Pyrazole pharmaceutical composition

Abstract

Pharmaceutical compositions of pyrazole compounds and surfactants and methods of using same for the treatment of atopic dermatitis.

Description

[Background technology]

[0001] WO2018 / 108969 discloses compounds of formula I that are selective Janus kinase (JAK) inhibitors and, as such, are useful for treating JAK-mediated diseases such as atopic dermatitis, arthritis, and cancer. Specifically, 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) is disclosed. [ka]

[0002] In the cIL-31-induced pruritus test, the compound of formula (I) significantly inhibited pruritus relative to placebo and to the same extent as oclacitinib (Apoquel®). Apoquel® is a commercially available product for the treatment of atopic dermatitis in dogs. A method for treating atopic dermatitis by oral administration of compound (I) is also disclosed.

[0003] WO2013 / 041042 discloses pyrazole carboxamides as Janus kinase inhibitors useful for the treatment of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD) and cancer. The compounds of the disclosure are of the following formula: [ka]

[0004] Atopic dermatitis (AD) is a recurrent, pruritic, and chronic inflammatory skin disease characterized by immune system dysregulation and epidermal barrier abnormalities in humans. The pathological and immunological attributes of atopic dermatitis have been extensively reviewed [reviewed in Rahman et al., Inflammation & Allergy-drug target 10:486-496 (2011) and Harskamp et al., Seminar in Cutaneous Medicine and Surgery 32:132-139 (2013)]. Atopic dermatitis is also a common condition in companion animals, particularly dogs, with its prevalence estimated at approximately 10-15% of the canine population. The pathogenesis of atopic dermatitis in dogs and cats [reviewed by Nuttall et al., Veterinary Records 172(8):201-207 (2013)] involves a variety of immune cells, including a predominance of IL-4, IL-13, and IL-31, and CD4 + It shows significant similarities to the pathogenesis of human atopic dermatitis, which involves skin infiltration by a Th2-polarized cytokine milieu. Moreover, IL-22 is involved in the enhanced epithelial proliferation that leads to the epidermal hyperplasia characteristic of atopic dermatitis. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2018 / 108969 issue [Patent Document 2] WO2013 / 041042 issue [Non-patent literature]

[0006] [Non-Patent Document 1] Inflammation&Allergy-drug target 10:486-496(2011) [Non-Patent Document 2] Seminar in Cutaneous Medicine and Surgery 32:132-139(2013) [Non-Patent Document 3] Veterinary Records 172(8):201-207(2013)

[0007] The applicants have found that the inclusion of the surfactant D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in a formulation of a compound of formula (I) improves the bioavailability of the compound of formula (I) when compared to a formulation without TPGS. Summary of the Invention [Problem to be solved by the invention]

[0008] Summary of the Invention An embodiment of the present invention is a pharmaceutical composition comprising a pharma- ceutical effective amount of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide and a surfactant which is an ester of tocopherol, polyethylene glycol (PEG) and a dicarboxylic acid.

[0009] Another embodiment of the present invention is a method of treating atopic dermatitis, comprising orally administering to an animal in need thereof an effective amount of the above-described pharmaceutical composition. [Brief description of the drawings]

[0010] [Figure 1] This is a pharmacokinetic (PK) study using sodium lauryl sulfate (SLS) surfactant. [Diagram 2] This is a PK study using TPGS surfactant. [Diagram 3] This was a PK study comparing 5% w / w with 2.5% w / w and 1% w / w TPGS.

[0011] Detailed Description Applicants have developed formulations of the compound of formula (I), 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide. [ka]

[0012] The compound of formula (I) is a selective Janus kinase (JAK) inhibitor. However, the compound of formula (I) is a compound with low water solubility. In general, the low water solubility of a pharma- ceutically active agent leads to poor oral bioavailability in dogs, and therefore poor biological effectiveness of the agent. Applicants have found that the inclusion of surfactants of tocopherol, polyethylene glycol (PEG) and dicarboxylic acid ester in solid pharmaceutical compositions of the compound of formula I results in a formulation with improved bioavailability of the compound after oral administration to animals, compared to formulations without surfactant.

[0013] An embodiment of the present invention comprises: a) a pharma- ceutical effective amount of a compound of formula (I) or a salt or solvate thereof; [ka] and b) a pharma- ceutically acceptable carrier, wherein the carrier comprises a surfactant that is an ester of tocopherol, polyethylene glycol (PEG) and a dicarboxylic acid; A solid pharmaceutical composition comprising:

[0014] In one embodiment, the compound of formula (I) is present in crystalline form.

[0015] In one embodiment, the amount of the compound of formula (I) in the composition is between about 0.5 and about 10%, or between about 1.0 and about 5.0%, or about 2% (w / w).

[0016] Tocopherols are a class of organic compounds, many of which have vitamin E activity. There are four tocopherol forms (α (alpha), β (beta), γ (gamma), and δ (delta)) (see below). All are characterized by a chroman ring, a hydroxyl group and a hydrophobic side chain, and differ by the number and position of methyl groups on the chroman ring.

[0017] [Table 1]

[0018] In one embodiment, the tocopherol is alpha tocopherol, particularly D-alpha tocopherol.

[0019] Polyethylene glycol is H-(O-CH 2 -CH 2 ) is a polyether compound having an n-OH structure. The molecular weight of PEG is preferably in the range of 100 to 10,000 Da. In one embodiment, the molecular weight of PEG is 1000 Da.

[0020] Dicarboxylic acids are organic compounds that contain two carboxyl functional groups (-COOH). The general molecular formula for dicarboxylic acids is HO 2 CR-CO 2 H, where R can be aliphatic or aromatic. The dicarboxylic acid can also be represented by C 2 -C 20 In one embodiment, the dicarboxylic acid is succinic acid, C 4 It is an alkyl dicarboxylic acid.

[0021] In one embodiment, such a surfactant is D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS or Vitamin E TPGS). TPGS is formed by esterification of polyethylene glycol 1000 with Vitamin E succinate. Thus, in TPGS, the molecular weight of PEG is 1000 Da, the tocopherol is α-tocopherol, and the dicarboxylic acid is succinic acid.

[0022] In one embodiment, the amount of TPGS in the composition is between about 0.5 and about 10%, or between about 1.0 and about 5.0%, or between about 1.0 and about 2.5% (w / w).

[0023] In one embodiment, the weight ratio of the compound of formula (I) and TPGS in the composition is between about 0.1:1 and about 10:1, preferably between about 0.5:1 and about 4:1.

[0024] The pharmaceutical composition may further contain one or more lubricants. Lubricants reduce the friction between the formed tablet and the wall of the die used to form the tablet, thus making it easier for the tablet to be removed from the die. Examples of lubricants are magnesium stearate, talc, colloidal silica, and sodium stearyl fumarate. In one embodiment, the lubricant is magnesium stearate.

[0025] The pharmaceutical composition may further contain one or more glidants. Glidants are used to improve flowability. In one embodiment, the glidant is colloidal silica, talc, or a mixture thereof.

[0026] The pharmaceutical composition may further contain one or more fillers / compression aids. Fillers / compression aids are used to increase the bulk or volume of pharmaceutical dosage forms with low dose active ingredients and to increase the mechanical strength of dosage forms such as tablets. Examples of fillers are microcrystalline cellulose (MCC) (Avicel PH102), lactose anhydrous, lactose monohydrate (Fast Flo 316), starch, polyols (e.g., sorbitol, mannitol, maltitol), maltodextrin, dextrose, calcium phosphate, and calcium sulfate. In one embodiment, the filler is microcrystalline cellulose, lactose monohydrate cellulose, or a mixture thereof.

[0027] The pharmaceutical composition may further comprise one or more disintegrants. Disintegrants help break tablets into smaller pieces once they come into contact with liquid. Examples of disintegrants are sodium starch glycolate, croscarmellose sodium, and crospovidone. In one embodiment, the disintegrant is sodium starch glycolate (type A).

[0028] The pharmaceutical composition may further comprise one or more binders. Binders are used to increase the mechanical strength of dosage forms such as tablets. Binders are also used to aid granule formation in (wet or dry) granulation processes. Granule formation increases the uniformity and flowability of the (drug) content of the final blend. Examples of binders are PVP, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). In one embodiment, the binder is hydroxypropyl cellulose (HPC).

[0029] In one embodiment of the invention, the formulation is of the following composition: [Table 2]

[0030] In alternative embodiments of the invention, the concentrations of the components of the formulation may vary as shown below: [Table 3]

[0031] In an embodiment, the combined w / w percentage of microcrystalline cellulose and lactose monohydrate should be at least 60%.

[0032] In an embodiment, the pharmaceutical composition is a solid, preferably a capsule or tablet.

[0033] Preparation process of TPGS formulation TPGS is a waxy material and can be difficult to add to powder blends. In practice, TPGS can be added to powder blends either as a molten liquid or as an aqueous solution in either a high shear granulator or a hot melt extruder. In wet granulation, a granulating fluid such as water or a binder solution is used to bind smaller particles together to form granules. Examples of wet granulation processes are fluidized bed granulation and high shear wet granulation.

[0034] In a high shear granulator, the TPGS water solution or TPGS binder solution is sprayed onto the solid ingredients in the formulation, except for the lubricant. The wet mass is then dried to remove the water and obtain dry granules. The granules are milled and blended with the lubricant. Extragranular excipients such as fillers and disintegrants may also be added prior to lubrication. The resulting lubricated blend is compressed into tablets.

[0035] Alternatively, TPGS may be heated to a molten state and incorporated into the formulation using a high shear granulator or hot melt extruder. The granules, which are composed of the active substance, filler, disintegrant and TPGS, are cooled to room temperature, but water removal is not required. As with wet granulation, the granules can then be milled and blended with a lubricant before compression. Extragranular excipients such as fillers and disintegrants can also be added before lubrication.

[0036] Granules can be dried in a fluid bed or tray, regardless of scale. Fluid bed drying may be more efficient than tray drying. The use of either method is contemplated in the context of preparing the pharmaceutical compositions of the invention.

[0037] The concentration of the TPGS solution is determined based on the desired TPGS concentration in the final pharmaceutical composition. The lower the desired concentration of TPGS in the final formulation, the more dilute the TPGS solution can be. The concentration of the TPGS solution is determined based on the desired TPGS content in the formulation and the amount of granulation liquid required to produce granules with the desired attributes for downstream processing.

[0038] An embodiment of the present invention is a method for producing a pharmaceutical composition, the method comprising: i) forming a powder blend of a compound of formula (I) with a filler and a disintegrant; ii) spraying the aqueous TPGS solution onto the dry powder and mixing to combine the solution with the powder; iii) drying the product of step ii) to produce granules; iv) reducing the size of the granules; v) lubricating the product of step iv); and vi) compressing the product of step v) into tablets to produce a pharmaceutical composition; The process includes:

[0039] In one embodiment, the formation of the powder blend in step i) or the mixing in step ii) is accomplished using a high shear granulator.

[0040] Another embodiment of the invention is a method for producing a pharmaceutical composition, the method comprising: i) forming a powder blend of a compound of formula (I) with a filler and a disintegrant and heating the powder blend; ii) melting TPGS and mixing it with the heated powder blend of step i); iii) cooling the product of step ii) to produce granules; and iv) reducing the size of the granules of step iii); v) lubricating the product of step iv); and vi) compressing the product of step v) into tablets to produce a pharmaceutical composition.

[0041] In one embodiment, the compound of formula (I) is further combined with a binder in step i).

[0042] In one embodiment, the filler is microcrystalline cellulose, lactose, or a mixture thereof.

[0043] In one embodiment, the disintegrant is sodium starch glycolate.

[0044] In one embodiment, the lubricant is magnesium stearate.

[0045] In one embodiment, the binder is hydroxypropylene cellulose.

[0046] Treatment method An embodiment of the present invention is a method of treating atopic dermatitis, comprising administering to an animal in need thereof a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a salt or solvate thereof; and a pharma- ceutical acceptable carrier: [ka] Here, the carrier comprises a surfactant which is an ester of tocopherol, polyethylene glycol (PEG) and a dicarboxylic acid.

[0047] 1. A method of treating atopic dermatitis, comprising administering to an animal in need thereof a pharmaceutical composition of a compound of formula (I), or a salt or solvate thereof; and a pharma- ceutically acceptable carrier: [ka] wherein the carrier comprises a surfactant which is an ester of tocopherol, polyethylene glycol (PEG) and a dicarboxylic acid; Here, the effective amount of the compound of formula (I) is between about 0.1 and about 2.0 mg / kg body weight.

[0048] The pharmaceutical composition is administered orally.

[0049] In one embodiment, the animal to be treated is a companion animal mammal. In another embodiment, the companion animal is a dog, cat or horse. In another embodiment, the companion animal is a dog.

[0050] In one embodiment of the present invention, the dosage of the active ingredient administered to an animal is about 0.1 mg / kg to about 2.0 mg / kg, about 0.2 to about 0.8 mg / kg, about 0.3 to about 0.7 mg / kg, about 0.5 mg / kg, or about 1.0 mg / kg.

[0051] In one embodiment, the pharmaceutical composition is administered once daily for 28 days.

[0052] In another embodiment, the pharmaceutical composition is administered twice daily for 14 days, followed by once daily for 14 days.

[0053] In other embodiments, administration of the pharmaceutical composition is administered daily in excess of the aforementioned dosing regimens for as long as medically necessary, including for the life of the animal.

[0054] In one embodiment, the pharmaceutical composition is administered once daily for as long as medically necessary, including for the life of the animal.

[0055] In one embodiment, the pharmaceutical composition is administered twice daily for up to 14 days, then once daily for as long as medically necessary, including for the life of the animal.

[0056] In an embodiment, the pharmaceutical composition is administered twice on each of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th or 13th days, and then once daily for as long as medically necessary, including for the life of the animal.

[0057] The pharmaceutical compositions of the compounds of formula (I) and TPGS can be administered in combination with antihistamines, antibiotics, antipruritic agents and ceramides. These combinations can be administered simultaneously or sequentially. EXAMPLES

[0058] Example 1 - Surfactant Selection and Comparative Examples Many surfactants were screened to increase the solubility of the compound and promote increased bioavailability. The following table lists the solubility of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide in the surfactant solutions tested. [Table 4]

[0059] Due to the strong solubilization of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide by SLS and its ability to be easily incorporated into powder blends, pharmacokinetic (PK) studies were performed with 3% w / w SLS added to the formulation. The composition of the tested formulation containing 1% active ingredient is shown below. A test formulation containing 0.2% active ingredient was also prepared.

[0060] [Table 5]

[0061] [Table 6]

[0062] The results in Figure 1 show that, despite favorable in vitro solubility, the addition of SLS did not succeed in promoting the increased bioavailability of the compound at two different doses. The bioavailability of the formulation containing SLS was not improved compared to that of the formulation not containing SLS. For the SLS-containing formulation and the non-SLS formulation, Cmax was less than 0.1 μM for a 0.2 mg / kg dose of the compound of formula (I) and about 0.26 μM for a 1.0 mg / kg dose of the compound of formula (I). See Figure 1: No significant difference was shown between the SLS formulation and the non-SLS formulation.

[0063] TPGS-containing preparations Example 2 A formulation containing 4% active ingredient (API) and 5% TPGS was prepared by wet granulation. 34 g of a 15% w / w aqueous solution of TPGS was sprayed onto approximately 90 g of powder blend containing 4 g of API. Water was removed by tray drying overnight in a 40° C. oven. The granules were milled and blended with approximately 1 g of magnesium stearate. The magnesium stearate weight was adjusted to maintain 1% w / w in the final blend.

[0064] [Table 7]

[0065] The following TPGS formulations were prepared as described above. When binders were added, the MCC and lactose concentrations were reduced so that all component compositions were loaded to 99%. The ratio of MCC to lactose was maintained at a 3:1 weight ratio. After granulation, magnesium stearate was added to obtain a 1% w / w concentration.

[0066] Example 3 (2% active ingredient, 2.5% TPGS melt granulation): TPGS is pre-melted in an oven. All solids remaining in the formulation were pre-heated except for magnesium stearate. 2.5g of molten TPGS was added to approximately 95g of powder blend containing 2g of API. Air cooled to room temperature on a tray under ambient conditions. Granules were milled and then blended with approximately 1g of magnesium stearate. The weight of magnesium stearate was adjusted to maintain 1% w / w of the final blend.

[0067] Example 4 - Bioavailability of TPGS-containing formulations in dogs TPGS was evaluated as a surfactant to promote increased bioavailability of the active ingredient, 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide, in dogs. The formulation was prepared as described above. The composition of the formulation is shown below:

[0068] [Table 8]

[0069] The percentages of microcrystalline cellulose and lactose monohydrate were adjusted slightly to accommodate changes in the concentration of the active ingredient.

[0070] The bioavailability of the compound of formula (I) in dogs was evaluated for a range of TPGS formulations from 1% to 10% TPGS w / w. All formulations were dosed at 1 mg / kg body weight. Figure 2 shows data comparing the pharmacokinetic (PK) profiles of the compound when formulated with 10% w / w TPGS, 5% w / w TPGS, and no TPGS. The Cmax of the formulation without TPGS was measured to be about 0.3 μM. The Cmax of the 5% TPGS and 10% formulations were about 0.6 μM and 0.4 μM, respectively. See Figure 2.

[0071] These results demonstrated that although the inclusion of TPGS is important to promote bioavailability, a reduced concentration of TPGS may be beneficial. Therefore, a follow-up study was conducted comparing 5% w / w to 2.5% w / w and 1% w / w TPGS. The results are shown in Figure 3. In this study, the Cmax of the formulation without TPGS was measured to be approximately 0.2 μM. The Cmax of the 1%, 2.5% and 5% TPGS formulations was approximately 0.3 μM, 0.3 μM and 0.25 μM, respectively. See Figure 3. Here, the data demonstrated that lower concentrations of TPGS improve bioavailability. Due to variability between clinical trial sites, the data in Figures 2 and 3 cannot be directly compared or compared to the data in Figure 1. However, in both TPGS studies, the formulation with TPGS had higher bioavailability than the formulation without TPGS. This was unexpected given the results of the bioavailability studies with SLS, where the SLS formulation did not result in improved bioavailability of the compound of formula (I) over formulations without SLS, despite its much greater solubility for the compound of formula (I). At a 1% concentration, SLS has a solubility of the compound of formula (I) of 0.1952 mg / mL, and at a 1% concentration, TPGS has a solubility of the compound of formula (I) of 0.099 mg / mL.

[0072] Example 6 (3% active ingredient, 3.5% TPGS) A formulation containing 3% active ingredient (API) and 3.75% TPGS was prepared by high shear wet granulation. A solution containing 11% w / w TPGS and 15% polyvinylpyrrolidone was sprayed onto approximately 2 kg of a powder blend containing 3% w / w API. The wet granules were dried in a fluid bed dryer until the loss on drying was 2.5% or less. The dried granules were milled and blended with additional sodium starch glycolate type A and magnesium stearate as appropriate. The weight of sodium starch glycolate type A added extragranularly was adjusted to maintain 3% w / w of the final blend. The weight of magnesium stearate was adjusted to maintain 0.5% w / w of the final blend. [Table 9]

[0073] Example 7 A formulation containing 3% active ingredient (API) and 3.75% TPGS was prepared by high shear wet granulation. A solution containing approximately 10% w / w TPGS was sprayed onto approximately 2 kg of a powder blend containing 3% w / w API. The wet granules were dried in a fluid bed dryer until the loss on drying was 2.5% or less. The dried granules were milled and blended with additional sodium starch glycolate type A and magnesium stearate as appropriate. The weight of sodium starch glycolate type A added extragranularly was adjusted to maintain 3% w / w of the final blend. The weight of magnesium stearate was adjusted to maintain 0.5% w / w of the final blend.

[0074] [Table 10]

[0075] Example 8 - Efficacy Testing The compound is being evaluated in a masked, randomized, proof-of-concept study in dogs diagnosed with atopic dermatitis. The objective of the study is to evaluate the efficacy and tolerability of the compound for atopic dermatitis in customer-owned dogs. The compound will be evaluated at two doses and compared to a placebo control. Dogs will be dosed orally twice daily for up to 14 days, followed by once daily for up to 28 days or once daily for 28 days, and will be assessed for pruritus and skin lesions using the Pruritus Visual Analog Scale (PVAS) and Canine Atopic Dermatitis Severity Index (CADESI-4) scoring tools, respectively.

[0076] The Canine Atopic Dermatitis Extent and Severity Index (CADESI-4) is a severity scale used to grade skin lesions in clinical trials for the treatment of dogs with atopic dermatitis (AD). Three lesion types (erythema, lichenification and alopecia / epidermal peeling) are scored from 0 to 3 for each of 20 body sites, with a maximum score of 180, with suggested benchmarks of 10, 35 and 60 for mild, moderate and severe AD skin lesions, respectively. CADESI-4: Thierry, O., Manolis, S., Nuttall, T., Bensignor, E., Griffin, C., Hill, P., for the International Committee on Allergic Diseases of Animals (ICADA). Validation of the Canine Atopic Dermatitis Extent and Severity Index (CADESI)-4, a simplified severity scale for assessing skin lesions of atopic dermatitis in dogs.Vet,Dermatol.25:77-e25,2014.

[0077] The Itch Visual Analog Scale (PVAS) is a visual analog scale that includes features of both itch severity and itch-related behavior. It is commonly used to determine the severity of pruritus in clinical trials for the treatment of dogs with AD. PVAS: Hill, P.B., Lau, P. and Rybnicek, J.Development of an owner-assessed scale to measure the severity of pruritus in dogs., Vet.Dermatol.18:301-308,2007.

Claims

1. a) a pharma- ceutical effective amount of a compound of formula (I) or a salt or solvate thereof; 【Chemistry 1】 and b) a pharma- ceutically acceptable carrier comprising a surfactant, wherein the carrier is D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS); 1. A solid pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is present in crystalline form.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the amount of the compound of formula (I) in the composition is between about 0.5 and about 10%, or between about 1.0 and about 5.0%, or about 2% (w / w).

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the amount of TPGS in the composition is between about 0.5 and about 10%, or between about 1.0 and about 5.0%, or between about 1.0 and about 2.5% (w / w).

5. The pharmaceutical composition according to any one of claims 1 to 4, further comprising one or more excipients selected from fillers, lubricants, binders and disintegrants.

6. 6. The pharmaceutical composition of claim 5, wherein the filler is microcrystalline cellulose, lactose or a mixture thereof.

7. 7. The pharmaceutical composition of claim 5 or 6, wherein the lubricant is magnesium stearate.

8. The pharmaceutical composition according to any one of claims 5 to 7, wherein the disintegrant is sodium starch glycolate.

9. The pharmaceutical composition according to any one of claims 5 to 8, wherein the binder is hydroxypropyl cellulose.

10. A method for treating atopic dermatitis, comprising administering to an animal other than a human in need thereof an effective amount of the pharmaceutical composition according to any one of claims 1 to 9.

11. A method for treating atopic dermatitis, comprising administering to an animal other than a human in need thereof a pharmaceutical composition according to any one of claims 1 to 9, wherein the effective amount of the compound of formula (I) is between about 0.1 and about 2.0 mg / kg of body weight.

12. The method according to any one of claims 10 to 11, wherein administration is oral.

13. The method according to any one of claims 10 to 12, wherein the animal is a companion animal, preferably a dog.

14. The method according to any one of claims 10 to 13, wherein the composition is administered once a day or twice a day, preferably once a day.

15. The method of any one of claims 10 to 14, wherein the composition is administered with food.

16. 16. The method of any one of claims 10 to 15, wherein the composition is administered twice daily for 14 days, then once daily for 14 days.

17. The method of any one of claims 10 to 16, wherein the composition is administered once daily for 28 days.

18. The method of any one of claims 16 to 17, wherein daily administration of the pharmaceutical composition continues for as long as medically necessary, including for the life of the animal.

19. A method for producing a pharmaceutical composition according to any one of claims 1 to 9, comprising the steps of: i) forming a powder blend of a compound of formula (I) with a filler and a disintegrant; ii) spraying the aqueous TPGS solution onto the dry powder and mixing to combine the solution with the powder; iii) drying the product of step ii) to produce granules; iv) reducing the size of the granules; v) lubricating the product of step iv); and vi) compressing the product of step v) into tablets to produce a pharmaceutical composition; A method comprising the steps of:

20. 20. The method of claim 19, wherein forming the powder blend of step i) or mixing of step ii) is accomplished using a high shear granulator.

21. A method for producing a pharmaceutical composition according to any one of claims 1 to 9, comprising the steps of: i) forming a powder blend of a compound of formula (I) with a filler and a disintegrant and heating the powder blend; ii) melting TPGS and mixing it with the heated powder blend of step i); iii) cooling the product of step ii) to produce granules; and iv) reducing the size of the granules of step iii); v) lubricating the product of step iv); and vi) compressing the product of step v) into a tablet to produce a pharmaceutical composition.

22. The method of any one of claims 19 to 21, wherein the compound of formula (I) is further combined with a binder in step i).

23. The method according to any one of claims 19 to 22, wherein the filler is microcrystalline cellulose, lactose or a mixture thereof.

24. The method according to any one of claims 19 to 23, wherein the disintegrant is sodium starch glycolate.

25. The method of any one of claims 19 to 24, wherein the lubricant is magnesium stearate.

26. The method of any one of claims 22 to 25, wherein the binder is hydroxypropyl cellulose.

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