Pharmaceutical compositions containing pyrazole compounds dispersed in a polymer matrix - Patents.com

Abstract

Pharmaceutical compositions of pyrazole compounds dispersed in a polymer matrix 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] Applicants have found that dispersion of a compound of formula (I) in a hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer matrix results in improved bioavailability of the compound of formula (I). Summary of the Invention [Problem to be solved by the invention]

[0008] 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 dispersed in a HPMCAS polymer matrix and a pharma- ceutical acceptable carrier.

[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.

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

[0011] [Figure 1] Powder X-ray diffraction (PXRD) measured the amount of amorphous compound present in an amorphous solid dispersion (ASD). [Diagram 2] Pharmacokinetic (PK) study demonstrating the bioavailability of an amorphous solid dispersion of the compound of formula (I) in hydroxypropyl methylcellulose acetate succinate (HPMCAS). [Diagram 3] Several antinucleation polymers were evaluated for their ability to retain compounds of formula (I) in an in vitro screen. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description Applicant has developed a formulation 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]

[0013] Although the compound of formula (I) is a selective Janus kinase (JAK) inhibitor, the compound of formula (I) is a compound with low water solubility. Generally, low water solubility of a pharma- ceutically active agent leads to poor oral bioavailability in dogs, and therefore poor biological effectiveness of the agent. However, the compound of formula (I) is a compound with low water solubility. Low water solubility leads to poor oral bioavailability in dogs, often 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 compound's high melting point (>250°C) and low solubility in volatile solvents such as isopropanol, acetone and dichloromethane, conventional techniques for producing ASDs, such as spray drying and hot melt extrusion, were not conducive to producing ASDs containing the compound of formula (I). Therefore, ASDs were prepared by co-precipitation or cPAD (co-precipitation amorphous dispersion). In this method, the compound and polymer were dissolved in a solvent. The compound-polymer solution was then rapidly precipitated in a poor solvent under high shear in a rotor-stator homogenizer. A compound-polymer amorphous solid dispersion was then formed.

[0014] The applicant has found that the use of a compound of formula (I) in an amorphous state as part of an amorphous solid dispersion results in a formulation with improved bioavailability when compared to a formulation having a compound of formula (I) in a crystalline form.

[0015] By substantially amorphous form is meant 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] A tablet is a solid dosage form containing the active ingredient, with or without suitable excipients, and prepared either by 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), pp. 18-25. When the active ingredient is in amorphous form, it is called an amorphous solid dispersion (ASD).

[0018] In a drug-polymer matrix, some polymer chains physically entrap the 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 and 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 hydroxylpropyl contents. For example, AquaSolve™ brand (Ashland) 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, antinucleating agents, and disintegrants.

[0023] The pharmaceutical composition may 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.

[0024] The pharmaceutical composition may contain one or more glidants. Glidants are used to improve flowability. In one embodiment, the glidant 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 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, lactose monohydrate cellulose, or a mixture thereof.

[0026] The pharmaceutical composition further comprises 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 (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. 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).

[0028] The pharmaceutical composition further comprises one or more antinucleating agents. Antinucleating agents inhibit the crystallization of the formulation. Examples include cellulose-based polymers such as methylcellulose and hydroxypropylmethylcellulose, 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-co-glycolic acid) (PLGA), methylcellulose A4C, hydroxypropylmethylcellulose E50, and polycaprolactone (PCL). In one embodiment, the antinucleating agent is methylcellulose A4C or hydroxypropylmethylcellulose E50.

[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] *The total w / w% of microcrystalline cellulose and lactose monohydrate must be at least 40%.

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

[0032] An embodiment of the present invention is a) A compound of formula (I) dispersed in a hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer matrix [ka] and b) a pharma- ceutically acceptable carrier, wherein the compound of formula (I) is present in a substantially amorphous form and the pharmaceutical composition is a tablet.

[0033] In one embodiment, 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.

[0034] In one embodiment, the amount of the 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] Manufacturing method of amorphous solid dispersion (ASD) formulation In this method, the active ingredient (API) and polymer () were dissolved in a solvent. The API-polymer solution was then rapidly precipitated in an anti-solvent. The precipitate was washed and dried. An amorphous solid dispersion of 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 anti-solvent is an acidic aqueous solution having a pH less than 5, preferably hydrochloric acid, preferably 0.1 N HCl.

[0041] In one embodiment, api-polymer precipitation from the solvent; anti-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:anti-solvent precipitation followed by 10 slurry washes, followed by 5 displacement washes.

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

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

[0045] In one embodiment, surfactants, disintegrants and antinucleating agents are added within or between the ASDs, hi one embodiment, fillers, binders, lubricants are blended after the ASD is formed and dried.

[0046] An embodiment of the present invention is a method for producing the above pharmaceutical composition, the method comprising the steps of: i) dissolving a compound of formula (I) and a polymer in a solvent; ii) combining the solution of step i) with a poor 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; Here, the solvent is dimethylacetamide (DMAc) and the anti-solvent is an acidic aqueous solution with a pH of less than 5, preferably a hydrochloric acid solution, more preferably 0.1 N hydrochloric acid.

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

[0048] In one embodiment, the precipitate of step ii) is washed with additional anti-solvent.

[0049] In one embodiment, the pharma- ceutically acceptable carrier comprises one or more of a filler, a disintegrant, a lubricant, a binder, and an antinucleating agent.

[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 antinucleating agent is methylcellulose A4C or hydroxypropyl methylcellulose E50.

[0055] An embodiment of the invention is a method for producing a pharmaceutical composition, the method comprising: i) dissolving a compound of formula (I) and a 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; Here, the pharmaceutical carrier comprises one or more excipients selected from a filler, a lubricant, a binder, an antinucleating agent and a disintegrant.

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

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

[0058] The pharmaceutical composition is administered orally.

[0059] 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.

[0060] 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.

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

[0062] In one embodiment, the composition is administered in a fed state.

[0063] In one embodiment, the composition is administered in the fasted state.

[0064] In one embodiment, the pharmaceutical composition is administered once daily 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, 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.

[0067] In one embodiment, the pharmaceutical composition is administered once daily for as long as medically necessary, including for the life of the animal.

[0068] 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.

[0069] In an embodiment, the pharmaceutical composition is administered twice on each of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, and then once daily for as long as medically necessary, including for the life of the animal.

[0070] The pharmaceutical compositions of the compounds 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 testing with compounds of formula (I) was conducted with a number of polymers (vinylpyrrolidone-vinyl acetate copolymer (VA64), hydroxypropyl methylcellulose (HPMC), and HPMCAS) with volatile solvents (tetrahydrofuran (THF), methyl ethyl ketone (MEK), methyl tert-butyl ether (MTBE), and heptane). These experiments resulted in solutions, semi-solids, solids containing crystalline material, or amorphous solids that did not lend themselves to downstream processing such as grinding and compaction. Many of the solvents and polymers used to make ASDs with compounds of formula (I) resulted in sticky materials that could not be blended and compressed. Other solvent / polymer combinations resulted in extremely hard materials that could not be ground to a uniform particle size in a conventional mill.

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

[0073] [Table 4]

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

[0075] [Table 5]

[0076] Samples of amorphous solid dispersions (ASDs) with different ratios of HPMACAS polymer to active ingredient compound of formula (I) were prepared and analyzed by powder x-ray diffraction (PXRD) to determine the amount of amorphous compound present in the ASDs. The ASDs with a polymer to compound ratio of 3:1 showed a small amount of crystallinity. However, the ASDs with polymer to compound ratios of 5:1 and 10:1 did not show substantial crystallinity. See Figure 1. The baseline trace was the crystalline form of the compound of formula (I). The other traces showed some degree of crystallinity in the ASDs with varying ratios of api to polymer. The traces of the ASDs with a polymer to compound ratio of 3:1 showed the most similarity to the crystalline traces, thus indicating that a significant amount of the crystalline form of the compound of formula (I) was present in the 3:1 ASDs. The traces from ASDs with polymer to compound ratios of 5:1, 7:1 and 10:1 were less similar to the crystalline traces, thus indicating that 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 of formula (I) with hydroxypropyl methylcellulose acetate succinate (HPMCAS) In this process, the compound of formula (I) (i.e., the active ingredient (API)) and polymer (hydroxypropyl methylcellulose acetate succinate, grade L) were dissolved in a solvent (DMAc). The API-polymer solution was then rapidly precipitated in an anti-solvent (0.1N HCl) under high shear in a rotor-stator homogenizer. Precipitation and washing conditions were achieved using a solvent:anti-solvent ratio of 1:10. Precipitation was followed by 10 slurry washes, followed by 5 displacement washes. Amorphous solid dispersions of the compound and polymer were formed and compressed into tablets.

[0078] An amorphous solid dispersion (ASD) with a 10:1 ratio of HPMCAS-L polymer to compound of formula (I) was formed by dissolving 750 mg of compound and 7500 mg of HPMCAS-L polymer in 56.25 mL of DMAc solvent. The solution was stirred overnight to ensure complete dissolution. 500 mL of cold 0.1 N HCl was then added to a 1 L beaker. An IKA T25 rotor-stator homogenizer was added to the beaker and brought to 20,000 RPM. 50 mL of the compound / polymer solution was then added to the high shear zone of the rotor-stator mixer by a syringe through a 14G needle. The compound / polymer mixture precipitated rapidly and was mixed for an additional 2 minutes on ice. The resulting suspension was filtered and added to 500 mL of fresh cold 0.1 N HCl. The resulting suspension was slurry washed for an additional 2 minutes and then filtered. 250 mL of fresh cold 0.1N HCl was then added to the top of the resulting cake and washed by displacement. The final cake was then dried under vacuum and blown with nitrogen overnight. The resulting dry ASD had an assay of 82.5%. To make the 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 for 15 minutes at 49 RPM using a Turbula mixer. 100 mg of magnesium stearate was then added and mixed for an additional 5 minutes. The tablets were then made using a Carver press that presses 5 / 16 inch round standard concave tablets at 1500 pounds.

[0079] An amorphous solid dispersion (ASD) with a 5:1 ratio of HPMCAS-L polymer to the compound of formula (I) was formed by dissolving 1500 mg of compound and 7500 mg of HPMCAS-L polymer in 56.25 mL of DMAc solvent. The solution was stirred overnight to ensure complete dissolution. 500 mL of cold 0.1 N HCl was then added to a 1 L beaker. An IKA T25 rotor-stator homogenizer was added to the beaker and turned on to 20,000 RPM. 50 mL of the compound / polymer solution was then added to the high shear zone of the rotor-stator mixer by a syringe through a 14G needle. The compound / polymer mixture precipitated rapidly and was mixed for an additional 2 minutes on ice. The resulting suspension was filtered and added to 500 mL of fresh cold 0.1 N HCl. The resulting suspension was slurry washed for an additional 2 minutes and then filtered. 250 mL of fresh cold 0.1N HCl was then added to the top of the resulting cake and washed by displacement. The final cake was then dried under vacuum and blown with nitrogen overnight. The resulting ASD had an assay of 93.3%. 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. 100 mg of magnesium stearate was then added and mixed for an additional 5 minutes. Tablets were then produced using a Carver press pressing 5 / 16 inch round standard 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 using a Turbula mixer at 49 RPM for 15 minutes. Tablets were then prepared using a Carver press which presses 5 / 16 inch round standard concave tablets at 1500 pounds.

[0081] Example 3 - Bioavailability of compounds of formula (I) Pharmacokinetic (PK) studies of the ASD and crystal formulations were conducted in fed and fasted dogs. Animals were fasted overnight and fed 4 hours after dosing. At this time, blood samples were taken before feeding the animals. After an overnight fast, the animals were fed their daily food approximately 30 minutes before administration of the pharmaceutical composition. .

[0082] The results suggest that in the fasted state, significant improvement in bioavailability is achieved for the formulation containing the compound of formula (I) in an amorphous solid dispersion (ASD) formulation with HPMCAS-L. However, in the fed state, there is no significant change in bioavailability compared to the formulation prepared with the crystalline compound of formula (I). See Figure 2.

[0083] Example 4 - Antinucleating Agent In an attempt to improve the bioavailability of the compound of formula (I) in animals administered in a fed state, antinucleating agents were added to pharmaceutical compositions to reduce the likelihood of the compound crystallizing. Several antinucleating agent polymers were evaluated for their ability to maintain the compound of formula (I) in an in vitro screen. A 0.5% solution of each antinucleating polymer was prepared in simulated gastric fluid (pH 1.8). 75 uL of 10 mg / mL API in DMSO was added to 5 mL of the 0.5% polymer solution and monitored for 2 hours at 272 nm with a PION UV probe. See Figure 3. The concentration of the compound of formula (I) was maintained for the entire 2 hour test when using the antinucleating polymers methylcellulose A4C (MC A4C) and hydroxypropyl methylcellulose E50 (HPMC E50). When using the other polymers, the concentration of the compound of formula (I) was maintained initially but eventually declined before the 2 hour test was completed. This is in contrast to the control sample using only simulated gastric fluid (SGF), where the concentration of compound of formula (I) decreased almost immediately. The results suggest that MC A4C and HPMC E50 are suitable antinucleating polymers for improving bioavailability in the fed state, because these polymers are able to maintain the supersaturation level of compound of formula (I) for a long period of time compared to the other polymers tested.

[0084] Example 5 - 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.

[0085] 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.

[0086] The Itch Visual Analog Scale (PVAS) is a visual analog scale that includes features of both itch severity and itch-related behaviors. 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-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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