Quetiapine or a composition comprising quetiapine for use in treatment of animals and a veterinary composition comprising quetiapine

Abstract

The invention relates to quetiapine, a salt or solvate thereof, or a composition comprising quetiapine, a salt or solvate thereof for use in treatment, characterized in that it is used in the treatment of animals. The invention also relates to a composition comprising quetiapine, a salt or solvate thereof, characterized in that it is in a veterinary-acceptable dose and form.

Description

[0001] QUETIAPINE OR A COMPOSITION COMPRISING QUETIAPINE FOR USE IN TREATMENT OF ANIMALS AND A VETERINARY COMPOSITION COMPRISING QUETIAPINE

[0002] The invention relates to quetiapine, a salt or solvate thereof, or a composition comprising quetiapine, a salt or solvate thereof for use in the treatment of animals. The subject of the invention is also a composition comprising quetiapine, a salt or solvate thereof, in a veterinary-acceptable dose and form. The invention will find application in veterinary medicine, particularly in animal medicine, especially for reducing aggression, for sedation, and as a hypnotic.

[0003] Quetiapine was first synthesized and patented in 1987 (US4879288). Since then, despite the passage of almost 40 years since its discovery, quetiapine has been used exclusively in human therapy. Furthermore, according to the summary of product characteristics, quetiapine is indicated for the treatment of schizophrenia and bipolar disorder - diseases specifically related to humans. Quetiapine itself has been tested in animals solely to determine the toxicity (of high doses) required by law for human medications. Until now, both the results of the aforementioned toxicological studies and the current perception of quetiapine (even among veterinarians and animal toxicology services) have clearly perceived and presented quetiapine as an undesirable and potentially dangerous source of animal poisoning, with beneficial effects only in humans with psychiatric problems, rather than as a promising veterinary medicine.

[0004] Meanwhile, during their research, the inventors unexpectedly discovered that quetiapine can be effectively and safely used in animal therapy. The present invention provides a long-undiscovered, nonobvious new veterinary use for quetiapine — specifically, for reducing aggression and / or for sedation and / or as a hypnotic. Thus, the present invention solves the long-unsolved technical problem of providing a new (alternative and / or potentially more advantageous) substance and composition for use in treating aggression, improving socialization, inducing sedation, and as a hypnotic in various animal species, including — particularly importantly — farm and pet animals. The subject of the invention is quetiapine, a salt or solvate thereof or a composition comprising quetiapine, a salt or solvate thereof for use in treatment, characterized in that it is used in the treatment of animals.

[0005] Preferably, quetiapine or composition comprising quetiapine for use in the treatment according to the invention is characterized in that it is used for the treatment of farm animals, in particular poultry, pigs, cattle, horses and / or pets, in particular dogs and cats.

[0006] Preferably, quetiapine or composition comprising quetiapine for use in the treatment according to the invention is characterized in that it is used to reduce aggression and / or for sedation and / or as a hypnotic.

[0007] More preferably, quetiapine or composition comprising quetiapine for use in the treatment according to the invention is characterized in that it is used to reduce aggression at a dose from 0.5 mg / kg b.w. to 2 mg / kg b.w.

[0008] Even more preferably, quetiapine or composition comprising quetiapine for use in the treatment according to the invention is characterized in that it is used to reduce aggression at a dose of 0.5 mg / kg b.w.

[0009] More preferably, quetiapine or composition comprising quetiapine used in the treatment according to the invention is characterized in that it is used for sedation at a dose from 1 mg / kg b.w. to 10 mg / kg b.w.

[0010] Even more preferably, quetiapine or composition comprising quetiapine for use in the treatment according to the invention is characterized in that it is used for sedation at a dose of 2 mg / kg b.w.

[0011] More preferably, the quetiapine or composition comprising quetiapine for use in the treatment according to the invention is characterized in that it is used for as a hypnotic at a dose from 5 mg / kg b.w. to 15 mg / kg b.w.

[0012] Even more preferably, quetiapine or composition comprising quetiapine for use in the treatment according to the invention is characterized in that it is used as a hypnotic at a dose of 5 mg / kg b.w.

[0013] Preferably, quetiapine or composition comprising quetiapine for use in the treatment according to the invention is characterized in that it is administered in combination with another veterinary-acceptable active substance, preferably acting on the nervous system.

[0014] The subject of the invention is also a composition comprising quetiapine, a salt or a solvate thereof, characterized in that it is in a veterinary-acceptable dose and form. Preferably, the composition according to the invention is characterized in that it is in veterinary solid form or in a veterinary liquid form.

[0015] More preferably, the composition according to the invention is characterized in that the veterinary solid form is selected from a tablet, a capsule, a powder, a granulate, micropellets or a food or feed additive.

[0016] More preferably, the composition according to the invention is characterized in that the veterinary liquid form is selected from a liquid concentrate, an oral liquid or an injectable preparation.

[0017] Preferably, the composition according to the invention is characterized in that it is in a modified release form, preferably delayed, accelerated, controlled or extended release.

[0018] In this application, the abbreviation b.w. stands for body weight.

[0019] The term "quetiapine" refers to quetiapine and its active metabolites, including norquetiapine, and their pharmaceutically acceptable salts — in particular fumarate, hemifumarate, maleate, hydrochloride — and solvates. The invention encompasses the use of racemic mixtures, for example, equal amounts of enantiomers quetiapine, as defined above. Furthermore, the invention encompasses quetiapine enriched with a selected enantiomer of quetiapine. The invention also includes substantially pure enantiomers of quetiapine. Of particular note are enantiomerically pure embodiments of the more active isomer. Quetiapine, as defined above, may contain additional chiral centers. The use of this invention includes racemic mixtures, as well as enriched and substantially pure stereo configurations at these additional chiral centers. Reference to quetiapine in this application includes enantiomers, salts, and solvates, as well as N-oxides thereof, which may be prepared by conventional methods.

[0020] The terms "combination" and "co-administration" refer to the administration of an active substance or a composition comprising it with at least one additional active substance or composition comprising it. Such administration may take place in a time-separated manner or simultaneously by administering two or more active substances or compositions comprising these substances at the same time. In such a case, the active substances or compositions comprising them may be part of a single formulation that is a combination or mix of these active substances or compositions comprising them, or they may be separate formulations (co-administered at the same time).

[0021] The term "reduce aggression" generally refers to a calming effect, a reduction in anxiety level, a reduction of aggression, and an increase in socialization, both with other animals and with people. Reduction of aggression, as defined in the application, encompasses various levels, ranging from a mild reduction of aggression, anxiety, and improved calmness and socialization, to a profound reduction of aggression with associated psychomotor impairment, loss of consciousness, memory loss, confusion, and stupor.

[0022] The term "sedation" generally refers to an effect intended to calm, reduce anxiety, consciousness and sometimes induce amnesia. Sedation, as defined in this application, encompasses various levels, ranging from mild sedation and anxiety reduction to profound sedation with associated psychomotor impairment, loss of consciousness, memory loss, confusion, and stupor.

[0023] The present invention provides a new, unexpected, and long-undiscovered veterinary use of quetiapine. Quetiapine or a composition comprising quetiapine for use according to the invention is particularly beneficial in the treatment of aggression, inducing sedation, and use as a hypnotic in animals. Equally advantageous, quetiapine or a composition comprising quetiapine for use according to the invention is effective and safe in various animal species, including particularly important farm and domestic animals. Finally, due to lack of patent protection of the molecule, wide availability, and long presence on the market, the invention not only provides a new and alternative veterinary medicine for use in the aforementioned indications but is also more accessible, less expensive, and more researched than unavailable, expensive, and insufficiently understood future chemical compounds.

[0024] The invention will be described in more detail in the following preferred and nonlimiting embodiments.

[0025] In one embodiment, a composition comprising quetiapine, a salt or solvate thereof was administered in a veterinary-acceptable dose and form. A composition comprising quetiapine, a salt or solvate thereof according to the invention is prepared by conventional methods known in the art. These methods include, without departing from the scope of the invention: mixing, granulation, calibration, drying, tableting, coating, micropelletizing, encapsulating, dissolving, suspending, etc. In this case, the composition according to the invention was prepared by mixing the ingredients until a visually homogeneous mixture was obtained and confirmed by analytical homogeneity tests, calibration of the mixture on 0.5 mesh sieves, and finally tableting on a rotary tableting machine (I KA Pressima, oval punches) using dosing and tableting parameters to obtain pharmacopoeial-acceptable tablets (i.e., appropriate hardness, friability, and solubility). In a preferred embodiment, the composition according to the invention was in a veterinary solid form. A non-limiting embodiment of such a veterinary solid dosage form is a tablet developed for the above embodiment having a composition according to Table 1 below.

[0026] Table 1. Preferred embodiment of the solid composition according to the invention.

[0027] Without departing from the scope of the invention, the veterinary solid form of the composition according to the invention may be modified accordingly. In preferred embodiments, the veterinary solid form of the composition according to the invention was in the form of a tablet, capsule, powder, granulate, micropellets or a food or feed additive. A non-limiting embodiment of such a preferred veterinary solid form was a feed additive having the following composition according to Table 2 below.

[0028] Table 2. Preferred embodiment of the solid composition according to the invention.

[0029] In another preferred embodiment, the composition of the invention was in a veterinary liquid form. A non-limiting embodiment of such a veterinary liquid form is an oral liquid formulated for the above embodiment having the following composition as shown in Table 3 below. Table 3. Preferred embodiment of the liquid composition according to the invention.

[0030] Without departing from the scope of the invention, the veterinary liquid form of the composition according to the invention may be modified accordingly. In preferred embodiments, the veterinary liquid form of the composition according to the invention is in the form of a liquid concentrate, an oral liquid or an injectable preparation.

[0031] Without departing from the scope of the invention, the veterinary solid form or the veterinary liquid form of the composition of the invention may be modified accordingly. In the preferred embodiments, the veterinary solid form and the veterinary liquid form of the composition of the invention are in a modified release form. In one preferred embodiment, the modified release form has a delayed release profile. In another preferred embodiment, the modified release form has an accelerated release profile. In another preferred embodiment, the modified release form has a controlled release profile. In yet another preferred embodiment, the modified release form has an extended release profile. The modified release form of the composition comprising quetiapine, a salt or a solvate thereof according to the invention is prepared by conventional methods known in the art. These methods include, without departing from the scope of the invention: micropelletization, micronization, coating (e.g. with commercially available universal coatings for modified release), adding excipients accelerating or delaying disintegration, etc. In this case, the composition according to the invention was prepared by coating the prepared and abovedescribed tablets with a commercially available EC coating (for delayed enteric administration). The coating was applied in a drum coater (of our own production) until a 2% increase in the weight of the tablets was reached.

[0032] In one embodiment, quetiapine for use in the treatment of the invention is used in the treatment of animals. Such quetiapine for use in the invention may be in the form of any pharmaceutically acceptable salt (e.g., fumarate ), solvate, or quetiapine. In a preferred embodiment, quetiapine, a salt or solvate thereof for use in the invention is part of a composition. Non-limiting examples of such compositions are given in the embodiments above. Such a composition for use has the advantages of, among others, facilitating dosing and increasing acceptability, e.g. by liver flavoring. In one embodiment, quetiapine or a composition comprising quetiapine used in the treatment according to the invention was used to reduce aggression. In a preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 0.5 mg / kg b.w. In another preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 1 mg / kg b.w. In yet another preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 2 mg / kg b.w. The dose depended on the desired degree of effect - mild, moderate, or large reduction of aggression, respectively. In an even more preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 0.5 mg / kg b.w.

[0033] In another embodiment, quetiapine or a composition comprising quetiapine used in the treatment according to the invention was used for sedation. In a preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of

[0034] 1 mg / kg b.w. In another preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 5 mg / kg b.w. In yet another preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 10 mg / kg b.w. The dose depended on the required degree of effect - light, medium and deep sedation, respectively. In an even more preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of

[0035] 2 mg / kg b.w.

[0036] In yet another embodiment, quetiapine or a composition comprising quetiapine used in the treatment according to the invention was used as a hypnotic. In a preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 5 mg / kg b.w. In another preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 10 mg / kg b.w. In yet another preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 15 mg / kg b.w. The dose depended on the desired degree of effect - light, medium and deep sleep, respectively. In an even more preferred embodiment, quetiapine or a composition comprising quetiapine was used for this purpose at a dose of 5 mg / kg b.w. In yet another embodiment, quetiapine or a composition comprising quetiapine used in the treatment of the invention was used to reduce aggression and simultaneously provide sedation and as a hypnotic. The dose was dependent on the desired degree of effect.

[0037] To test the efficacy of the invention, quetiapine or a composition comprising quetiapine according to the invention was administered to selected animals. The study assessed the reduction of aggression, sedation, and hypnotic effects of quetiapine or a composition comprising quetiapine by assessing animals' mobility and sleepiness overtime. Mobility was graded on a five-point scale as shown in Table 4 below.

[0038] Table 4. The scale of effectiveness of using quetiapine or a composition comprising quetiapine according to the invention on reducing aggression, sedation and sleepiness in animals

[0039] In one embodiment, quetiapine or a composition comprising quetiapine used in the treatment of the invention was administered to pets. In one embodiment, quetiapine or a composition comprising quetiapine was administered orally to 8 dogs (Canis familiaris) in the form of tablets comprising 8 mg of quetiapine, which corresponds to approximately 2 mg / kg based on body weight. The results of the study are presented in Table 5 below. Reduced mobility was observed as early as 30 minutes after administration, and after 40 minutes, all animals showed slowed down or lack of mobility, demonstrating the clinical and time effectiveness of the invention. From 50 to 110 minutes, a significant reduction in mobility was observed, resulting in reduced aggression and / or sedation. Approximately one hour after administration, lethargy and sleep were evident in most animals. Importantly, 210 minutes after administration, all animals had regained full mobility. Table 5. Study results of the effectiveness of the reduction of aggression, sedative and hypnotic effects of quetiapine or a composition comprising quetiapine according to the invention by observational study of the mobility and sleepiness of dogs. In one embodiment, quetiapine or a composition comprising quetiapine was administered orally to six cats (Felis catus) in the form of tablets comprising 8 mg of quetiapine, which corresponds to approximately 2 mg / kg based on body weight. The study results are presented in Table 6 below. Reduced mobility was observed as early as 20 minutes after administration, and after 40 minutes all animals showed slowed down or lack of mobility, demonstrating the clinical and time effectiveness of the invention. From 50 to 110 minutes, a significant reduction in mobility was observed, resulting in reduced aggression and / or sedation. Approximately one hour after administration, lethargy and sleep were evident in most animals. Equally important, 240 minutes after administration, all animals had regained full mobility. Table 6. Study results of the effectiveness of the reduction of aggression, sedative and hypnotic effects of quetiapine or a composition comprising quetiapine according to the invention by observational study of the mobility and sleepiness of cats. In other embodiments, quetiapine or a composition comprising quetiapine for use in the treatment of the invention has been administered to a farm animal.

[0040] In one embodiment, quetiapine or a composition comprising quetiapine was administered orally to four pigs (Sus domesticus) in the form of tablets containing 8 mg of quetiapine, which corresponds to approximately 2 mg / kg based on body weight. The study results are presented in Table 7 below. Reduced mobility was observed as early as 20 minutes after administration, and after 40 minutes, all animals showed slowed down or lack of mobility, demonstrating the clinical and time effectiveness of the invention. From 30 to 150 minutes, a significant reduction in mobility was observed, resulting in reduced aggression and / or sedation. Approximately 70 minutes after administration, lack of mobility was evident in all animals. Equally important, 210 minutes after administration, all animals had regained full mobility.

[0041] Table 7. Study results of the effectiveness of the reduction of aggression, sedative and hypnotic effects of quetiapine or a composition comprising quetiapine according to the invention by observational study of the mobility and sleepiness of pigs.

[0042] In one embodiment, quetiapine or a composition comprising quetiapine was administered orally to 30 chickens (Gallus gallus domesticus) in the form of a liquid added to drinking water at a dose of approximately 2 mg / kg. The study results are presented in Table 8 below. Reduced mobility was observed as early as 20 minutes after administration, and after 40 minutes, all animals showed slowed down or lack of mobility, demonstrating the clinical and time effectiveness of the invention. From 30 to 150 minutes, a significant reduction in mobility was observed, resulting in reduced aggression and / or sedation. Approximately 50 minutes after administration, lack of mobility was visible in all animals. Equally important, 210 minutes after administration, most animals had regained full mobility. Table 8. Study results of the effectiveness of the reduction of aggression, sedative and hypnotic effects of quetiapine or a composition comprising quetiapine according to the invention by observational study of the mobility and sleepiness of chickens. Identical effects and safety were obtained in studies on smaller groups of cattle (Bos taurus) and horses (Equus caballus), but the above results for pigs and poultry were chosen as more representative and sufficient to understand the essence of the invention.

[0043] Importantly, no long-term adverse effects were observed in the animal groups studied. These observations confirm the lack of significant clinical risk associated with the use of quetiapine or the composition comprising quetiapine according to the invention. Furthermore, given the literature on toxicity (of high doses) of quetiapine in animals and the ethical constraints associated with repeating them, there was no need to conduct separate toxicological studies.

[0044] In other embodiments, the possibility of administering quetiapine or a composition comprising quetiapine for use in the treatment according to the invention in combination with other veterinary-acceptable active substances was investigated. In a preferred embodiment, such veterinary-acceptable active substances act on the nervous system. In a more preferred embodiment, such veterinary-acceptable active substances act on the central nervous system. A general example of such active substances are psychotropic drugs. In one embodiment, quetiapine or a composition comprising quetiapine for use in the treatment of the invention was administered with the veterinary-acceptable a2-adrenergic receptor agonist - xylazine. I n another embodiment, quetiapine or a composition comprising quetiapine for use in the treatment according to the invention was administered with the veterinary-acceptable NMDA receptor antagonist - ketamine. In yet another embodiment, quetiapine or a composition comprising quetiapine for use in the treatment according to the invention is administered with the veterinary-acceptable benzodiazepine receptor agonist - diazepam. Such administrations have been found to be advantageous in terms of the ability to reduce the dose of at least one of the active substances administered in combination. This is particularly advantageous when the active substances administered in combination with quetiapine or a composition comprising quetiapine for use in the treatment according to the invention are administered concurrently or when the additional active substance is of the same class as quetiapine or has the same indication.

[0045] Quetiapine, a salt or solvate thereof or a composition comprising quetiapine, a salt or solvate thereof for use according to the invention and the composition of the invention exclude human use and non-veterinary dosage and form.

Claims

Claims:

1. Quetiapine, a salt or solvate thereof or a composition comprising quetiapine, a salt or solvate thereof for use in treatment, characterized in that it is used in the treatment of animals.

2. Quetiapine or a composition comprising quetiapine for use in treatment according to claim 1, characterized in that it is used for treatment of farm animals, in particular poultry, pigs, cattle, horses and / or pets, in particular dogs and cats.

3. Quetiapine or a composition comprising quetiapine for use in treatment according to any preceding claim, characterized in that it is used to reduce aggression and / or for sedation and / or as a hypnotic.

4. Quetiapine or a composition comprising quetiapine for use in treatment according to claim3, characterized in that it is used to reduce aggression at a dose from 0.5 mg / kg b.w. to 2 mg / kg b.w.

5. Quetiapine or a composition comprising quetiapine for use in treatment according to claim4, characterized in that it is used to reduce aggression at a dose of 0.5 mg / kg b.w.

6. Quetiapine or a composition comprising quetiapine for use in treatment according to claim3, characterized in that it is used for sedation at a dose from 1 mg / kg b.w. to 10 mg / kg b.w.

7. Quetiapine or a composition comprising quetiapine for use in treatment according to claim 6, characterized in that it is used for sedation at a dose of 2 mg / kg b.w.

8. Quetiapine or a composition comprising quetiapine for use in treatment according to claim3, characterized in that it is used for as a hypnotic at a dose from 5 mg / kg b.w. to 15 mg / kg b.w.

9. Quetiapine or a composition comprising quetiapine for use in treatment according to claim 8, characterized in that it is used as a hypnotic at a dose of 5 mg / kg b.w.

10. Quetiapine or a composition comprising quetiapine for use in treatment according to any of the preceding claims, characterized in that it is administered in combination with another veterinary-acceptable active substance, preferably acting on the nervous system.

11. A composition comprising quetiapine, a salt or a solvate thereof characterized in that it is in a veterinary-acceptable dose and form.

12. The composition according to claim 11, characterized in that it is in a veterinary solid form or in a veterinary liquid form.

13. The composition according to claim 12, characterized in that the veterinary solid form is selected from a tablet, a capsule, a powder, a granulate, micropellets or a food or feed additive.

14. The composition according to claim 12, characterized in that the veterinary liquid form is selected from a liquid concentrate, an oral liquid or an injectable preparation.

15. The composition according to any of claims 10 to 13, characterized in that it is in a modified release form, preferably delayed, accelerated, controlled or extended release.

Images