevent new infections caused by bacteria such as F. necrophorum. This invention has the potential to have a significant impact on farm productivity and animal welfare. Because the invention consists of a single treatment that reduces the need for animal restraint, it is advantageous for farm management. Furthermore, since tildipyrosin is also used in the treatment and prevention of bovine respiratory disease (BRD), it may help control two of the most important diseases in centralized beef cattle with a single treatment.

[0016] The present invention is also useful for treating hoof rot in pigs, offering the same advantages as described above for cattle, including ease of administration and the ability to treat or prevent two diseases with a single treatment.

[0017] One embodiment of the present invention is an injectable pharmaceutical composition for use in the treatment and / or prevention of foot rot in animals, comprising tilmicosin, a salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0018] In one embodiment of the present invention, the pharmaceutically acceptable carrier comprises one or more excipients.

[0019] In one embodiment of the present invention, the injectable pharmaceutical composition is a solution or a suspension.

[0020] In one embodiment of the present invention, the injectable pharmaceutical composition is a solution.

[0021] In one embodiment of the present invention, the excipient is one or more solvents.

[0022] In one embodiment of the present invention, the solvent is propylene glycol, water or a mixture thereof.

[0023] In one embodiment of the present invention, tilmicosin is in the form of a free base.

[0024] In one embodiment of the present invention, the pharmaceutical composition further comprises an acid, preferably citric acid.

[0025] In one embodiment of the present invention, the dosage of tilmicosin is about 1 mg / kg to about 10 mg / kg of animal body weight, or about 3 mg / kg to about 7 mg / kg, or preferably about 4 mg / kg.

[0026] In one embodiment of the present invention, the animal is a sheep, a goat, a cow or a pig, preferably a cow.

[0027] In another embodiment of the present invention, the animal is a pig.

[0028] In another embodiment of the present invention, the animal is a sheep.

[0029] In another embodiment of the present invention, the animal is a goat.

[0030] In one embodiment of the present invention, the concentration of tildipyrosine is about 10% by weight / volume to about 25% by weight / volume, or about 15% by weight / volume to about 20% by weight / volume, or preferably 18% by weight / volume.

[0031] In one embodiment of the present invention, the concentration of tildipyrosine is about 0.1% by weight / volume to about 9.9% by weight / volume, or about 2% by weight / volume to about 6% by weight / volume, or preferably 4% by weight / volume.

[0032] One embodiment of the present invention is an injectable pharmaceutical composition for use in the treatment and / or prevention of hoof rot in animals, wherein 1 mL of each composition is a) 180 mg of tildipyrosine as free base; b) Citric acid monohydrate 82.5 mg; c) Propylene glycol 400 mg; and d) an appropriate amount of water This is an injectable pharmaceutical composition containing [a specific ingredient].

[0033] In one embodiment of the present invention, the animal is a cow.

[0034] In one embodiment of the present invention, the injectable pharmaceutical composition is a suspension.

[0035] In one embodiment of the present invention, the injectable pharmaceutical composition comprises a salt or solvate of tildipyrosine.

[0036] Another embodiment of the present invention is a method for treating hoof rot in animals, comprising administering to the animal a pharmaceutical composition containing an effective amount of tildipyrosine.

[0037] In another embodiment, the pharmaceutical composition is administered intravenously.

[0038] In another embodiment, the method includes a single dose of the pharmaceutical composition.

[0039] In another embodiment, the effective dose of tildipyrosine is approximately 1 mg / kg to approximately 10 mg / kg of animal body weight.

[0040] In another embodiment, the effective dose of tildipyrosine is about 3 mg / kg to about 7 mg / kg, preferably about 4 mg / kg.

[0041] In another embodiment, the animal is a sheep, a goat, a cow, or a pig.

[0042] In another embodiment, the pharmaceutical composition further comprises one or more excipients.

[0043] In another embodiment, tildipyrosine is in the form of a free base.

[0044] In another embodiment, the pharmaceutical composition comprises a solvent selected from propylene glycol, water, or a mixture thereof.

[0045] In another embodiment, the pharmaceutical composition contains an acid.

[0046] In another embodiment, the acid is citric acid.

[0047] In another embodiment, use is by single injection. [Examples]

[0048] This study aimed to demonstrate the efficacy of tildipyrosin injection (Zuprevo®), used in bovine animals, administered subcutaneously at a single dose of 4 mg of the active ingredient per kg of body weight (BW), for the treatment of spontaneously occurring hoof rot.

[0049] Thirty animals were enrolled in a control group, and another 30 animals were enrolled in a tildipyrosine treatment group. The tildipyrosine treatment group received a single dose subcutaneously, while the control group was treated with sterile saline. Both groups (treatment group and control group) were raised in the same pasture under typical Brazilian fattening conditions.

[0050] Sixty animals were included in the trial in two different phases, according to the number of available animals that met the selection criteria. The trial was blinded; that is, the trial staff who performed post-treatment clinical evaluations, including lameness, were not informed of their treatment assignments. The animals were randomized and evenly distributed across the treatment groups according to 15 blocks of two animals each on both participation days (there were two participation days for the total of 60 animals).

[0051] The effectiveness of tildipyrosin for treating hoof rot was evaluated by comparing the treatment response / improvement rate in the tildipyrosin-treated group with that of the saline-treated control group on day 7.

[0052] There were no abnormal health findings before or after treatment. One adverse event, a broken toenail, was observed in one animal in the tildipirosin-treated group on day 7. According to the researchers, this adverse event was unrelated to tildipirosin administration, and the animal was excluded from the study.

[0053] The scoring for lameness and lesions is described in Tables 1 and 2 below.

[0054] Table 1: Guidelines for scoring lameness

[0055] [Table 1]

[0056] Table 2: Guidelines for scoring lesions

[0057] [Table 2]

[0058] The researchers assessed the animals' lesions and lameness scores on day -1 and day 0 of the study. To evaluate the effectiveness portion of the study, animals were diagnosed with hoof rot if they met the following criteria.

[0059] • The lameness score for at least one leg is ≥3 for two consecutive days. • Lesion score of ≥2 in at least one leg for two consecutive days. • Clinically healthy (excluding limping) • Weight (348-499 kg) • Animal age (20-24 months)

[0060] On day 0, bacteriological samples were taken from the infected hooves of registered cattle prior to treatment. Lesions and lameness were also evaluated on days 2, 4, and 7. The success, improvement, or failure of the treatment was determined on day 7, based on lameness and lesion scores compared to day 0. On day 7, another bacteriological sample was taken from all animals.

[0061] Bacteriological samples were collected using sterile scrapers and sterile cotton swabs from the boundary between healthy and necrotic tissue (around the hoof lesion) of infected hooves of registered cattle. The tip of the scraper containing the exudate from the lesion was broken off and placed in a 15 mL tube containing 7 mL of a semi-solid transport medium formulated specifically for anaerobic bacteria, and the swab was sent out for semi-solid transport. The test tubes were stored under refrigeration (4-8°C) until arrival in the laboratory. In the laboratory, the samples were grown in media suitable for the isolation of F. necrophorum and Dichelobacter nodosus. Isolated strains were identified using confirmatory biochemical tests and polymerase chain reaction (PCR) specific to F. necrophorum and D. nodosus species.

[0062] The tildipyrosine-treated group showed a reduction in symptom scores for both lameness and lesions. In the treatment group, the mean lameness score of the animals was 3.1 on day 0. This group's lameness score decreased to 1.3 by day 7. For lesion scores, the mean score of the treated group animals on day 0 was 2.3, which decreased to 1.9 by day 7. In contrast, the mean lameness score of the control group on day 0 was 3.1, which only decreased to 2.4 by day 7. Their mean lesion score of 2.3 on day 0 increased slightly to 2.4 by day 7.

[0063] Figure 1 provides lameness score data. Both the treatment group and the control group had the same mean score (3.1). After treatment, the groups exhibited different behaviors. The score of the tildipirosin-treated animals decreased to 1.3, while the control group's score remained at 2.4. As shown in Figure 1, it is clear that tildipirosin treatment improved the score evaluation in the tildipirosin-treated animals.

[0064] Figure 2 shows the lesion score data. Before treatment, lesion scores were similar in both groups: 2.3 in the tildipyrosin treatment group and 2.2 in the control group. However, there were noticeable differences in the behavior of each group after the evaluation on day 7. In the control group, the lesion score increased (2.4), in other words, worsened, while in the tildipyrosin-treated animals, the lesion score decreased (1.9), bringing them closer to clinical resolution.

[0065] Although the bacterial assessment was not conclusive, compared to the control group, a greater number of tildipyrosin-treated animals that were positive for Fusobacterium necrophorum PCR identification before treatment became negative after treatment, and a smaller number of tildipyrosin-treated animals that were previously negative became positive.

Claims

1. A pharmaceutical composition for injection comprising tildipyrosine, a salt or solvate thereof, and a pharmaceutically acceptable carrier, for use in the treatment and / or prevention of hoof rot in bovine animals.

2. The pharmaceutical composition for injection according to claim 1, wherein the pharmaceutically acceptable carrier comprises one or more excipients.

3. The injectable pharmaceutical composition according to any one of claims 1 to 2, wherein the injectable pharmaceutical composition is a solution or a suspension.

4. The injectable pharmaceutical composition according to claim 3, wherein the injectable pharmaceutical composition is a solution.

5. The pharmaceutical composition for injection according to claim 4, wherein the excipient is one or more solvents.

6. The pharmaceutical composition for injection according to claim 5, wherein the solvent is propylene glycol, water, or a mixture thereof.

7. The injectable pharmaceutical composition according to any one of claims 1 to 6, wherein the tildipyrosine is in the form of a free base.

8. The injectable pharmaceutical composition according to claim 7, wherein the injectable pharmaceutical composition further comprises an acid.

9. The injectable pharmaceutical composition according to claim 8, wherein the acid is citric acid.

10. The injectable pharmaceutical composition according to any one of claims 1 to 9, wherein the dose of tildipyrosine is about 1 mg / kg of animal body weight to about 10 mg / kg of animal body weight, or about 3 mg / kg to about 7 mg / kg, or preferably about 4 mg / kg.

11. The injectable pharmaceutical composition according to claim 4, wherein the concentration of tildipyrosine is about 10% by weight / volume to about 25% by weight / volume, about 15% by weight / volume to about 20% by weight / volume, preferably 18% by weight / volume.

12. A pharmaceutical composition for injection for use in the treatment and / or prevention of hoof rot in bovine animals, wherein per mL of the composition, a) 180 mg of tildipyrosine as a free base; b) 82.5 mg of citric acid monohydrate; c) Propylene glycol 400 mg; and d) an appropriate amount of water A pharmaceutical composition for injection containing the following:

13. The injectable pharmaceutical composition according to claim 3, wherein the injectable pharmaceutical composition is a suspension.

14. The pharmaceutical composition for injection according to claim 13, comprising a salt or solvate of tildipyrosine.

15. The injectable pharmaceutical composition according to any one of claims 1 to 14, wherein the use described above is a single injection.

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