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    • 专利摘要:
    Veterinary composition for ruminants. The present invention refers to a composition that comprises a combination of eprinomectin with other active principles, such as meloxicam and danofloxacin, which allow a synergistic action of said principles, increasing the therapeutic action. This composition has a synergistic antiparasitic and anti-inflammatory or antibiotic effect useful in the treatment of ruminants. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2863583A1
    申请号:ES202030290
    申请日:2020-04-08
    公开日:2021-10-11
    发明作者:De Felipe Ana I Alvarez；Merino Peláez Gracia；Mateos Dafne García；LINO ALBA Mª GARCÍA
    申请人:Universidad de Leon；
    IPC主号:
    专利说明:

    [0002] FIELD OF THE INVENTION
    [0004] The present invention belongs to the technical field of veterinary medicine. More specifically, the present invention provides a composition comprising a combination of active principles, with a synergistic effect, for the treatment of animal health.
    [0006] BACKGROUND OF THE INVENTION
    [0008] Macrocyclic lactones with anthelmintic activity are antiparasitic drugs with remarkable broad spectrum activity, widely used for the treatment of internal and external parasites in animals and humans.
    [0010] One of the advantages of macrocyclic lactones is that, due to their lipophilicity, they are distributed throughout the body in the blood and lymphatic circulation, which produces a long persistence in the host organism and, therefore, a long period of protection. against parasitic infection [1,2]. Macrocyclic lactones are poorly metabolized in vivo and their elimination is mainly through the faeces. Furthermore, macrocyclic lactones are intensively secreted into milk during lactation, causing very long suppression times in dairy cattle.
    [0012] A large number of the macrocyclic lactones have been developed to overcome the disadvantages of using these drugs. In fact, a macrocyclic lactone has been developed whose secretion in milk is very low, and its suppression time is zero, eprinomectin [3]. Eprinomectin is a macrocyclic lactone considered as a semisynthetic drug derived from avermectin B1 (abamectin), which has a broad spectrum activity against endoparasites and exoparasites, nematodes and arthropods.
    [0014] Unlike other avermectins such as ivermectin or doramectin, eprinomectin has a low elimination rate in milk due to its chemical structure, which prevents passage to the mammary gland and results in a low residue in milk [3]. This low residue in milk is the reason why it is one of the few licensed dewormers for use in veterinary therapy, being administered in cows, sheep and dairy goats due to the lack of a withdrawal period in milk.
    [0016] The rest of the macrocyclic lactones have variable suppression periods, specifically that of ivermectin is 20 days. This represents an economic loss for the livestock sector, but is necessary for the food safety of the product.
    [0018] There is multiple scientific evidence on the molecular interaction of anthelmintics of the macrocyclic lactone family with a special type of transporter, membrane proteins, called ABC (ATP-Binding-Cassette). These transporters participate in a multitude of cellular functions, actively removing, exporting, through the hydrolysis of ATP, their substrates outside the cells (Exporter Transporters).
    [0020] The importance of their study lies in the fact that they participate in cellular resistance to a multitude of drugs and that the interaction between drugs and transporters can significantly alter the processes of "ADME" of drugs, being able to modify their "Absorption, Availability, Metabolism and Elimination ”.
    [0022] Ivermectin, one of the main macrocyclic lactones, was initially described as a substrate for P-glycoprotein (P-gp), later it was found that it also acted as a very potent inhibitor of this same transporter, interfering with the transport of other substrates of the P-gp. This example serves to illustrate the complexity of the molecular interactions that can occur between different types of drugs and these transporters when they act as substrates being expelled from the cells, a process that can be altered by co-administering another drug that acts as an inhibitor on the transporter.
    [0024] It is usual in veterinary therapy that drugs are administered concomitantly, which can affect the pharmacokinetics, pharmacodynamics and elimination of the compounds due to the interaction between them and ABC transporters, among other factors.
    [0026] Drug interaction with ABCG2 is very important in dairy cattle, since the expression of ABCG2 in the mammary gland is induced during lactation and is implicated in the presence of residues in milk with potential risk for consumers [4] . In fact, ABCG2 plays an important role in the active secretion of many drugs in the milk of cattle, sheep, and goats [6-9].
    [0027] Drug interactions mediated by ABC transporters with macrocyclic lactones have been described. For example, the combination of two antiparasitic drugs, such as moxidectin and triclabendazole, has been reported to cause a decrease in the presence of moxidectin in milk due to the inhibition of ABCG2 caused by triclabendazole [5].
    [0029] However, in the state of the art there is no concomitant administration as the only formulation of eprinomectin (as an antiparasitic) and other pharmaceutical compounds, with which synergistic results are obtained from this co-administration.
    [0031] DESCRIPTION OF THE INVENTION
    [0033] The present invention solves the existing problems in the state of the art by means of a veterinary composition that comprises a combination of active principles, which when applied together allow a synergistic action of said principles, increasing or optimizing the therapeutic action.
    [0035] In a first aspect, the present invention provides a veterinary composition, characterized in that it comprises eprinomectin and an active principle selected from meloxicam or danofloxacin.
    [0037] The joint administration as the only formulation of two compounds that are currently given separately, the anti-inflammatory meloxicam and the anti-parasite eprinomectin, ensures a longer time of action of the anti-inflammatory and its analgesic action together with the antiparasitic action of the endectocide.
    [0039] This antiparasitic does not have a withdrawal period in milk because it does not pass into it, which is a great advantage in food safety and in the economy of the livestock sector and makes it a compound with great potential in animal health. On the other hand, the increasing demand in the animal welfare guidelines in the various farms has notably increased the use of NSAIDs and among them, one of the most important is meloxicam.
    [0041] In another aspect of the invention, in the composition of the present invention, eprinomectin and meloxicam are found in a ratio of 1: 0.5 per mg / kg.
    [0042] Similarly, it has been observed for the antibiotic danofloxacin and the antiparasitic eprinomectin, ensuring greater efficacy of the antibiotic together with the antiparasitic action of the endectocide.
    [0044] In another aspect of the invention, in the composition of the present invention, eprinomectin and danofloxacin are in a ratio of 0.5: 1.25 per mg / kg.
    [0046] In another aspect of the invention, the composition is administered subcutaneously.
    [0048] In a last aspect, the composition described above is used in ruminants, more specifically in cows, goats and sheep.
    [0050] BRIEF DESCRIPTION OF THE FIGURES
    [0052] Figure 1. Plot of plasma concentration versus time curve for meloxicam obtained from lactating Assaf sheep treated with a single dose of 0.5 mg / kg (subcutaneous) of meloxicam and sheep treated with 0.5 mg / kg of meloxicam co-administered with Eprinomectin at 1 mg / kg (subcutaneous).
    [0054] Figure 2. Plot of plasma concentration versus time curve for danofloxacin obtained from lactating Assaf sheep treated with a single dose of 1.25 mg / kg (subcutaneous) of danofloxacin and sheep treated with 1.25 mg / kg of danofloxacin administered. together with eprinomectin at 0.5 mg / kg (subcutaneous).
    [0056] DESCRIPTION OF IMPLEMENTATION MODES
    [0058] The following are studies conducted on the effect of co-administration of eprinomectin with meloxicam and danofloxacin.
    [0060] Example 1. Pharmacokinetic study of the veterinary composition: Eprinomectin and Meloxicam
    [0062] Lactating sheep of the Assaf breed (3-4 months in lactation) and weighing 70 to 85 kg were used. No differences were found in age, weight or milk production between the groups of ewes. The animals were free of parasites and drinking water was available at will. The normal milking routine for all the animals involved drinking milk twice a day.
    [0064] The study was carried out with animals divided into 2 groups:
    [0065] i. the first group (n = 6) received a single subcutaneous dose of 0.5 mg / kg meloxicam (Metacam® 20 mg / ml);
    [0066] ii. the second group (n = 6) was injected subcutaneously with 0.5 mg / kg of meloxicam (Metacam® 20 mg / ml) and was co-administered with a single subcutaneous dose of eprinomectin (Eprecis®) at 1 mg / kg .
    [0068] Blood samples were collected from the jugular vein prior to each treatment at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after meloxicam administration. Plasma was separated by centrifugation at 3000 x g for 15 min. Plasma samples were stored at -20 ° C until analysis by high performance liquid chromatography (HPLC).
    [0070] In sheep treated with meloxicam (0.5 mg / kg), plasma levels were significantly higher in animals treated with eprinomectin (1 mg / kg) compared to the control group (only meloxicam) at 6, 8, 10, 12, 24, 30 and 72 hours after the administration of meloxicam (Figure 1). The maximum plasma concentration (Cmax) and the time required to reach this concentration (Tmax) are significantly longer for animals treated with eprinomectin compared to animals treated with meloxicam alone (Table 1). Furthermore, significant differences in the pharmacokinetic parameters AUC ( 0 - 96 h) and AUC ( 0 - «) were found between two experimental groups of animals. These results clearly show that co-administration of eprinomectin at a dose of 1.25 mg / kg influences the systemic distribution of meloxicam in sheep.
    [0072] Table 1. Mean pharmacokinetic parameters (± standard deviation) of meloxicam in
    [0073] plasma after subcutaneous administration at a dose of 0.5 mg / kg in sheep
    [0074] co-administered subcutaneously with 1mg / kg of eprinomectin.
    [0076]
    [0077]
    [0079] statistically significant differences p <0.05 (Student's t)
    [0081] In conclusion, the joint administration of eprinomectin and the active principles danof! Oxacin and me! Oxicam results in an increase in the concentration in the! p! asthma of said active principles,! or which translates into a greater availability and efficacy of these in co-administration with eprinomectin.
    [0083] Example 2. Pharmacokinetic study of the veterinary composition: Eprinomectin and Danofloxacin
    [0085] Sheep of the Assaf! Actant breed (3-4 months old) and weighing 70 to 85 kg were used. No differences were found in age, weight or milk production between the groups of ewes. The animals were free of parasites and drinking water was available ad libitum. The normal milking routine for all the animals involved drinking milk twice a day.
    [0087] The study was carried out with animals divided into 2 groups:
    [0088] i. the first group (n = 6) received a single subcutaneous dose of 1.25 mg / kg of danofloxacin (Advocin® 2.5%);
    [0089] ii. the second group (n = 6) was injected subcutaneously with 1.25 mg / kg of danofloxacin (Advocin® 2.5%) and was co-administered with a single subcutaneous dose of eprinomectin (Eprecis®) at 0.5 mg / kg.
    [0091] Blood samples were collected from the jugular vein before each treatment at 0.25, 1.2, 3.75, 6.25, 8, 9.5, 12, 24.32, and 48 hours after danofloxacin administration. Plasma was separated by centrifugation at 3000 x g for 15 min. Plasma samples were stored at -20 ° C until analysis by high performance liquid chromatography (HPLC).
    [0093] In sheep treated with danofloxacin (1.25 mg / kg) there were significant differences in plasma levels between the control group (only danofloxacin) and the group treated with eprinomectin at 4 and 24 hours after the administration of danofloxacin (Figure 2 ).
    [0094] In addition, the values of the area under concentration (AUC o-48h) and the area under concentration (AUC o- «) increased significantly in the animals treated with eprinomectin (Table 2). Cmax represents the maximum concentration reached and Tmax the time at which the maximum concentration is reached. MRT is the residence time (or residence) is the time that the drug molecules reside in the body or that it takes to leave it
    [0096] This result shows that the co-administration of eprinomectin affects the systemic distribution of danofloxacin in sheep, increasing its plasma levels, directly related to its antimicrobial activity.
    [0098] Table 2. Mean pharmacokinetic parameters (± standard deviation) of danofloxacin
    [0099] in plasma after subcutaneous administration at a dose of 1.25 mg / kg in
    [0100] sheep co-administered subcutaneously with 0.5 mg / kg of eprinomectin.
    [0102]
    [0104] * statistically significant differences p <0.05 (t of Stuc ent)
    [0105] BIBLIOGRAPHIC REFERENCES
    [0107] [1] Chiu SH, Taub R, Sestokas E, Lu AY, Jacob TA. Comparative in vivo and in vitro metabolism of ivermectin in steers, sheep, swine, and rat. Drug Metab Rev 1987; 18: 289-302.
    [0108] [2] Craven J, Bjorn H, Hennessy DR, Friis C. The effects of body composition on the pharmacokinetics of subcutaneously injected ivermectin and moxidectin in pigs. J Vet Pharmacol Ther 2002; 25: 227-32.
    [0109] [3] Baoliang P, Yuwan W, Zhende P, Lifschitz AL, Ming W. Pharmacokinetics of Eprinomectin in Plasma and Milk following Subcutaneous Administration to Lactating Dairy Cattle. Vet Res Commun 2006; 30: 263-70.
    [0110] [4] Pavek P, Merino G, Wagenaar E, Bolscher E, Novotna M, Jonker JW, et al. Human breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo (4,5-b) pyridine, and transport of cimetidine. J Pharmacol Exp Ther 2005; 312: 144-52.
    [0111] [5] Barrera B, González-Lobato L, Otero JA, Real R, Prieto JG, Álvarez AI, et al. Effects of triclabendazole on secretion of danofloxacin and moxidectin into the milk of sheep: Role of triclabendazole metabolites as inhibitors of the ruminant ABCG2 transporter. Vet J 2013; 198: 429-36. https://doi.org/10.1016/j.tvjl.2013.07.033.
    [0112] [6] Mealey KL. ABCG2 transporter: therapeutic and physiologic implications in veterinary species. J Vet Pharmacol Ther 2012; 35: 105-12.
    [0113] [7] Halwachs S, Wassermann L, Honscha W. A novel MDCKII in vitro model for assessing ABCG2-drug interactions and regulation of ABCG2 transport activity in the caprine mammary gland by environmental pollutants and pesticides. Toxicol Vitr 2014; 28: 432-41.
    [0114] [8] Garcia-Mateos D, Garcia-Lino AM, Alvarez-Fernandez I, Blanco-Paniagua E, de la Fuente A, Alvarez AI, et al. Role of ABCG2 in secretion into milk of the anti-inflammatory flunixin and its main metabolite: in vitro-in vivo correlation in mice and cows. Drug Metab Dispos 2019; 47: 516-24.
    [0115] [9] García-Lino AM, Álvarez-Fernández I, Blanco-Paniagua E, Merino G, Álvarez AI.
    [0116] Transporters in the Mammary Gland— Contribution to Presence of Nutrients and Drugs into Milk. Nutrients 2019; 11: E2372.
    权利要求:
    Claims (6)
    [1]
    1. Veterinary composition, characterized in that it comprises eprinomectin and an active principle selected from meloxicam or danofloxacin.
    [2]
    The composition according to claim 1, characterized in that it comprises eprinomectin and meloxicam in a ratio 1: 0.5 per mg / kg.
    [3]
    3. The composition according to claim 1, characterized in that it comprises eprinomectin and danofloxacin in a ratio 0.5: 1.25 per mg / kg.
    [4]
    4. The composition according to any of the preceding claims, which is administered subcutaneously.
    [5]
    The composition according to any of the preceding claims, for use in ruminants.
    [6]
    6. The composition according to claim 5, wherein said ruminants are selected from the group consisting of cows, goats and sheep.
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