Pharmaceutical compositions of pyrazole compounds dispersed in a polymer matrix

Abstract

Pharmaceutical compositions of pyrazole compounds dispersed in a polymer matrix and methods of using same for the treatment of atopic dermatitis.

Description

Background Art

[0001] WO2018 / 108969 discloses compounds of Formula I which are selective Janus kinase (JAK) inhibitors and are useful per se in the treatment of 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.

Chemical formula

[0002] In a cIL-31-induced pruritus test, the compounds of formula (I) significantly suppressed 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 in the treatment of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD) and cancer. The compounds of the present disclosure are of the following formula.

Chemical formula

[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 studied [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 an estimated prevalence of approximately 10-15% of the canine population. The etiology of atopic dermatitis in dogs and cats [review by Nuttall et al., Veterinary Records 172(8):201-207(2013)] involves various immune cells, including the dominance of IL-4, IL-13, and IL-31, and CD4 + The study shows significant similarities to the pathogenesis of human atopic dermatitis, including skin infiltration induced by a Th2-polarizing cytokine environment. Furthermore, IL-22 is involved in the enhancement of epithelial proliferation that leads to 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 applicant found that the dispersion of the compound of formula (I) in a hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer matrix resulted in improved bioavailability of the compound of formula (I). [Overview of the project] [Problems that the invention aims to solve]

[0008] Embodiments of the present invention are pharmaceutical compositions comprising a pharmaceutically effective amount of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide dispersed in an HPMCAS polymer matrix and a pharmaceutically acceptable carrier.

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

[0010] Another embodiment is a method for producing a pharmaceutical composition. [Brief explanation of the drawing]

[0011] [Figure 1] This is a powder X-ray diffraction (PXRD) measurement of the amount of amorphous compounds present in an amorphous solid dispersion (ASD). [Figure 2] This is a pharmacokinetic (PK) study to demonstrate the bioavailability of an amorphous solid dispersion of the compound of formula (I) in hydroxypropyl methylcellulose acetate succinate (HPMCAS). [Figure 3] The ability of several nucleation-preventing polymers to maintain the compound of formula (I) was evaluated in in vitro screening.

Mode for Carrying Out the Invention

[0012] Detailed Description The applicant has developed a formulation of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide, which is a compound of formula (I);

Chemical formula

[0013] The compound of formula (I) is a selective Janus kinase (JAK) inhibitor, but the compound of formula (I) is a compound with low water solubility. Generally, when the water solubility of a pharmaceutically active agent is low, the oral bioavailability in dogs deteriorates, and thus the biological effectiveness of the agent deteriorates. However, the compound of formula (I) is a compound with low water solubility. When the water solubility is low, the oral bioavailability in dogs decreases, often to less than 50%. The logP of the compound of formula (I) is calculated to be 1.25 (ChemDraw and Insight for Excel). To increase solubilization and promote bioavailability, the applicant administered the compound in an amorphous state as part of an amorphous solid dispersion (ASD). Due to the high melting point (>250 °C) of the compound and its low solubility in volatile solvents such as isopropanol, acetone, and dichloromethane, conventional techniques for manufacturing ASD such as spray drying and hot melt extrusion were not useful for manufacturing ASD containing the compound of formula (I). Therefore, the ASD was produced by co-precipitation or cPAD (co-precipitated amorphous dispersion). In this method, the compound and the polymer were dissolved in a solvent. Then, the compound-polymer solution was rapidly precipitated in a poor solvent under high shear in a rotor-stator homogenizer. And a compound-polymer amorphous solid dispersion was formed.

[0014] The applicant has found that when a compound of formula (I) in an amorphous state is used as part of an amorphous solid dispersion, a formulation having improved bioavailability can be obtained as compared to a formulation having the compound of formula (I) in crystalline form.

[0015] Substantially amorphous form means that at least 80% of the compound is in amorphous form, preferably at least 90% or 95% of the compound is in amorphous form. The percentage of amorphous form relative to crystalline form is measured by PXRD or NMR.

[0016] Tablets are solid dosage forms that contain or do not contain appropriate excipients, contain an active ingredient, and are prepared by either compression or molding. Compressed tablets are tablets formed by compression.

[0017] A solid dispersion is a dispersion of a drug in a solid matrix where the matrix is a small molecule or a polymer. Methods for preparing solid dispersions are melt extrusion, spray drying, and co-precipitation. See Huang et al., Acta Pharmaceutica Sinica B 2014;4(1), pages 18 - 25. When the active ingredient is in amorphous form, this is called an amorphous solid dispersion (ASD).

[0018] In a drug-polymer matrix, some polymer chains physically trap drug molecules. In an ideal situation, the drug molecules are uniformly distributed throughout the polymer matrix.

[0019] Hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymers, also known as hypromellose acetate succinate, are commonly used in oral pharmaceutical formulations as film coatings for tablets or granules, as well as as enteric coating materials. These polymers are solubility enhancers for solid dispersion formulations. HPMCAS polymers have been used as carriers for amorphous solid dispersions of poorly water-soluble drugs prepared by spray drying and hot-melt extrusion. Hydroxypropyl methylcellulose acetate succinate polymers are mixtures of succinic acid and acetate ethers of hydroxypropyl methylcellulose. HPMCAS polymers are available in several grades with different acetyl, succinoyl, methoxyl, and hydroxypropyl content. For example, the AquaSolve (Ashland) brand of hydroxypropyl methylcellulose acetate succinate has three grades, as shown below.

[0020] [Table 1]

[0021] In one embodiment, the HPMCAS polymer is grade L. In one embodiment, the HPMCAS polymer is grade M. In one embodiment, the HPMCAS polymer is grade H. In one embodiment, the HPMCAS polymer is a mixture of two or more grades.

[0022] In one embodiment, the pharmaceutical carrier comprises one or more excipients selected from fillers, lubricants, binders, nucleation inhibitors, and disintegrants.

[0023] The pharmaceutical composition may contain one or more lubricants. The lubricants reduce friction between the formed tablet and the wall of the die used to form the tablet, and thus make it easier to remove the tablet from the die. Examples of lubricants include magnesium stearate, talc, colloidal silica, and sodium stearyl fumarate. In one embodiment, the lubricant is magnesium stearate.

[0024] The pharmaceutical composition may contain one or more flow promoters. Flow promoters are used to improve fluidity. In one embodiment, the flow promoter is colloidal silica, talc, or a mixture thereof.

[0025] The pharmaceutical composition further comprises one or more fillers / compression aids. Fillers / compression aids are used to increase the bulk or volume of a pharmaceutical dosage form having a low dose of active ingredient, and to increase the mechanical strength of a dosage form such as a tablet. Examples of fillers include 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.

[0026] The pharmaceutical composition further comprises one or more disintegrants. The disintegrants, once in contact with a liquid, help to break down the tablet into smaller pieces. Examples of disintegrants include sodium starch glycolate (type A), croscarmellose sodium, and crospovidone. In one embodiment, the disintegrant is sodium starch glycolate (type A).

[0027] The pharmaceutical composition further comprises one or more binders. The binders are used to increase the mechanical strength of dosage forms such as tablets. The binders are also used to assist in granulation in (wet or dry) granulation processes. Granulation increases the uniformity and fluidity of the (drug) content of the final blend. Examples of binders include PVP, hydroxypropyl methylcellulose (HPMC), and hydroxypropyl cellulose (HPC). In one embodiment, the binder is hydroxypropyl cellulose (HPC).

[0028] The pharmaceutical composition further comprises one or more nucleation inhibitors. The nucleation inhibitors inhibit the crystallization of the formulation. Examples include cellulosic polymers such as methylcellulose and hydroxypropyl methylcellulose, poloxomers such as P68, P88, P98, P108, P125, P188, P237, P338, and P407, polyethylene glycols, polyvinyl alcohol (PVA), vinylpyrrolidone-vinyl acetate copolymer (VA64), polyvinylpyrrolidone (PVP), poly(lactic acid-coglycolic acid) (PLGA), methylcellulose A4C, hydroxypropyl methylcellulose E50, and polycaprolactone (PCL). In one embodiment, the nucleation inhibitor is methylcellulose A4C or hydroxypropyl methylcellulose E50.

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

[0030] In an alternative embodiment of the present invention, the concentrations of the formulation components may vary as follows: [Table 3] *The total w / w% of microcrystalline cellulose and lactose monohydrate must be at least 40%.

[0031] In the embodiment, the pharmaceutical composition is a solid, preferably a tablet.

[0032] Embodiments of the present invention are; a) Compound of formula (I) dispersed in a hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer matrix [ka] The pharmaceutically effective amount of, b) A solid pharmaceutical composition comprising a pharmaceutically acceptable carrier, Here, the compound of formula (I) exists in a substantially amorphous form, and the pharmaceutical composition is a tablet.

[0033] In one embodiment, the ratio of polymer to compound (I) in the dispersion is between approximately 1:1 and approximately 20:1 or between approximately 10:1 and approximately 5:1.

[0034] In one embodiment, the amount of compound of formula (I) in the pharmaceutical composition is between about 0.5% and about 10%, or between about 1.0% and about 5.0%, or about 2% (w / w).

[0035] In one embodiment, the amount of HPMCAS-L polymer in the pharmaceutical composition is between about 10% and about 30%, or between about 15% and about 25%, or about 20% (w / w).

[0036] Method for producing amorphous solid dispersions (ASDs) In this method, the active ingredient (API) and polymer were dissolved in a solvent. The API-polymer solution was then rapidly precipitated in a poor solvent. The precipitate was washed and dried. An amorphous solid dispersion of the API and polymer was formed and compressed into tablets.

[0037] In one embodiment, the API is a compound of formula (I).

[0038] In one embodiment, the polymer is hydroxypropyl methylcellulose acetate succinate, grade L.

[0039] In one embodiment, the solvent is dimethylacetamide (DMAc or DMA). DMA is an organic compound having the formula CH3C(O)N(CH3)2.

[0040] In one embodiment, the poor solvent is an acidic aqueous solution having a pH of less than 5, preferably hydrochloric acid, preferably 0.1N HCl.

[0041] In one embodiment, the precipitation of API polymers from a solvent (poor solvent) was carried out under high shear in a rotor-stator homogenizer.

[0042] In one embodiment, the precipitation and washing conditions were 1:10 solvent:poor solvent precipitation followed by 10 slurry washes, followed by 5 displacement washes.

[0043] In one embodiment, the ratio of the compound of formula (I) to the HPMCAS-L polymer in the amorphous solid dispersion is 10:1.

[0044] In one embodiment, the ratio of the compound of formula (I) to the HPMCAS-L polymer in the amorphous solid dispersion is 5:1.

[0045] In one embodiment, surfactants, disintegrants, and nucleation inhibitors are added within or between ASDs. In one embodiment, fillers, binders, and lubricants are blended after the ASD has been formed and dried.

[0046] Embodiments of the present invention are methods for producing the above-mentioned pharmaceutical composition, and the method is i) Dissolve the compound and polymer of formula (I) in a solvent; ii) Combine the solution from step i) with a poor solvent to precipitate an amorphous solid dispersion of the compound of formula (I) in the polymer; iii) Blend the amorphous solid dispersion from step ii) with a pharmaceutically acceptable carrier; and iv) The product of step iii) is compressed into tablets to produce a pharmaceutical composition; the process includes this step; Here, the solvent is dimethylacetamide (DMAc), and the poor solvent is an acidic aqueous solution with a pH of less than 5, preferably a hydrochloric acid solution, more preferably 0.1N hydrochloric acid.

[0047] In one embodiment, the solvent-to-poor solvent ratio is between 1:1 and 1:50, or between 1:5 and 1:10.

[0048] In one embodiment, the precipitate from step ii) is washed with an additional poor solvent.

[0049] In one embodiment, the pharmaceutically acceptable carrier comprises one or more of the following: fillers, disintegrants, lubricants, binders, and nucleation inhibitors.

[0050] In one embodiment, the filler is microcrystalline cellulose, lactose, or a mixture thereof.

[0051] In one embodiment, the disintegrant is sodium starch glycolate.

[0052] In one embodiment, the lubricant is magnesium stearate.

[0053] In one embodiment, the binder is hydroxypropylene cellulose.

[0054] In one embodiment, the nucleation inhibitor is methylcellulose A4C or hydroxypropylmethylcellulose E50.

[0055] Embodiments of the present invention are methods for producing pharmaceutical compositions, the method being i) Dissolve the compound and polymer of formula (I) in a solvent; ii) Combine the solution from step i) with a poor solvent to precipitate a dispersion of the compound of formula (I) in the polymer; iii) Blend the dispersion from step ii) with a pharmaceutically acceptable carrier; the process includes the step of, Here, the pharmaceutical carrier comprises one or more excipients selected from fillers, lubricants, binders, nucleation inhibitors, and disintegrants.

[0056] Treatment method A method for treating atopic dermatitis, comprising administering an effective amount of a pharmaceutical composition containing a compound of formula (I) and an HPMCAS polymer to an animal in need thereof.

[0057] A method for treating atopic dermatitis, comprising administering to an animal in need of such treatment a pharmaceutical composition comprising a compound of formula (I) and an HPMCAS polymer, wherein the effective dose of the compound of formula (I) is between approximately 0.1 and approximately 2.0 mg / kg body weight.

[0058] The pharmaceutical composition is administered orally.

[0059] In one embodiment, the animal being treated is a companion animal mammal. In another embodiment, the companion animal is a dog, cat, or horse. In yet another embodiment, the companion animal is a dog.

[0060] In one embodiment of the present invention, the dose of the active ingredient administered to the animal is approximately 0.1 mg / kg to approximately 2.0 mg / kg, approximately 0.2 to approximately 0.8 mg / kg, approximately 0.3 to approximately 0.7 mg / kg, approximately 0.5 mg / kg, and approximately 1.0 mg / kg.

[0061] In one embodiment, the composition is administered without food.

[0062] In one embodiment, the composition is administered while the patient is being fed.

[0063] In one embodiment, the composition is administered to a fasted patient.

[0064] In one embodiment, the pharmaceutical composition is administered once a day for 28 days.

[0065] In another embodiment, the pharmaceutical composition is administered twice daily for 14 days, followed by once daily for 14 days.

[0066] In other embodiments, the pharmaceutical composition is administered daily beyond the aforementioned drug regimen for as long as medically necessary, including throughout the animal's life.

[0067] In one embodiment, the pharmaceutical composition is administered once a day for as long as medically necessary, including throughout the animal's life.

[0068] In one embodiment, the pharmaceutical composition is administered twice daily for up to 14 days, and thereafter once daily for as long as medically necessary, including throughout the animal's life.

[0069] In this embodiment, the pharmaceutical composition is administered twice on each of the following days: day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, or day 13, and thereafter once a day for as long as medically necessary, including throughout the animal's life.

[0070] Pharmaceutical compositions of the compound of formula (I) can be administered in combination with antihistamines, antibiotics, antipruritic agents, and ceramides. These combinations can be administered simultaneously or sequentially. [Examples]

[0071] Example 1 - Polymer Matrix Selection Preliminary tests using the compound of formula (I) were conducted with numerous polymers (vinylpyrrolidone-vinyl acetate copolymer (VA64), hydroxypropyl methylcellulose (HPMC), and HPMCAS) containing volatile solvents (tetrahydrofuran (THF), methyl ethyl ketone (MEK), methyl tert-butyl ether (MTBE), and heptane). These experiments yielded solutions, semi-solids, solids containing crystalline material, or amorphous solids unsuitable for downstream processing such as grinding and compression. Many solvents and polymers used to produce ASD using the compound of formula (I) resulted in sticky materials that could not be blended or compressed. Other solvent / polymer combinations resulted in extremely hard materials that could not be ground to a uniform particle size using conventional mills.

[0072] Amorphous solid dispersions of the compounds of formula (I) listed below were prepared in 10 mL scale using an IKA Ultra-Turrax Tube Drive. The properties of the prepared ASDs are also reported below.

[0073] [Table 4]

[0074] Next, aqueous solvent systems were evaluated, and success was found using HPMCAS combined with DMAc:0.1N hydrochloric acid solvent:poor solvent system.

[0075] [Table 5]

[0076] Samples of amorphous solid dispersions (ASDs) with different ratios of HPMACAS polymer and the compound of active ingredient formula (I) were prepared and analyzed by powder X-ray diffraction (PXRD) to determine the amount of amorphous compound present in the ASDs. ASDs with a polymer-to-compound ratio of 3:1 showed a small degree of crystallinity. However, ASDs with polymer-to-compound ratios of 5:1 and 10:1 showed virtually no crystallinity. See Figure 1. The baseline trace was the crystalline form of the compound of formula (I). Other traces showed the crystallinity of several ASDs with varying polymer-to-API ratios. The trace of the ASD with a polymer-to-compound ratio showed the most similarity to the crystalline trace, thus indicating the presence of a significant amount of the crystalline form of the compound of formula (I) in the 3:1 ASD. The trace amounts of ASDs with polymer-to-compound ratios of 5:1, 7:1, and 10:1 showed low similarity to the crystalline trace amounts, and therefore, no significant amount of the crystalline form of the compound of formula (I) was present in each of these ASDs.

[0077] Example 2 - Co-precipitation formulation of compound (I) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) In this process, the compound of formula (I) (i.e., the active ingredient (API)) and the polymer (hydroxypropyl methylcellulose acetate succinate, grade L) were dissolved in a solvent (DMAc). The API-polymer solution was then rapidly precipitated in a rotor-stator homogenizer under high shear in a poor solvent (0.1N HCl). Precipitation and washing conditions were achieved using a solvent:poor solvent ratio of 1:10. Following precipitation, 10 slurry washes were performed, followed by 5 substitution washes. Amorphous solid dispersions of the compound and polymer were formed and compressed into tablets.

[0078] An amorphous solid dispersion (ASD) having a 10:1 ratio of HPMCAS-L polymer to compound (I) was prepared by dissolving 750 mg of the compound and 7500 mg of HPMCAS-L polymer in 56.25 mL of DMAc solvent. This solution was stirred overnight to ensure complete dissolution. Next, 500 mL of cold 0.1N HCl was added to a 1 L beaker. An IKA T25 rotor-stator homogenizer was added to the beaker and the mixture was heated to 20,000 RPM. Then, 50 mL of the compound / polymer solution was added to the high-shear zone of the rotor-stator mixer using a syringe with a 14G needle. The compound / polymer mixture rapidly precipitated and was mixed on ice for a further 2 minutes. The resulting suspension was filtered and added to 500 mL of fresh cold 0.1N HCl. The resulting suspension was slurry-washed for a further 2 minutes and then filtered. Next, 250 mL of fresh, cold 0.1N HCl was added to the top of the resulting cake and washed by displacement. The final cake was then dried under vacuum and blown over with nitrogen overnight. The resulting dried ASD had an assay of 82.5%. To prepare tablets, 4850 mg of ASD was added to 3050 mg of microcrystalline cellulose, 1500 mg of lactose monohydrate, and 500 mg of sodium starch glycolate, and blended using a Turbula mixer at 49 RPM for 15 minutes. Next, 100 mg of magnesium stearate was added and mixed for a further 5 minutes. Then, tablets were prepared using a carver press that pressed 5 / 16 inch round standard concave tablets at 1500 pounds.

[0079] An amorphous solid dispersion (ASD) containing HPMCAS-L polymer in a 5:1 ratio to compound (I) was formed by dissolving 1500 mg of the compound and 7500 mg of HPMCAS-L polymer in 56.25 mL of DMAc solvent. The solution was stirred overnight to ensure complete dissolution. Next, 500 mL of cold 0.1N HCl was added to a 1 L beaker. An IKA T25 rotor-stator homogenizer was added to the beaker and heated to 20,000 RPM. Then, 50 mL of the compound / polymer solution was added to the high-shear zone of the rotor-stator mixer by syringe through a 14G needle. The compound / polymer mixture rapidly precipitated and was mixed for a further 2 minutes on ice. The resulting suspension was filtered and added to 500 mL of fresh cold 0.1N HCl. The resulting suspension was slurry-washed for a further 2 minutes and then filtered. Next, 250 mL of fresh, cold 0.1N HCl was added to the top of the resulting cake and washed by displacement. The final cake was then dried under vacuum and blown over nitrogen overnight. The resulting ASD had a 93.3% assay rate. 2150 mg of the intermediate was added to 4750 mg of microcrystalline cellulose, 2500 mg of lactose monohydrate, and 500 mg of sodium starch glycolate and blended for 15 minutes at 49 RPM using a Turbula mixer. Next, 100 mg of magnesium stearate was added and mixed for a further 5 minutes. Then, tablets were manufactured using a carver press that pressed standard 5 / 16 inch round concave tablets at 1500 pounds.

[0080] Tablets containing the crystalline compound of formula (I) were prepared by blending 150 mg of the compound, 3375 mg of microcrystalline cellulose, 3525 mg of lactose monohydrate, and 375 mg of sodium starch glycolate in a Turbula mixer at 49 RPM for 15 minutes. Tablets were then prepared using a carver press that pressed standard 5 / 16-inch round concave tablets at 1500 pounds.

[0081] Example 3 - Bioavailability of the compound of formula (I) Pharmacokinetic (PK) studies of the above-mentioned ASD and crystalline formulations were conducted using fed and fasted dogs. In the fasted group, the animals were fasted overnight after administration 4 hours prior to feeding. At this point, blood samples were taken before feeding the animals. In the fed group, the animals were fasted overnight approximately 30 minutes before administration of the pharmaceutical composition, and then fed daily.

[0082] The results suggest that, under fasting conditions, formulations containing the compound of formula (I) in amorphous solid dispersions (ASDs) with HPMCAS-L achieve a significant improvement in bioavailability. However, under feeding conditions, there is no significant change in bioavailability compared to formulations prepared using the crystalline compound of formula (I). See Figure 2.

[0083] Example 4 - Nucleation inhibitor In an attempt to improve the bioavailability of the compound of formula (I) in animals administered under feeding conditions, nucleation inhibitors were added to the pharmaceutical composition to reduce the likelihood of the compound crystallizing. Several nucleation inhibitor polymers were evaluated for their ability to maintain the compound of formula (I) in in vitro screening. A 0.5% solution of each nucleation inhibitor polymer was prepared in simulated gastric juice (pH 1.8). 75 μL of 10 mg / mL API in DMSO was added to 5 mL of the 0.5% polymer solution and monitored at 272 nm for 2 hours using a PION UV probe. See Figure 3. The concentration of the compound of formula (I) was maintained throughout the entire 2-hour test when using the nucleation inhibitor polymers methylcellulose A4C (MC A4C) and hydroxypropylmethylcellulose E50 (HPMC E50). When using other polymers, the concentration of the compound of formula (I) was initially maintained but eventually decreased before the completion of the 2-hour test. This is in contrast to the control sample, which used only simulated gastric juice (SGF), in which the concentration of compound (I) decreased almost immediately. The results suggest that MC A4C and HPMC E50 are suitable antinucleation polymers for improving bioavailability under feeding conditions because these polymers can maintain supersaturation levels of compound (I) for longer periods compared to the other polymers tested.

[0084] Example 5 - Efficacy Test This compound is currently being evaluated in a masked and randomized proof-of-concept trial using dogs diagnosed with atopic dermatitis. The purpose of this study is to evaluate the efficacy and tolerability of this compound for atopic dermatitis in customer-owned dogs. The compound will be evaluated in two doses and compared to a placebo control. Dogs will be administered orally twice daily for up to 14 days, followed by administration once daily for up to 28 days or once daily for 28 days. Pruritus and skin lesions will be evaluated using the Visual Pruritus Analog Scale (PVAS) and the Canine Atopic Dermatitis Severity Index (CADESI-4) scoring tools, respectively.

[0085] The Canine Atopic Dermatitis Severity Index (CADESI-4) is a severity scale used to grade skin lesions in clinical trials for the treatment of atopic dermatitis (AD) in dogs. Three lesion types (erythema, lichenification, and alopecia / exfoliation) are scored on a scale of 0 to 3 for each of 20 body parts, with a maximum score of 180. We propose 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.

[0086] The Visual Analog Scale for Itch (PVAS) is a visual analog scale that includes features for both the severity of itching and the behaviors associated with itching. It is commonly used in clinical trials for the treatment of dogs with Alzheimer's disease (AD) to determine the severity of pruritus. PVAS: Hill, PB, Lau, P., and Rybnicek, J. Development of an owner-rated scale to measure the severity of pruritus in dogs. Vet. Dermatol. 18:301-308, 2007.

Claims

1. a) a compound of formula (I) dispersed in a hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer matrix 【Chemistry 1】 and b) a pharma- ceutically acceptable carrier, wherein the compound of formula (I) is present in a substantially amorphous form, and wherein the pharmaceutical composition is a tablet; and wherein the pharmaceutical composition is administered to the animal in a fasted state. Pharmaceutical compositions.

2. 2. The pharmaceutical composition of claim 1, wherein the ratio of polymer to compound of formula (I) in the dispersion is between about 1:1 and about 20:1, or between about 10:1 and about 5:

1.

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the hydroxypropyl methylcellulose acetate succinate polymer is L grade (HPMCAS-L).

4. 4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the amount of the compound of formula (I) in the pharmaceutical composition is between about 0.5 to about 10%, or between about 1.0 to about 5.0%, or about 2% (w / w).

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the amount of HPMCAS-L polymer in the pharmaceutical composition is from about 10 to about 30%, or between about 15 to about 25%, or about 20% (w / w).

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the pharmaceutical carrier comprises one or more excipients selected from fillers, lubricants, binders, antinucleating agents and disintegrants.

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

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

9. The pharmaceutical composition according to any one of claims 6 to 8, wherein the disintegrant is sodium starch glycolate.

10. The pharmaceutical composition of any one of claims 6 to 9, wherein the binder is hydroxypropyl cellulose.

11. The pharmaceutical composition according to any one of claims 6 to 10, wherein the antinucleating agent is methylcellulose or hydroxypropylmethylcellulose.

12. A method for treating atopic dermatitis, comprising administering to a non-human animal in need thereof an effective amount of the pharmaceutical composition of any one of claims 1 to 11.

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

14. The method according to any one of claims 12 to 13, wherein administration is oral.

15. The method of any one of claims 12 to 14, wherein the animal is a companion animal.

16. The method of any one of claims 12 to 15, wherein the composition is administered once a day or twice a day.

17. 17. The method of any one of claims 12 to 16, wherein the composition is administered twice daily for 14 days, followed by once daily for 14 days.

18. The method of any one of claims 12 to 17, wherein the composition is administered once daily for 28 days.

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

20. A method for producing a pharmaceutical composition according to any one of claims 1 to 11, comprising the steps of: i) dissolving the compound of formula (I) and the polymer in a solvent; ii) combining the solution of step i) with an anti-solvent to precipitate an amorphous solid dispersion of the compound of formula (I) in the polymer; iii) blending the amorphous solid dispersion of step ii) with a pharma- ceutically acceptable carrier; and iv) compressing the product of step iii) into a tablet to produce a pharmaceutical composition; A process wherein the solvent is dimethylacetamide (DMAc) and the anti-solvent is an acidic aqueous solution having a pH of less than 5, preferably a hydrochloric acid solution, more preferably 0.1 N hydrochloric acid.

21. the ratio of solvent to anti-solvent is between 1:1 and 1:50, or between 1:5 and 1:10; 21. The method of claim 20.

22. The method according to any one of claims 20 to 21, wherein the precipitate of step ii) is washed with additional anti-solvent.

23. The method of any one of claims 20 to 22, wherein the pharma- ceutically acceptable carrier comprises one or more of a filler, a disintegrant, a lubricant, a binder and an antinucleating agent.

24. 24. The method of claim 23, wherein the filler is microcrystalline cellulose, lactose or a mixture thereof.

25. 25. The method of claim 23 or 24, wherein the disintegrant is sodium starch glycolate.

26. The method of any one of claims 23 to 25, wherein the lubricant is magnesium stearate.

27. The method of any one of claims 23 to 26, wherein the binder is hydroxypropyl cellulose.

28. The method of any one of claims 23 to 27, wherein the antinucleating agent is methylcellulose or hydroxypropylmethylcellulose.

29. 1. A method for producing a pharmaceutical composition, the method comprising: i) dissolving the compound of formula (I) and the polymer in a solvent; ii) combining the solution of step i) with a poor solvent to precipitate a dispersion of the compound of formula (I) in the polymer; iii) blending the dispersion of step ii) with a pharma- ceutically acceptable carrier; wherein the pharmaceutical carrier comprises one or more excipients selected from fillers, lubricants, binders, antinucleating agents and disintegrants.

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