Modified Release Formulation of a Pyrimidinylaminopyrazole Compound and Treatment Methods

Abstract

This disclosure relates to modified-release formulations of a pyrimidinylaminopyrazole compound and treatment methods.

Description

1 / 65 Modified Release Formulation of a Pyrimidinylaminopyrazole Compound and Treatment Methods CROSS-REFERENCE TO RELATED REQUESTS

[001] This application claims priority from U.S. Provisional Patent Application No. 62 / 855,740, filed May 31, 2019, disclosure of which is incorporated herein by full reference for all purposes. FIELD

[002] This disclosure relates to formulations of 2-methyl2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2yl)amino)-1H-pyrazol-1-yl)propanenitrile for use in the treatment of peripheral and neurodegenerative diseases, including Parkinson's disease. This disclosure also relates to processes for obtaining modified-release formulations. BACKGROUND OF THE INVENTION

[003] Parkinsonism is a term that encompasses several conditions, including Parkinson's disease (PD) and other conditions with similar symptoms, collectively known as parkinsonism, such as slow movement, rigidity (inflexibility), and problems walking. Most people with parkinsonism have idiopathic Parkinson's disease, also known as Parkinson's disease. Idiopathic means that the cause is unknown. The most common symptoms of idiopathic Parkinson's are tremor, rigidity, and slowness of movement. Although the exact causes of Parkinson's disease are unknown, a combination of genetic and environmental factors is believed to contribute to the etiology of the disease.Approved medications for the treatment of Parkinson's disease include dopamine replacement therapies (levodopa / carbidopa), dopamine agonists (pramipexole, ropinirole, rotigotine, apomorphine), catechol-O-methyltransferase (COMT) inhibitors (entacapone, levodopa / carbidopa / entacapone, tolcapone, opicapone), monoamine oxidase B (MAO-B) inhibitors (selegiline hydrochloride, rasagiline, safinamide), amantadine, anticholinergic medications (trihexyphenidyl, benztropine mesylate), acetylcholinesterase inhibitor (rivastigmine), and 5-HT2A receptor antagonists. Petition 870210111193, dated 11 / 30 / 2021, pp. 157 / 267 2 / 65 of serotonin, receptor agonist (pimavanserin), and dopamine transporter for image generation (ioflupane I-123). However, these medications provide symptomatic benefits for patients with Parkinson's disease and do not reduce disease progression.

[004] Combined genetic and biochemical evidence implicates certain kinase functions in the pathogenesis of neurodegenerative disorders (Christensen, KV (2017) Progress in medicinal chemistry 56:37-80; Fuji, RN et al (2015) Science Translational Medicine 7(273):273ra15; Taymans, JM et al (2016) Current Neuropharmacology 14(3):214-225). Among the genes that have been implicated in Parkinson's disease is Park8, which encodes leucine-rich repeat kinase 2 (LRRK2), a complex signaling protein that is a key therapeutic target, particularly in Parkinson's disease (PD). Mutations in Park8 are found in both familial and non-familial (sporadic) forms of Parkinson's disease, and increased LRRK2 kinase activity is implicated in the pathogenesis of Parkinson's disease.Mutations in the LRRK2 gene are the most frequent genetic cause of familial Parkinson's disease and a major driver of lysosomal dysfunction, which contributes to the formation of Lewy body protein aggregates and neurodegeneration. LRRK2 regulates lysosomal genesis and function, which is impaired in Parkinson's disease and can be restored by inhibiting LRRK2, potentially reducing disease progression in patients with an LRRK2 gene mutation, as well as in patients with sporadic or idiopathic Parkinson's disease.

[005] LRRK2 kinase inhibitors represent a new class of therapeutics with the potential to address the underlying biology of Parkinson's disease, ALS and other neurodegenerative diseases (Estrada, AA et al (2015) Jour.Med.Chem.58(17):6733-6746; Estrada, AA et al (2013) Jour.Med.Chem.57:921-936; Chen, H. et al (2012) Jour.Med.Chem.55:5536-5545; Estrada, AA et al (2015) Jour.Med.Chem.58:6733-6746; Chan, BK et al (2013) ACS Med.Chem.Lett.4:85-90; US 8354420; US 8569281; US 8791130; US 8796296; US 8802674; US 8809331; US 8815882; US 9145402; US Petition 870210111193, dated 11 / 30 / 2021, pp. 158 / 267 3 / 65 9212173; US 9212186; US 9932325; WO 2011 / 151360; WO 2012 / 062783; WO 2013 / 079493). LRRK2 activity is linked to central mechanisms of Parkinson's disease pathology through its role in lysosomal function. An LRRK2 kinase inhibitor, a genetically validated target, may improve lysosomal function in LRRK2-PD and potentially in idiopathic Parkinson's disease. Therefore, LRRK2 inhibition may intervene in an important pathway in Parkinson's disease and prevent or moderate the accumulation of motor and non-motor deficits that define Parkinson's disease progression.

[006] There is a need for new therapies aimed at mitigating or delaying disease progression and postponing late motor complications for neurodegenerative disorders. In addition, there is a need for solid oral dosage forms of effective pharmaceutical compositions to achieve optimal blood concentrations between the maximum tolerated dose and the minimum effective dose. Optimized solid oral dosage forms modulate release and pharmacokinetic profile, minimize dosing frequency, and minimize tablet burden in patients with limited swallowing ability and other compliance factors. DESCRIPTION

[007] This disclosure relates to modified-release formulations of a pyrimidinylaminopyrazole kinase inhibitor, referred to herein as the compound of Formula I, named 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin2-ylamino)-1H-pyrazol-1-yl)propanenitrile, and having the structure: h3c ch3ou tautomers, polymorphs or their pharmaceutically acceptable salts.

[008] One aspect of this disclosure includes a formulation of Petition 870210111193, dated 11 / 30 / 2021, pp. 159 / 267 4 / 65 modified-release comprising a therapeutically effective amount of 2-methyl-2-(3-methyl-4-(4-(methylamino)5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1yl)propanenitrile and at least one release-modifying agent.

[009] An example embodiment of the formulation comprises pellets containing 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and coated with at least one release-modifying agent. In another example embodiment, the pellets contain 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile in their core. In another example embodiment, the pellets contain an inert core coated with 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)1H-pyrazol-1-yl)propanenitrile.

[010] An example representation of the formulation is one in which the release of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1yl)propanenitrile is less than 60% in two hours and greater than 60% in 8 hours when tested using a USP Type II instrument at 50-75 rpm and 37°C in McIlvaine buffer pH 3, wherein the formulation is a tablet.

[011] An example representation of the formulation is one in which the release of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1yl)propanenitrile is less than 60% in one hour and greater than 70% in 8 hours when tested using the USP Type II apparatus at 100 rpm and 37°C in McIlvaine buffer pH 3, wherein the formulation is a capsule containing pellets.

[012] An example representation of the formulation is one in which the release of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is less than 60% in one hour, wherein the formulation is a capsule containing pellets. In some representations, less than 60% of the compound of Formula I is released in 2 hours (per Petition 870210111193, dated 11 / 30 / 2021, pp. 160 / 267 5 / 65 example, 5-40% and 5-15%). In some representations, less than 60% of the Formula I compound is released in 4 hours (e.g., 15-60% and 15-25%). In some representations, less than 60% of the Formula I compound is released in 12 hours (e.g., 35-55% and 40-60%).

[013] An example representation of the formulation is where 2methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin2-ylamino)-1H-pyrazol-1-yl) propanenitrile has a Cmax that is decreased relative to an immediate-release formulation after administration to a subject (e.g., a human subject).

[014] An example representation of the formulation is one in which Cmax is decreased by at least 20% (e.g., 20-80%, 40-80%, 60-80% and 65-75%).

[015] An example representation of the formulation is one in which the steady-state Cmax / Cmin ratio of 2-methyl-2-(3methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)1H-pyrazol-1-yl)propanenitrile in blood varies from about 1.5 to about 4.5 during the first 12 hours after administration to a subject.

[016] An example representation of the formulation is one in which the modified-release formulation comprises 10% to 50% by weight of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1yl)propanenitrile.

[017] An example representation of the formulation is in which 2methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin2-ylamino)-1H-pyrazol-1-yl)propanenitrile is crystalline.

[018] An example representation of the formulation is in which crystalline 2methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin2-ylamino)-1H-pyrazol-1-yl)propanenitrile is milled or micronized.

[019] An example representation of the formulation is one in which the release modifier comprises from 3% to 60% by weight of the formulation (e.g., 3-10%, approximately 5%, approximately 7%, or approximately 9%).

[020] An example representation of the formulation is one in which Petition 870210111193, dated 11 / 30 / 2021, pp. 161 / 267 6 / 65 The release modifier agent is selected from the group consisting of MCC (Microcrystalline cellulose), HPC (Hydroxypropylcellulose), HPMC (Hydroxypropylmethylcellulose), PEG (Polyethylene glycol glycerides), PVA (Polyvinyl alcohol), PVP (Polyvinylpyrrolidone), CAP (Cellulose acetate phthalate), CMC-Na (Sodium carboxymethylcellulose), HPMCAS (Hydroxypropylmethylcellulose acetate succinate), HPMCP (Hydroxypropylmethylcellulose phthalate), (Poly)methylacrylate-co-methyl methacrylate-co-methacrylic acid, (Poly)methacrylic-co-ethyl acrylate acid, (Poly)methacrylic-co-methyl methacrylate acid, CA (Cellulose acetate); CAB (Cellulose acetate butyrate); EC (Ethylcellulose), Poly(ethyl acrylate-co-methyl methacrylate), Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), PVAc (Polyvinyl acetate) and HPMC / CMC.

[021] An example representation of the formulation is one in which the release modifier agent is selected from the group consisting of Aquacoat®, Walocel®, HP 50 / HP 55, Aqoat®, EUDRAGIT® FS 30 D, EUDRAGIT® L 30 D-55 / L 100-55, EUDRAGIT® L 12.5 / EUDRAGIT® L 100, EUDRAGIT® S 12.5 / EUDRAGIT® S 100, Carbopol® polymers, Eastman CA, Eastman CAB, Eastman CAB, Ethocel™, Aquacoat® ECD or Surelease® or Glyceride GatteCoat™, EUDRAGIT® NE 30 D, EUDRAGIT® NM 30 D, EUDRAGIT® RL 30 D, EUDRAGIT® RL 100 / RL PO, EUDRAGIT® RS 30 D, EUDRAGIT® RS 100 / RS, Kollicoat® SR 30 D, Kollidon®, Walocel® HM-PPA, Kollicoat® MAE 30 DP / 100 P and Eastacryl 30 D.

[022] An example representation of the formulation is one in which the release modifier agent is selected from the group consisting of microcrystalline cellulose, hydroxypropylmethylcellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, Kollicoat®, Carbopol® and Aquacoat.

[023] An example representation of the formulation is one in which the release modifier is polyvinyl acetate.

[024] As an example representation, the release modifier agent is a mixture of polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate. In some Petition 870210111193, dated 11 / 30 / 2021, pp. 162 / 267 In some representations, the mixture of polyvinyl acetate, polyvinylpyrrolidone, and sodium lauryl sulfate is present in a ratio of approximately 90:9:1. In some representations, the mixture provides a weight gain coating of approximately 59% to a pellet containing 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1yl)propanenitrile. In some representations, the mixture provides a weight gain coating of approximately 5% to the pellet. In some representations, the mixture provides a weight gain coating of approximately 6% to the pellet. In some representations, the mixture provides a weight gain coating of approximately 7% to the pellet. In some representations, the mixture provides a weight gain coating of approximately 8% to the pellet. In some representations, the mixture provides a weight gain coating of approximately 9% to the pellet.

[025] In an example representation of the formulation, the release modifier agent is Kollicoat® SR 30D. In an example representation of the formulation, Kollicoat® SR 30D provides a weight gain coating of approximately 5-9% for the pellet. In an example representation of the formulation, Kollicoat® SR 30D provides a weight gain coating of approximately 5% for the pellet. In an example representation of the formulation, Kollicoat® SR 30D provides a weight gain coating of approximately 6% for the pellet. In an example representation of the formulation, Kollicoat® SR 30D provides a weight gain coating of approximately 7% for the pellet. In an example representation of the formulation, Kollicoat® SR 30D provides a weight gain coating of approximately 8% for the pellet. In an example representation of the formulation, Kollicoat® SR 30D provides a weight gain coating of around 9% for the pellet.

[026] An example representation of the formulation comprises one or more excipients selected from the group consisting of microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, purified talc, Petition 870210111193, dated 11 / 30 / 2021, pp. 163 / 267 8 / 65 colloidal silicon dioxide and magnesium stearate coating.

[027] An example representation of the formulation is one in which the formulation is a tablet.

[028] An example representation of the formulation in which the tablet comprises 10 to 500 mg of 2-methyl-2-(3-methyl-4-(4(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile.

[029] An example representation of the formulation is one in which the tablet comprises 40 to 120 mg of 2-methyl-2-(3-methyl-4-(4(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile.

[030] An example representation of the formulation is one in which the tablet comprises 30 to 80 mg of 2-methyl-2-(3-methyl-4-(4(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile.

[031] An example representation of the formulation is one in which the release modifier is HPMC.

[032] An example representation of the formulation is one in which the release modifier is a PARTECK® polymer.

[033] An example representation of the formulation is one in which the release modifier comprises 20-30% w / w of the formulation.

[034] An example representation of the formulation where the formulation is a capsule containing pellets.

[035] An example representation of the formulation is one in which the capsule is a combination of multiple particles of immediate-release pellets and modified-release pellets contained within the capsule.

[036] An example representation of the formulation is one in which the pellets comprise a release modifier selected from Kollicoat®, Carbopol® and Aquacoat®.

[037] An example representation of the formulation is one in which the formulation is a combination of multiple particles of immediate-release pellets and delayed-release pellets contained in a capsule. Petition 870210111193, dated 11 / 30 / 2021, pp. 164 / 267 9 / 65

[038] An example representation of the formulation is one in which the modified-release formulation is selected from a delayed-release pellet formulation, a controlled-release pellet formulation, a prolonged-release pellet formulation, and a pulsed-release pellet formulation.

[039] An example representation of the formulation is one in which the formulation comprises a coating agent, wherein that agent is EUDRAGIT®.

[040] An example representation of the formulation is one in which the coating agent comprises from 3% to 60% EUDRAGIT® by weight of the formulation.

[041] An example representation of the formulation is one in which the coating agent comprises EUDRAGIT® RS 30 D up to 20% w / w.

[042] An example representation of the formulation is one in which the coating agent comprises EUDRAGIT® NM 30 D up to 60% w / w.

[043] One aspect of the present disclosure includes a method for preparing a modified-release formulation comprising: (a) coating of an inert core selected from the group consisting of sugar, MCC and tartaric acid, with 2-methyl-2-(3methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)1H-pyrazol-1-yl)propanenitrile to form an API core pellet; (b) coating the API core pellet with a cosmetic, non-functional sealing coating to form a sealing-coated pellet; and (c) coating the sealing-coated pellet with a release-modifying agent to form the modified-release formulation.

[044] An example representation of the method for preparing a modified-release formulation is one in which the inert core is selected from a sugar, microcrystalline cellulose (MCC), tartaric acid, polyols, carnauba wax, dioxide Petition 870210111193, dated 11 / 30 / 2021, pp. 165 / 267 10 / 65 silicon and combinations thereof.

[045] An example representation of the method of preparing a modified-release formulation is one in which the non-functional cosmetic sealing coating is selected from hydroxypropyl methylcellulose (HPMC) and a mixture of hypromellose and ethylcellulose.

[046] An example representation of the method of preparing a modified-release formulation is one in which the release-modifying agent is selected from the group consisting of KOLLICOAT®, EUDRAGIT®, hydroxypropylmethylcellulose (HPMC) and a mixture of hypromellose and ethylcellulose.

[047] One aspect of the present disclosure includes a method for preparing a modified-release formulation comprising: (a) roller compaction of 2-methyl-2-(3-methyl-4-(4(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and one or more excipients selected from the group consisting of microcrystalline cellulose, hydroxypropylmethylcellulose, croscarmellose sodium, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, purified talc, colloidal silicon dioxide and magnesium stearate, in which a pellet is formed; and (b) polymer coating of the pellet with a dispersion of a coating agent selected from KOLLICOAT®, Carbopol®, Aquacoat® and OPADRY® White.

[048] An example representation of the method for preparing a modified-release formulation further comprises one or more selected extrusion, spheronization and compression steps.

[049] An example representation of the method for preparing a modified-release formulation further comprises filling a soft or hard capsule shell with the coated pellets.

[050] One aspect of the present disclosure includes a method for preparing tablets of a modified-release formulation comprising: (a) combination of a dry mixture of 2-methyl-2-(3-methyl-4-(4 Petition 870210111193, dated 11 / 30 / 2021, pp. 166 / 267 11 / 65 (methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, povidone, croscarmellose sodium, silicon dioxide, talc, microcrystalline cellulose and magnesium stearate; (b) preparation of a dry granulation of the dry mixture by roller compaction into granules; (c) grinding of the granules; (d) addition of croscarmellose sodium, silicon dioxide, talc and magnesium stearate to the milled granules to form an extragranular mixture; (e) compression of the extragranular mixture into tablets; and (f) coating of the tablets with a coating agent selected from Kollicoat®, Carbopol®, Aquacoat® and EUDRAGIT®.

[051] One aspect of the present disclosure includes a method of treating an LRRK2-mediated disease, comprising administering to a subject in need of a formulation of the present disclosure.

[052] An example representation of the treatment method for an LRRK2-mediated disease is one in which one or more of the formulations are administered to the subject once daily, twice daily, or three times daily.

[053] An example representation of the treatment method for an LRRK2-mediated disease is one in which the formulations are administered to the subject twice a day.

[054] An example representation of the treatment method for an LRRK2-mediated disease is one in which the LRRK2-mediated disease is neurodegenerative.

[055] An example representation of the treatment method for an LRRK2-mediated disease is one in which the LRRK2-mediated disease is Parkinson's disease.

[056] According to one aspect of the present invention, a stable and consistent blood level of the modified-release formulation of the compound of Formula I is provided in a therapeutic range of about 0.2 pM to about 1.2 pM over a period of at least 12 hours. The blood concentration can be measured Petition 870210111193, dated 11 / 30 / 2021, pp. 167 / 267 12 / 65 as average plasma or serum concentrations from several individuals or studies. Blood concentration can be measured at the time of administration and at various time points to establish a blood concentration profile in a subject over time following administration of the modified-release formulation of the compound of Formula I.

[057] The modified-release delivery method of the present invention can be carried out by administering various single-unit dosage forms of equal or varying concentrations of the compound of Formula I. Each of these units would be designed to release its contents at varying times over a period of at least twelve hours, so as to maintain a blood level of the compound of Formula I within the previously described therapeutic range.

[058] A preferred embodiment of the present invention states that the subject to be treated ingests at a single time a dosage form containing the compound of Formula I capable of maintaining the subject's blood concentration at about 0.2 pM to about 1.2 pM over a period of at least 12 hours. This dosage form may consist of one or more units, having the same or different concentrations of the compound of Formula I, designed to release their contents at varying times so as to maintain a blood concentration level of the compound of Formula I within the therapeutic range and for the period previously described.

[059] One embodiment may comprise a single dosage form containing multiple units, which are capable of releasing their contents at varying times (US 5326570). Another embodiment of the single dosage form may also consist of a unit capable of immediately releasing a concentration of the compound of Formula I, then modified to release the compound of Formula I at other times as needed to maintain blood levels within the therapeutic range. Another embodiment may be the dosage form being in multiple separate units capable of releasing the compound of Formula I at varying times, Petition 870210111193, dated 11 / 30 / 2021, pp. 168 / 267 13 / 65 The various separate units as described above would all be ingested by the subject being treated at the same time. The multi-particles allow flexibility in modifying the therapeutic dose. The capsules can be filled with different quantities of microparticles or pellets without any additional processing or formulation. BRIEF DESCRIPTION OF THE DRAWINGS

[060] Figure 1 shows the idealized blood concentrations of the compound of Formula I after dosing in an immediate-release (IR) formulation of a minimum effective dose, a modified-release formulation (MR-I) and a modified-release formulation at a reduced dose (MR-II).

[061] Figure 2 shows the ratio of cerebrospinal fluid (CSF) to plasma concentration of the Formula I compound in healthy young and elderly (non-PD) patients on Day 10 of a twice-daily (BID) multi-dose regimen of an immediate-release capsule formulation of the Formula IA compound. The mean ratio between CSF and unbound plasma was approximately 1.0. The data presented are from multiple-dose cohorts of 25, 80, and 100 mg BID.

[062] Figure 3 shows a pore-forming modified-release tablet where the compound of Formula I and other excipients comprise the core with coatings including Povidone K30 and polyvinyl acetate.

[063] Figure 4 shows a modified-release matrix tablet in which the compound of Formula I and other excipients are formulated in a matrix with polyvinylpyrrolidone and polyvinyl acetate.

[064] Figure 5 shows a representation of a pellet for a Multi-Unit Pellet System (MUPS) formulation, wherein the inner core of the pellet is an inert material, such as sugar, microcrystalline cellulose (MCC) or tartaric acid, covered with a drug layer, which is coated with a sealant. The outer layer is a polymeric coating, such as Kollicoat® (gain of approximately 5-12% by weight relative to the mass of the material to be coated) or EUDRAGIT® for release. Petition 870210111193, dated 11 / 30 / 2021, pp. 169 / 267 14 / 65 modified.

[065] Figure 6 shows a comparative formula table, Lot Nos. 1-3 modified release (MR) matrix, 80 mg tablets using 30, 40 and 50% w / w of PARTECK® polymers.

[066] Figure 7 shows comparative dissolution data for MR tablets of compound Formula I from Figure 6. A modified release effect is observed for each of the Lot Nos. 1-3 over a 12-hour period. A higher percentage of RSD (relative standard deviation) is observed throughout the release profile of Lots 1 and 2, respectively. The release profile of all three lots is similar regardless of the amount of PARTECK® SRP 80 used. Lot No. 3 containing 50% w / w of PARTECK® SRP 80 exhibits a low % of RSD compared to Lots Nos. 1 and 2 containing 30% and 40% of PARTECK® SRP 80, respectively.

[067] Figure 8 shows MR matrix tablets with 10, 15 and 20% w / w HPMC K-15M (intragranular with direct compression).

[068] Figure 9 shows comparative dissolution data for MR tablets from Figure 8.

[069] Figure 10 shows MR matrix tablets with PARTECK® SRP80 (extragranular with direct compression).

[070] Figure 11 shows comparative dissolution data for MR matrix tablets from Figure 10.

[071] Figure 12 shows the composition of MR pellets (MUPS), 80 mg.

[072] Figure 13 shows comparative drug release data from batches with different levels of pore former (Povidone).

[073] Figure 14 shows comparative dissolution profiles of Multi-Unit Pellet System (MUPS) capsules with different MR pellets and IR+MR pellets in pH 3 McIlvaine Buffer 900mL (37 °C) at 50 rpm paddle speed with weight: Samples: 12.02% w / w MR pellets; 5.2% w / w MR pellets; 8.2% w / w MR pellets; and 40 mg IR pellets + 40 mg 12.02% w / w MR pellets.

[074] Figure 15 shows time-averaged concentration profiles Petition 870210111193, dated 11 / 30 / 2021, pp. 170 / 267 15 / 65 normalized per dose for Formulations 1-5 in minipigs. Modified-release (MR) formulations show lower dose-normalized Cmax and generally slower absorption than the Formula I compound in capsule (API, active pharmaceutical ingredient) or IR tablets. Samples: API in gelatin capsule (1 mg / kg); (4 mg / kg); PARTECK® 40% MR tablet (80 mg; 4 mg / kg); PARTECK® 30% MR tablet (80 mg; 4 mg / kg); and EUDRAGIT® RS / RL MUPS capsule (1 mg / kg).

[075] Figure 16 shows a summary of dose-normalized data for Formulations 1-5 shown in Figure 15 in minipigs.

[076] Figure 17A shows time-to-mean oral concentration graphs for pellet formulations 1-5 in mini-pigs. Kollicoat® pellets exhibit a slower absorption rate. Enteric-coated pellets achieved similar exposure to IR pellets. Samples: 1. Uncoated pellet in capsule (immediate release); 2. 8% Kollicoat® pellet in capsule; 4. Enteric-coated pellet in capsule; and 5. 5% Kollicoat® pellet in capsule.

[077] Figure 17B shows time graphs of mean concentration of the Formula I compound in minipigs (N=3) after a single oral administration of the Formula I compound (1 mg / kg) as uncoated pellets in capsules (immediate release) and MUPS formulations.

[078] Figure 18 shows the modified-release formulations of Miniporco PK at 1 mg / kg. Kollicoat® pellets exhibit a slower absorption rate and reduced Cmax vs. IR pellets. The bioavailability of Kollicoat® 8% relative to IR was 73%. The bioavailability of Kollicoat® 5% relative to IR was 86%. Enteric-coated pellets achieved similar Cmax and AUC (area under the curve) to IR pellets.

[079] Figure 19 shows the modified-release (MR) formulations of Cyno PK at 2 mg / kg.

[080] Figure 20A shows the PK study for formulations in cynomolgus monkeys. Samples: 1. Uncoated pellets in capsules (immediate release); 2. 8% Kollicoat® pellets in capsules; 3. IFA Petition 870210111193, dated 11 / 30 / 2021, pp. 171 / 267 16 / 65 (Formula I compound) in capsule; 4. Enteric-coated pellet in capsule; 5. 5% Kollicoat® pellet in capsule; 6. 3% Kollicoat® pellet in capsule.

[081] Figure 20B shows time graphs of mean concentration of the Formula I compound in monkeys (N=4) after a single oral administration of the Formula I compound (2 mg / kg) as uncoated pellets in the capsule and API in the capsule (both immediate-release, without polymer coating) and MUPS formulations.

[082] Figure 21 shows modified-release (MR) pellet formulations in capsules with EUDRAGIT® L30D55 ​​and Carbopol® applied in the coating phase.

[083] Figure 22 shows modified-release (MR) pellet formulations in capsules with Aquacoat® and Carbopol® applied in the coating stage.

[084] Figure 23 shows modified-release (MR) pellet formulations in capsules with Kollicoat® and Carbopol® applied in the coating stage.

[085] Figure 24 shows tablet compositions of compound Formula I of 40, 80, 100, 106.68 and 160 mg.

[086] Figure 25 shows the steps in the manufacturing process for preparing tablets of Formula I compound of 40, 80, 100, 106.68 and 160 mg.

[087] Figure 26 shows the mean dissolution profiles of the four modified-release tablets with HMPC polymer formulations expressed as the percentage of drug release over time.

[088] Figure 27 shows the mean dissolution profiles of the four modified-release tablets with HMPC polymer formulations expressed as a percentage of drug release in mg over time.

[089] Figure 28 shows the mean dissolution profiles for low-dose 40 mg (1A) and high-dose 120 mg (2A) tablets with PARTECK® polymer formulations expressed as a percentage of drug release over time.

[090] Figure 29 shows the average dissolution profiles for Petition 870210111193, dated 11 / 30 / 2021, pp. 172 / 267 17 / 65 low-dose 40 mg (1A) and high-dose 120 mg (2A) tablets with PARTECK® polymer formulations expressed as cumulative drug release over time.

[091] Figure 30 shows the mean dissolution profiles of MR pellets with varying polymer coating expressed as drug release over time in pH 3 McIlvaine buffer (900 mL, USP Type II apparatus, 100 rpm, 37°C, weighted).

[092] Figure 31 shows the average dissolution profiles for EUDRAGIT® coated MUPS from Example 4. Definitions

[093] Unless defined otherwise, the technical and scientific terms used in this document have the same meaning as commonly understood by a person skilled in the art to which this invention pertains and are consistent with:

[094] The words comprise, including, include, and includes when used in this specification and claims are intended to indicate the presence of stated features, whole numbers, components, or steps, but do not preclude the presence or addition of one or more other features, whole numbers, components, steps, or groups thereof.

[095] The term about or approximately, in reference to defined parameters, for example, quantities of an ingredient in a formulation, water content, Cmax, tmax, AUC, intrinsic dissolution rates, temperature, and time, indicates the inherent variability in, for example, measuring the parameter or achieving the parameter. A person skilled in the art, with the advantage of this disclosure, would understand the variability of a parameter as connoted by the use of the word about or approximately. When used in conjunction with a numeral, the term about or approximately includes an interval of + / - 10% of that numeral.

[096] Polymorph, as used herein, refers to the occurrence of different crystalline forms of a compound differing in packing or conformation / configuration, but with the same chemical composition. The crystalline forms have different arrangements. Petition 870210111193, dated 11 / 30 / 2021, pp. 173 / 267 18 / 65 and / or conformations of the molecule in the crystalline structure. Therefore, a single compound can give rise to a variety of polymorphic forms, where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, morphology, density, flowability, packability, and / or X-ray diffraction peaks. The solubility of each polymorph can vary; therefore, identifying the existence of pharmaceutical polymorphs is essential to provide pharmaceutical products with predictable solubility profiles. It is desirable to characterize and investigate all solid-state forms of a drug, including all polymorphic forms, and determine the stability, dissolution, and flow properties of each polymorphic form.The polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffractometry and by other methods such as infrared or Raman or solid-state NMR spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs, see GM Wall, Pharm Manuf. 3:33 (1986); J.K. Haleblian and W. McCrone, J. Pharm. Sci., (1969) 58:911; Polymorphism in Pharmaceutical Solids, Second Edition (Drugs and Pharmaceutical Sciences), Harry G. Brittain, Ed. (2011) CRC Press (2009); and J.K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all incorporated herein by reference.

[097] A solvate is a crystal form that contains stoichiometric or non-stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate. Hydrates / solvates can exist as polymorphs for compounds with the same solvent content but with different bead packing or conformation.

[098] The term hydrate refers to the complex in which the solvent molecule is water.

[099] The phrase "pharmaceutically acceptable salt," as used in this document, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Example salts include, but are not limited to, sulfate salts, Petition 870210111193, dated 11 / 30 / 2021, pp. 174 / 267 19 / 65 citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Other salts include acid salts, such as the coformers described above. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or another counterion. The counterion may be any organic fraction. or inorganic that stabilizes the charge in the original compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Cases where multiple charged atoms are part of the pharmaceutically acceptable salt may have multiple counterions.Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[100] The desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art. For example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, methanesulfonic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid or the like.The acids that are generally considered suitable for the formation of pharmaceutically acceptable or useful salts from basic pharmaceutical compounds are discussed, for example, by Stahl PH. Petition 870210111193, dated 11 / 30 / 2021, pp. 175 / 267 20 / 65 Wermuth CG, editors. Handbook of Pharmaceutical Salts; Properties, Selection and Use, 2nd Revision (International Union of Pure and Applied Chemistry). 2012, New York: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1 19; P. Gould, International J. of Pharmaceutics (1986) 33 201 217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; Remington's Pharmaceutical Sciences, 18th ed., (1995) Mack Publishing Co., Easton PA; and in The Orange Book (Food & Drug Administration, Washington, DC on its website). These disclosures are incorporated herein by reference.

[101] The phrase pharmaceutically acceptable indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising a formulation and / or the mammal to be treated with it.

[102] The term therapeutically effective amount is an amount of a drug that is low enough to be non-toxic, yet sufficient to achieve a therapeutic result, including eliminating, reducing and / or delaying the progression of a condition or symptom thereof. The therapeutically effective amount may depend on biological factors. Achieving a therapeutic result may be measured by a physician or other qualified medical team using objective assessments known in the art or may be measured by individual subjective assessment of the patient.

[103] The term subject refers to a mammal to which a pharmaceutical composition is administered. Exemplary subjects include humans, as well as veterinary and laboratory animals such as monkeys, horses, pigs, mini-pigs, cattle, dogs, cats, rabbits, rats, mice and aquatic mammals.

[104] The term chiral refers to molecules that have the property of non-superimposability of the mirror image partner, while the term achiral refers to molecules that are superimposable on their mirror image partner.

[105] The term stereoisomers refers to compounds that have identical chemical constitution but differ with respect to Petition 870210111193, dated 11 / 30 / 2021, pp. 176 / 267 21 / 65 to the arrangement of atoms or groups in space.

[106] Diastereomer refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis and chromatography.

[107] Enantiomers refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[108] The stereochemical definitions and conventions used in this document generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is planned that all stereoisomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, will be part of the present invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule around its chiral center(s).The prefixes del or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of these isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where not. Petition 870210111193, dated 11 / 30 / 2021, pp. 177 / 267 22 / 65 there was stereoselection or stereospecificity in a chemical reaction or process. The terms racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, without optical activity.

[109] The term tautomer or tautomeric form refers to structural isomers of different energies that are interconvertible through a low-energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions through the migration of a proton, such as keto-enol and imineenamine isomerizations. Valence tautomers include interconversions by rearrangement of some of the bonding electrons.

[110] A solid oral dosage form refers to a formulation that is ready for administration to a subject orally. Examples of oral dosage forms include, but are not limited to, tablets, minitablets, capsules, oval tablets, powders, pellets, spheres, granules, and pelletized tablets containing polymer-coated pellets. A dosage form may be a unit dosage form, which is intended to deliver a therapeutic dose per administration.

[111] The term excipient refers to a substance formulated with an active pharmaceutical ingredient (API) of a therapeutic drug, included for purposes of long-term stabilization, bulking up solid formulations containing potent active ingredients in small amounts, or to confer a therapeutic increase of the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or increasing solubility. Excipients can also be useful in the manufacturing process to aid in handling the active substance in question, such as facilitating powder flowability or providing anti-adherent properties, as well as aiding in in vitro stability, such as preventing denaturation or aggregation over the expected shelf life. The selection of appropriate excipients also depends on the route of administration and dosage form, as well as the active ingredient and other factors. In some Petition 870210111193, dated 11 / 30 / 2021, pp. 178 / 267 23 / 65 formulations, excipients can be an important determinant of dosage form performance, affecting pharmacodynamics and pharmacokinetics. Types of excipients for oral dosage formulations include anti-adherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles.

[112] The term pellet encompasses any particle shape, including spheres, granules, irregularly shaped particles and / or spherical particles. Granules may be of any suitable size, for example, from about 0.1 mm to about 1.0 mm. In a representation, the pellet size is from about 100 pM (micron) to about 1200 pM (micron), from about 100 pM to about 1100 pM, from about 150 pM to about 600 pM, or from about 100 pM to about 400 pM as measured by methods also known in the art.

[113] Spheronization is a fast and flexible process in which pharmaceuticals are made into small spheres, generally involving wetting a dry mixture comprising the API, filler, spheronizing agent, superdisintegrant binder or other excipients, a granulation fluid (e.g., water optionally mixed with an alcohol), granulating the wet mixture, extruding the resulting granulated mass, spheronizing the extrudate to provide spheres, and drying the spheres. The flow characteristics of spheres make them suitable for transport and movement. Spheres provide the lowest surface area to volume ratio and therefore pharmaceutical compounds can be coated with a minimum of coating material.

[114] The term modified-release means that the release of the drug is different from immediate release, i.e., dosage forms that release about 60% or more of the drug in vivo in about 2 hours. Alternatively, drug release can be measured in vitro by dissolving the drug in a dissolution medium according to methods known in the art. Examples of modified-release profiles include, but are not limited to Petition 870210111193, dated 11 / 30 / 2021, pp. 179 / 267 24 / 65 limited to, modified release, slow release, delayed release and pulsed release.

[115] A release-modifying agent is a composition, including a polymeric material that may be a mixture of different polymeric structures, chain lengths and branching, that has the property of modifying the release rate of a drug in a formulation. Release-modifying agents alter the release rate of the drug from the dosage form, so that the release rate of a dosage form with a release-modifying agent is different from the release rate of an identical dosage form but without the release-modifying agent, under identical conditions.Examples of release modifiers include: MCC (microcrystalline cellulose), HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), PEG (polyethylene glycol glycerides), PVA (polyvinyl alcohol), PVP (polyvinylpyrrolidone), Carbopol, (a) enteric coating polymers, including: CAP (cellulose acetate phthalate), such as Aquacoat®; CMC-Na (sodium carboxymethylcellulose), such as Walocel®; HPMCAS (hydroxypropylmethylcellulose acetate succinate), such as Aqoat®; HPMCP (hydroxypropylmethylcellulose phthalate), such as HP 50 / HP 55; (poly)methylacrylate-co-methyl methacrylate-co-methacrylic acid), such as EUDRAGIT® FS 30 D; (poly)methacrylic acid-co-ethylacrylate, such as EUDRAGIT® L 30 D-55 / L 100-55, or Kollicoat® MAE 30 DP / 100 P, or Eastacryl 30 D; (poly)methacrylic acid-co-methyl methacrylate), such as EUDRAGIT® L 12.5 / EUDRAGIT® L 100 or EUDRAGIT® S 12.5 / EUDRAGIT® S 100, etc.(b) Time-controlled release polymers, for example: CA (cellulose acetate), such as Eastman CA and Eastman CAB; (cellulose acetate butyrate), such as Eastman CAB; EC (ethylcellulose) Ethocel™, or Aquacoat® ECD, or Surelease® (ready to use), or GatteCoat™ Glyceride; (poly)acrylate (ethyl-co-methyl methacrylate), such as EUDRAGIT® NE 30 D or EUDRAGIT® NM 30 D; (poly)ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), such as EUDRAGIT® RL 30 D, EUDRAGIT® RL 100 / RL PO, EUDRAGIT® RS 30 D or. Petition 870210111193, dated 11 / 30 / 2021, pp. 180 / 267 25 / 65 EUDRAGIT® RS 100 / RS; PVAc (polyvinyl acetate) such as Kollicoat® SR 30 D; HPMC / CMC, such as Walocel® HM-PPA, etc. COMPOUND FORMULA IE PHARMACEUTICAL COMPOSITIONS

[116] This disclosure includes polymorphs and amorphous forms of the compound of Formula I, (CAS Registry Number 1374828-69-9), having the structure: h3c ch3e named: 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1yl)propanenitrile (WO 2012 / 062783; US 8815882; US 2012 / 0157427, each of which is incorporated by reference). As used herein, the compound of Formula I includes tautomers or their pharmaceutically acceptable salts. The compound of Formula I is the API (Active Pharmaceutical Ingredient) in formulations described herein for use in the treatment of Parkinson's Disease and Parkinsonism. Pharmacokinetics

[117] The components and configurations of the dosage form can have large effects on the dissolution rate and blood concentration.

[118] Figure 1 shows the idealized blood concentrations of the compound of Formula I after dosing in an immediate-release (IR) formulation of a minimum effective dose, a modified-release (MR) formulation and a MR formulation at a reduced dose.

[119] Figure 2 shows the ratio of cerebrospinal fluid (CSF) to plasma concentration of the Formula I compound in healthy young and elderly (non-PD) patients on Day 10 of a twice-daily (BID) dose regimen of an immediate-release capsule formulation of the Formula IA compound, mean ratio between CSF and unbound plasma. Petition 870210111193, dated 11 / 30 / 2021, pp. 181 / 267 The 26 / 65 ratio was approximately 1.0. The data presented are from multiple-dose cohorts of 25, 80, and 100 mg BID.

[120] The compound of Formula I was administered to healthy young human subjects as an API formulation in capsule form at doses of 25 mg, 40 mg, 80 mg, and 100 mg BID, and to healthy elderly subjects at 80 mg BID. Concentrations of the compound of Formula I were determined on Days 1 and 10 and at the selected day low during the 10 days of administration. Pharmacokinetic analysis of plasma concentrations obtained after dosing on Day 10 indicated a terminal plasma half-life of 14 to 26 hours. A plateau in trough (minimum) concentrations demonstrated that steady state was reached on Day 10. Plasma Cmax and AUC increased dose-proportionally over the 25 to 100 mg BID dose range. The terminal half-life, plasma concentrations, and pS935 inhibition at the trough (minimum) are consistent with twice-daily administration as an effective regimen.

[121] With the API in capsule formulation administered at doses of 25, 40, 80, and 100 mg BID, the Cmax / Cmin (Cmax / Clowpoint) ratio of the Formula I compound at steady state was 2.6 to 12 (mean 5.3). Intrasubject variability in the ratio was observed due to the parallel (non-crossover) nature of the study design. Although generally well tolerated, mild changes in pulse rate and blood pressure were observed at the higher doses. Physiologically based PK modeling was used to predict the Cmax / Cmin ratio for MUPS formulations containing various amounts of KOLLICOAT® polymer. For MUPS formulations containing KOLLICOAT® at 3%, 5%, and 8% polymer, the predicted Cmax / Cmin ratios under BID ranged from 1.5 to 2.6. SOLID ORAL DOSAGE FORMS

[122] The present invention surprisingly provides novel modified-release formulations of the compound of Formula I that achieve a desirable modified-release profile and novel methodologies for preparing them.

[123] Solid oral dosage forms of the compound of Formula I include delivery systems broadly classified into Petition 870210111193, dated 11 / 30 / 2021, pp. 182 / 267 27 / 65 single-unit dosage forms (capsules or tablets) and multi-unit dosage forms or pelletized dosage forms (pellets or pellets in capsules or tablets). Pellets offer certain therapeutic advantages as they spread uniformly throughout the gastrointestinal tract. Pellets can also empty gradually from the stomach with less intra- and interindividual variation, thus providing better predictability for an administered dose. With the use of pellets, the risk of high local drug concentrations and toxicity associated with the ingestion of locally restricted tablets can be avoided. Premature drug release from enteric-coated tablets in the stomach, potentially resulting in drug degradation or gastric mucosal irritation, can also be reduced with coated pellets due to their rapid transit time.Better distribution of pellets in the gastrointestinal tract could also improve the bioavailability of the drug they contain, leading to a possible reduction in drug dosage and adverse effects (Kushare, S. et al (2011) Asian J Pharm, 5: 203-8).

[124] Immediate-Release (IR) dosage forms are formulated to achieve a rapid or uncontrolled release of the drug into the patient's bloodstream after administration.

[125] Modified-release (MR) formulations achieve a slower release of the drug than conventional immediate-release dosage forms. The advantages of a modified-release dosage form include reduced dosing frequency, improved patient acceptance and adaptation, reduced gastrointestinal (GI) side effects, less fluctuation in plasma drug levels (as measured by the Cmax / Cmin ratio), improved efficacy / safety parameters, and a well-characterized and reproducible dosage form. An optimized modified-release profile can place the patient within the therapeutic window of more than the minimum effective concentration but less than the maximum tolerated dose of the drug for a longer post-administration duration. Modified-release (MR) formulations can achieve a delayed release. Petition 870210111193, dated 11 / 30 / 2021, pp. 183 / 267 28 / 65 of the drug in the patient's blood after administration, in order to maintain a constant concentration of the drug in the blood.

[126] The Multi-Unit Pellet System (MUPS) is a multiphasic or time-release dosage form used as an alternative to conventional tablets or capsules. Multi-Unit Pellet System (MUPS) tablets or capsules are a type of multi-particulate system that has become an important and successful dosage form for immediate or modified-release medication for oral administration. These multiple units are composed of tablets or capsules containing coated or uncoated pellets that allow for modified-release medication. The advantages of these systems compared to simple tablets or capsules include reduced gastric mucosal irritation due to drug degradation into single units, as well as improved dose adjustment. It also offers the possibility of administering incompatible medications due to the multi-particulate system.MUPS pellets in tablets or capsules can be coated or uncoated. The drug may be included in the core or as a layer applied to the inert core of the pellet. The inert core may be a neutral starting pellet composed of sugar, microcrystalline cellulose (MCC), polyols, carnauba wax, or silicon dioxide. In addition, the pellets may have one or more layers that may include suitable modified-release excipients, such as enteric-coated polymers or modified-release polymers. Uncoated pellets are made of suitable pharmaceutical excipients such as lactose and microcrystalline cellulose (MCC), among others. The pellets may be placed in a capsule or tablets in a tablet for oral administration.

[127] Coated pellets are produced with the appropriate polymer and quantity to form the coating film. The strength, ductility, and thickness properties of the polymer will influence the breaking and deformability of the pellets during tablet formation. In addition, the Petition 870210111193, dated 11 / 30 / 2021, pp. 184 / 267 29 / 65 The stability of the pellet coating film depends on the applied compression forces.

[128] The polymers used to create the pellet coating film include cellulosic and acrylic polymers. The advantages of acrylic polymers are flexibility and features that allow the compression process without rupture of the pellet coating film. The combination of two types of polymers can improve the flexibility of the coating film which is desirable for the production of coated pellets, as well as the addition of a plasticizer in a certain proportion.

[129] The core of the pellet can influence the drug release from the MUPS.The porosity of the pellet, both uncoated and coated pellets, affects the modified drug release profile.

[130] The excipients and binder used to produce the pellet core can affect the deformation and viscoelastic properties of the pellet during compression and thus cause changes in the drug release profile. The use of other components such as carrageenan polysaccharide in the production / manufacture of pellets allows them to have rapid disintegration and therefore rapid drug release (Kranz H. et al.:Eur.J. Pharm.Biopharm.73:302-309 (2009); Ghanam D. and Kleinebudde.P.:Int. J. Pharm.409:9-18 (2011).

[131] The manufacturing process of coated pellets can be divided into two stages, pellet manufacturing and tablet manufacturing containing pellets. First, the manufacturing process of pharmaceutical pellets begins with the mixing of pellet components, such as pharmaceuticals, buffering excipients such as microcrystalline cellulose, glyceryl monostearate (GMS) and lactose monohydrate (LM), which are widely used in this type of formulation. A liquid binder, such as water or glycerol, can be used for wet mixing. The resulting mass then undergoes the extrusion-spheronization process, and the drying of the newly formed pellets can be carried out in a fluidized bed dryer. The next stage, the Petition 870210111193, dated 11 / 30 / 2021, pp. 185 / 267 30 / 65 coating of the pellet, forms the coating film to obtain the desired drug release (Bashaiwoldu ABet al.:Advan.Powder Technol.(2011) 22:340-353).

[132] The compression process can be carried out by a rotary tablet compression machine with controlled parameters such as main compression force and speed. Pellets and cushioning excipients can be added to tablet formation to optimize certain properties, including the ability to withstand high compression forces.

[133] Tablets containing pellets with specific characteristics of shape, weight, thickness and hardness continue through the tablet coating process with the film. The tablet coating film is applied to improve the stability and appearance of the pharmaceutical composition.

[134] Coating films are frequently applied in the distribution of pharmaceutical drugs in solid oral dosage forms. The motivation for coating pharmaceutical forms varies from appearance considerations (color, gloss), improved stability (protection against light, moisture and gas barrier) and facilitating swallowing of the tablet. In addition, functional coatings can be used to modify the drug release behavior from the dosage form. Depending on the polymers used, it is possible to delay drug release (as in enteric coatings) or use the coating to maintain drug release from the dosage form for extended periods.

[135] A coating film is a thin polymer-based coating applied to a solid dosage form, such as a tablet. The thickness of this coating is generally between 20 and 100 μm. It is possible to monitor the dynamic curing effect on the coating structure of the tablet using non-destructive analytical methodologies.

[136] Multi-unit pellet systems (MUPS) are designed to achieve a modified drug release profile. This modified release can be considered a Petition 870210111193, dated 11 / 30 / 2021, pp. 186 / 267 31 / 65 Delayed or modified release. Delayed release can be achieved, for example, by enteric-coated pellets. Enteric coating allows active pharmaceutical ingredients that are unstable in the gastric environment or that may cause gastric irritation to be protected by an enteric coating. Copolymers of methacrylic acid, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate are enteric-coated polymers frequently used for this purpose.

[137] MUPS tablets containing modified-release pellets can achieve sustained action and prolong the pharmacological effect, extend the interval between doses and reduce side effects. Pellets coated with different polymers and different film thicknesses allow modulation of the pellet release rate. The polymers used can be, among others, cellulose derivatives, such as ethylcellulose and hydroxypropylmethylcellulose (HPMC). Uncoated pellets can be used as a polymeric matrix system for modified drug release. In this group, hydrophilic matrix systems based on the use of cellulosic polymers, carbomers or xanthan gums, among others, are frequently used.

[138] Figure 3 shows a pore-forming modified-release (MR) tablet where the compound of Formula I and other excipients comprise the core with coatings including KOLLICOAT® IR, Povidone K30 and polyvinyl acetate.

[139] Figure 4 shows a modified-release matrix tablet in which the compound of Formula I and other excipients are formulated in a matrix with polyvinylpyrrolidone and polyvinyl acetate.

[140] Figure 5 shows a representation of a pellet for a Multi-Unit Pellet System (MUPS) formulation, wherein the inner core of the pellet is an inert material, such as sugar, microcrystalline cellulose (MCC) or tartaric acid, covered with a drug layer, which is coated with a sealant. The outer layer is a polymeric coating, such as Petition 870210111193, dated 11 / 30 / 2021, pp. 187 / 267 32 / 65 Kollicoat® (approximately 5-12%) for modified release or EUDRAGIT® for extended release. EXCIPIENTS

[141] Suitable excipients are known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or expandable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. Excipients may have various and multiple useful effects and properties.

[142] PARTECK® SRP 80 (EMD Millipore) is a functional excipient based on the hydrophilic polymer polyvinyl alcohol (PVA). It forms a dilatable and erodible matrix and is used in the formulation of oral pharmaceutical dosage tablet forms that exhibit modified API release. PARTECK® SRP 80 contains a single ingredient – ​​PVA 40-88 – with no other additives, viscosity in mPa of a 4% aqueous solution at 20°C 88: degree of hydrolysis (saponification) in % molar. PARTECK® SRP 80 is milled polyvinyl alcohol (PVA 40-88) with a special particle size. CAS Registry number 9002-89-5

[143] KOLLICOAT® SR 30D (BASF) is an aqueous dispersion of polyvinyl acetate stabilized with Povidone and SLS (sodium lauryl sulfate). KOLLICOAT® SR 30D contains approximately 27% polyvinyl acetate, approximately 2.7% povidone K30, approximately 0.3% sodium lauryl sulfate, and approximately 70% water (CAS Registry No. 9003-20-7). Polyvinyl acetate, povidone (polyvinylpyrrolidone), and sodium lauryl sulfate are present in a ratio of approximately 90:9:1. PVA forms an insoluble matrix and reduces drug release. Povidone added to the aqueous dispersion is highly soluble in nature, and when the tablet comes into contact with the dissolving medium, it dissolves and acts as a pore-forming agent. The drug dissolves and spreads through the pores at a controlled rate, leaving an empty polymer shell. The viscosity of povidone (PVP K30 vs. PVP K90) and its concentration affect drug release. Depending on the viscosity and the Petition 870210111193, dated 11 / 30 / 2021, pp. 188 / 267 33 / 65 PVP concentration increases, drug release increases.

[144] Povidone (polyvinylpyrrolidone, PVP) is a synthetic polymer carrier used to disperse and suspend medications. It also acts as a disintegrant and binder for tablets. It is a white to off-white hygroscopic powder in its pure form and is readily soluble in water.

[145] Hypromellose, also known as hydroxypropylmethylcellulose and HPMC, is a semi-synthetic, inert, viscoelastic, water-soluble polymer used as an excipient and controlled delivery component in oral medications and found in a variety of commercial products. HPMC is used for its sealing coating effect, such as to create a smooth surface. In other uses, HPMC can rapidly hydrate into the outer skin of the tablet to form a gel-like layer. Rapid formation of a gel-like layer prevents wetting of the interior and disintegration of the tablet core. Once the original protective gel layer is formed, it controls further water penetration into the tablet. As the outer gel layer fully hydrates and dissolves, a new inner layer replaces it and is cohesive and continuous enough to retard water influx and control drug diffusion.A rapid rate of hydration followed by rapid gelation and polymer / polymer coalescence is required for a rate-control polymer to form a protective gel layer around the matrix. This prevents the tablet from disintegrating immediately, resulting in premature drug release. The optimized amount of polymer content, such as HPMC, in a matrix system forms a uniform barrier to prevent the drug from being released immediately into the dissolving medium. If the polymer level is too low, a complete gel layer may not form. Increasing the polymer level in the formulation results in lower drug release rates. As hydrophilic matrix tablets containing... Petition 870210111193, dated 11 / 30 / 2021, pp. 189 / 267 34 / 65 As HPMCs absorb water and swell, the polymer level in the outermost hydrated layers decreases over time. The outermost layer of the matrix eventually dilutes to the point where individual chains detach from the matrix and diffuse into the bulk solution. Polymer chains separate from the matrix when the surface concentration exceeds a critical concentration of macromolecular clearance polymer or surface erosion. The polymer concentration on the matrix surface can be defined as the polymer clearance concentration.

[146] METHOCEL® (The Dow Chemical Co.) is a commercial line of HPMC products, designated E, F, K, etc., and frequently used for controlled-release drug formulations. Methocel products differ in viscosity at certain concentrations in water. K15M refers to a high molecular weight HPMC having about 19-24% methoxyl, about 7-12% hydroxypropoxyl and a viscosity (2% in water at 20°C) of 10,000-18,000 cP (centipoise). K100LV refers to a low molecular weight HPMC having about 19-24% methoxyl, about 7-12% hydroxypropoxyl and a viscosity (2% in water at 20°C) of 80-120 cP (centipoise).

[147] EUDRAGIT® (Evonik) is a family of patented drug-release coating polymethacrylate polymers. EUDRAGIT® polymers can be acidic, neutral or basic and therefore be controlled-release or pH-dependent and thus delayed-release or sustained-release. These polymers allow drugs to be formulated in enteric, protective or sustained-release formulations to prevent drug degradation until it reaches an area with suitable pH in the gastrointestinal (GI) tract. Once the drug reaches its target area of ​​the gastrointestinal tract (i.e., duodenum, stomach), it can be released from the polymer matrix and absorbed.

[148] Carbopol® (Lubrizol) is a family of high molecular weight cross-linked polyacrylic acid polymers used as a coating agent. Carbopols form hydrogels in water or alkaline solution due to the hydration of the carboxyl groups and Petition 870210111193, dated 11 / 30 / 2021, pp. 190 / 267 35 / 65 can be used as a release modifier in tablet or pellet formulations.

[149] Croscarmellose sodium, or croscarmellose sodium, is an internally cross-linked sodium carboxymethylcellulose for use as a disintegrant in pharmaceutical formulations, providing drug dissolution and disintegration characteristics.

[150] AquacoatECD® (FMC Biopolymer) is a 30% (w / w) aqueous dispersion of ethylcellulose (EC) polymer. Ethylcellulose is a hydrophobic coating material used in a variety of coating applications to achieve sustained release, flavor masking, and moisture barrier / seal. Aquacoat® ECD is a 30% by weight aqueous dispersion of ethylcellulose polymer.

[151] Dampening agents, such as polyethylene glycol, can be used to prevent pellet deformation during compaction.

[152] A non-functional “coating agent”, such as OPADRY®, provides a cosmetic effect, such as color, without modifying the release rate of a drug in a formulation. MODIFIED RELEASE FORMULATIONS

[153] The compound of Formula I is formulated according to standard pharmaceutical practice and in accordance with the procedures of Example 2, for use in therapeutic treatment (including prophylactic treatment) in mammals, including humans. This disclosure provides several formulations comprising the compound of Formula I in association with one or more pharmaceutically acceptable excipients. A modified-release drug formulation releases active ingredients over several hours in order to maintain a constant concentration of the drug in the blood.

[154] Formulations can be prepared using conventional dissolution, combination, and mixing procedures. The compound of the present disclosure is commonly formulated in pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to allow patient compliance with the prescribed regimen. Petition 870210111193, dated 11 / 30 / 2021, pp. 191 / 267 36 / 65

[155] The pharmaceutical composition (or formulation) for application may be packaged in various ways, depending on the method used to administer the drug. Generally, an article for distribution includes a container that holds the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident set to prevent indiscreet access to the contents of the package. In addition, the container has a label describing its contents. The label may also include appropriate warnings. Pharmacokinetics of MR formulations in monkeys and minipigs

[156] Figure 15 shows the dose-normalized mean concentration time profiles for formulations 1-5 in minipigs. Modified-release (MR) formulations show lower dose-normalized Cmax and generally slower absorption than the Formula I compound in capsule (IFA) or IR tablets. Samples: IFA in softgel capsule (1 mg / kg); PARTECK® 40% MR tablet (80 mg; 4 mg / kg); PARTECK® 30% MR tablet (80 mg; 4 mg / kg); and EUDRAGIT® RS / RL MUPS capsule (1 mg / kg; Example 4).

[157] Figure 16 shows the summary of Normalized Dose Data for Formulations 1-5 shown in Figure 15 in minipigs.

[158] Figure 17A shows time-to-mean oral concentration graphs for Formulations 1-5 in minipigs. The uncoated drug pellet (IR) and the 5% and 8% KOLLICOAT® formulations in capsules were evaluated using a crossover design in fasted Göttingen minipigs (N=3). Kollicoat® pellets exhibit a slower absorption rate. Enteric-coated pellets achieved similar exposure to IR pellets. 1. IR pellet in capsule; 2. 8% Kollicoat® pellet in capsule; 3. IV (0.5 mg / kg); 4. Enteric-coated pellet in capsule; and 5. 5% Kollicoat® pellet in capsule. The 5% and 8% KOLLICOAT® formulations at 1 mg / kg exhibited slower absorption of the compound from Formula I. The mean Tmax values ​​were 2.0, 2.5 and Petition 870210111193, dated 11 / 30 / 2021, pp. 192 / 267 37 / 65 4.0 h for uncoated pellets and KOLLICOAT® at 5% and 8% of the formulations, respectively, while the corresponding Cmax values ​​were 0.197, 0.0940 and 0.0469 μM, respectively.

[159] Figure 17B shows time graphs of mean concentrations of the Formula I compound in minipigs (N=3) after a single oral administration of the Formula I compound (1 mg / kg) as immediate-release and MUPS formulations. In contrast to the case in monkeys, the bioavailability of the KOLLICOAT® formulations was similar to or slightly lower than that of the uncoated pellet formulation; the relative bioavailabilities of the 5% and 8% KOLLICOAT® formulations were 86% and 73%, respectively. Overall, the MUPS formulations showed a slower absorption rate and lower Cmax than the immediate-release formulations.

[160] Figure 18 shows the minipig PK:Modified-release formulations at 1 mg / kg.Kolliccoat® pellets exhibit a slower absorption rate and reduced Cmax vs IR pellets.The bioavailability of Kollicoat® 8%: relative to IR was 73%.The bioavailability of Kollicoat® 5%: relative to IR was 86%.The enteric-coated pellets achieved Cmax and AUC similar to those of the IR pellets.

[161] Figure 19 shows Cyno PK: Modified-release (MR) formulations at 2 mg / kg. Kollicoat® pellet formulations showed a slower absorption rate. The reduction in bioavailability was relative to the immediate-release capsule formulations. The magnitude of the reduction depended on the % of coating on the pellet, with a higher coating showing a lower F. The enteric-coated pellet formulation did not show improvement compared to the immediate-release (IR) formulation.

[162] Figure 20A shows PK's study for formulations in Cynomolgus monkeys (body weight approximately 5 kg). 1. IR pellet in capsule; 2. 8% Kollicoat® pellet in capsule; 3. IFA (compound of Formula I) in capsule; 4. Enteric-coated pellet in capsule; 5. 5% Kollicoat® pellet in capsule; 6. 3% Kollicoat® pellet in capsule. The formulations of Petition 870210111193, dated 11 / 30 / 2021, pp. 193 / 267 38 / 65 MUPS contained the compound of Formula I formulated as pellets with drug layers coated with the polymer KOLLICOAT® SR 30D at various levels (3%, 5%, and 8% w / w) designed to provide different drug release rates. In vitro dissolution results supported further characterization with in vivo PK studies. The MUPS formulations were evaluated in cynomolgus monkeys using a crossover design with a minimum elimination period of one week. The uncoated pellet (IR) and the API in capsule formulations served as comparators with immediate release rates. A single dose (2 mg / kg of compound of Formula I) of each formulation was administered to fasted animals (n=4), and timed blood samples were obtained over 24 hours post-dose.

[163] After oral administration to fasted monkeys, the uncoated pellet and the API in capsule formulations achieved similar Tmax, Cmax, and AUCc-inf. Formulations containing coated pellets of KOLLICOAT® SR 30D showed slower absorption of the Formula I compound compared to the two immediate-release formulations, as shown by a longer Tmax and reduced Cmax. Figure 20B shows time plots of mean concentrations of the Formula I compound in monkeys (N=4) after a single oral administration of the Formula I compound (2 mg / kg) as immediate-release and MUPS formulations. The mean Tmax for the API in the capsule formulation was 1.25 h compared to 2.0, 1.75, and 7.5 h for the KOLLICOAT® 3%, 5%, and 8% formulations, respectively, while the corresponding mean Cmax values ​​were 1.14, 0.585, and 0.190. and 0.0660 μM, respectively.The relative bioavailabilities, based on AUC ratios compared to the API in capsules, of the KOLLICOAT® formulations at 3%, 5%, and 8% were 84%, 40%, and 20%, respectively, indicating that the lower Cmax for the two formulations with higher polymer content was due to a combination of slower absorption rate and a decrease in the extent of absorption.

[164] Figure 21 shows modified-release (MR) pellet formulations in capsules with EUDRAGIT® L30D55 ​​and Carbopol® Petition 870210111193, dated 11 / 30 / 2021, pp. 194 / 267 39 / 65 applied in the coating phase.

[165] Figure 22 shows modified-release (MR) pellet formulations in capsules with Aquacoat® and Carbopol® applied in the coating stage.

[166] Figure 23 shows modified-release (MR) pellet formulations in capsules with Kollicoat® and Carbopol® applied in the coating stage.

[167] Figure 24 shows Formula I MR tablet compositions of 40, 80, 100, 106.68 and 160 mg.

[168] Figure 25 shows the steps of the Manufacturing Process to prepare tablets of Formula I compound of 40, 80, 100, 106.68 and 160 mg. Treatment methods for Parkinson's disease and Parkinsonism

[169] In another aspect, the present disclosure relates to a method of treating a disease or condition mediated, at least in part, by leucine-rich repeat kinase 2 (LRRK2) with a modified-release formulation comprising a therapeutically effective amount of the compound of Formula I and one or more of the excipients described herein. In particular, the disclosure provides methods for preventing or treating an LRRK2-associated disorder in a mammal, comprising the step of administering to said mammal a therapeutically effective amount of the compound of Formula I.In some representations, the disease or condition mediated, at least in part, by LRRK2 is a neurodegenerative disease, for example, a central nervous system (CNS) disorder such as Parkinson's disease (PD), Parkinsonism, Alzheimer's disease (AD), dementia (including Lewy body dementia and vascular dementia), amyotrophic lateral sclerosis (ALS), age-related memory dysfunction, mild cognitive impairment (e.g., including the transition from mild cognitive impairment to Alzheimer's disease), argyrophilic grain disease, lysosomal disorders (e.g., Niemann-Pick disease Type C, Gaucher disease), corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and chromosome 17-linked parkinsonism (FTDP-17), symptoms of. Petition 870210111193, dated 11 / 30 / 2021, pp. 195 / 267 40 / 65 withdrawal / relapse associated with drug dependence, L-Dopa-induced dyskinesia, Huntington's disease (HD), and HIV-associated dementia (HAD). In other representations, the disorder is an ischemic organ disease, including but not limited to the brain, heart, kidney, and liver. In some representations, the disease is Crohn's disease. EXAMPLES Example 1: Isolation and physicochemical characteristics of the compound with Formula I

[170] Compound of Formula I, 2-methyl-2-(3-methyl-4-(4(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-IH-pyrazol-1-yl)propanenitrile (CAS Reg. No. 1374828-69-9), prepared according to Example 394 of US 8815882, and Compound 12 of Estrada, AA et al (2013) J. Med. Chem. 57:921-936, each of which are specifically incorporated by reference, was dissolved in methyl tert-butyl ether (MTBE, 10 vol, 200 mL) to generate a brown solution. This solution was filtered through a 3M Zeta Plus activated carbon disc (R55SP, 5 cm diameter) at 3 mL / min. The filter was washed with MTBE (5 vol, 100 mL). The solution A clear, colorless solution (300 mL) was concentrated to 8 vol (160 mL) and charged into a 500 mL reactor. N-heptane (8 vol, 160 mL) was added at 20°C. The solution remained clear initially, but crystallization began after 2 minutes. The temperature was gradually increased (at a rate of 2°C / min). Complete dissolution was achieved only at 69°C.More heptane (4 vol, 80 mL) was added at 70°C; a clear solution was visually observed at 70°C. The temperature was adjusted to 65°C (1.0°C / min). At 65°C with the solution clear, seed crystals of the compound of Formula I (200 mg, same batch) were added and did not dissolve. The temperature was then lowered to 20°C over 8 hours. It was stirred at 20°C overnight. The solid was filtered and washed twice with the mother liquors. It was dried under vacuum at 40°C for 2 hours to yield 15.91 g of the crystalline compound of Formula I (79.6% yield). The mother liquors were evaporated to dryness to yield an additional 3.47 g (17.4% recovery). Petition 870210111193, dated 11 / 30 / 2021, pp. 196 / 267 41 / 65

[171] A Form C polymorph of the compound of Formula I was obtained from simple block crystals in an n-butyl acetate / cyclohexane solvent mixture system (n-butyl acetate was the solvent, while cyclohexane was the antisolvent) by liquid vapor diffusion at room temperature.

[172] A Form D polymorph of the compound of Formula I was obtained from simple block crystals in an acetone / n-heptane (1:10, v / v) solvent mixture system by slow evaporation at room temperature.

[173] The determination of the simple crystal structure was made from colorless block-shaped simple crystals selected from Form C simple crystals or Form D simple crystals and wrapped with Paratone-N (an oil-based cryoprotectant). The crystals were mounted on a mylar circuit in a random orientation and immersed in a nitrogen stream at 150 K. Preliminary examination and data collection were performed on an Agilent SuperNova® diffractometer (Cu / Kα λ = 1.54178 A) and analyzed with the CrysAlisPro® software package (Agilent, version: 1.171.38.41).

[174] The data collection details for the single crystal Forma C are as follows: The cell parameters and an orientation matrix for data collection were retrieved and refined by CrysAlisPro® software using the configuration angles of 6568 reflections in the range 4.0790° <θ <70.0660°. Data were collected at a maximum diffraction angle (θ) of 70.266° at 150.2 (2) K. The dataset was 99.9% complete, having an average I / σ of 19.4 and D min (Cu) of 0.82 A.

[175] The data reduction details of the single crystal Forma C are as follows: The frames were integrated into CrysAlisPro® software, Version: 1.171.38.41. A total of 12,836 reflections were collected, of which 6205 were single. Lorentz and polarization corrections were applied to the data. An empirical absorption correction was performed using spherical harmonics, implemented in the SCALE3 ABSPACK scaling algorithm. The absorption coefficient μ of this material is 0.964 mm-1 in this Petition 870210111193, dated 11 / 30 / 2021, pp. 197 / 267 42 / 65 wavelength (□□= 1.54178 Â) and the minimum and maximum transmissions are 0.80956 and 1.00000. The equivalent reflection intensities were calculated. The concordance factor for the average was 2.08% based on intensity.

[176] The C-Form structure was solved in the C2 / c space group by Direct Methods using the ShelXS™ structure solution program (Sheldrick, GM(2008).Acta Cryst.A64:112-122) and refined with ShelXS™, refinement package Version 2014 / 7 using full matrix least squares in F2 contained in OLEX2 (Dolomanov, OV, et al, (2009) J. Appl.Cryst.42:339341). All non-hydrogen atoms were anisotropically refined. The positions of hydrogen atoms on carbon atoms were geometrically calculated and refined using the transport model, but hydrogen atoms on nitrogen atoms were freely refined according to Fourier Maps.

[177] The data collection details for the single crystal of Form D are as follows: The cell parameters and an orientation matrix for data collection were retrieved and refined by CrysAlisPro® software using the configuration angles of 30349 reflections in the range 4.0180° <θ <70.5190°. Data were collected at a maximum diffraction angle (θ) of 70.562° at 150 K. The dataset was 89.9% complete, having an average I / σ of 29.3 and D min (Cu) of 0.82 Â.

[178] The data reduction details for the single crystal of Form D are as follows: The frames were integrated into CrysAlisPro® software, Version: 1.171.38.41. A total of 47670 reflections were collected, of which 11179 were single. Lorentz and polarization corrections were applied to the data. An empirical absorption correction was performed using spherical harmonics, implemented in the SCALE3 ABSPACK scaling algorithm. The absorption coefficient μ of this material is 0.980 mm-1 at this wavelength (2 = 1.54178 Å) and the minimum and maximum transmissions are 0.83622 and 1.00000. The equivalent reflection intensities were calculated. The concordance factor for the Petition 870210111193, dated 11 / 30 / 2021, pp. 198 / 267 43 / 65 average was 2.69% based on intensity.

[179] The D-Form structure was solved in the Pca21 space group by Direct Methods using the ShelXS structure-solving program and refined with ShelXS™, refinement package Version 2014 / 7 using full matrix least squares in F2 contained in OLEX2. All non-hydrogen atoms were anisotropically refined. The positions of the hydrogen atoms were geometrically calculated and refined using the transport model.

[180] Table 1. Single Crystal X-ray Diffraction Instrument (SCXRD) Parameters Agilent SuperNova X-ray Generator X-ray Sources SuperNova Microfocus (Cu / A: 1.54184 A) 50 KV, 0.8 mA Detector Eos CCD Detector (Detector resolution: 16.0450 pixels mm-1) Goniometer Four-circle Kappa Goniometer Low temperature devices Oxford Cryosystems CrysAlisPro Software (Version: 1.171.38.41)

[181] The polymorphic forms of the compound of Formula I were determined using the ShelXT (Sheldrick, GM (2015).Acta Cryst.A71, 3-8) structure solution program (Intrinsic Phase Method) and refined using the SHELXL2015 refinement package (Sheldrick, GM(2015).Acta Cryst.A71, 3-8)) (full matrix least squares in F2) contained in OLEX2 (Dolomanov, OV et al, OLEX2: a full structure solution, refinement and analysis program.J. Appl.Cryst.2009, 42, 339-341). The calculated XRPD pattern was obtained from Mercury (Macrae, CF, et al, Appl.Cryst.(2006) 39:453-457) and the crystal structure representations were generated by Diamond.Os data Petition 870210111193, dated 11 / 30 / 2021, pp. 199 / 267 44 / 65 Single-crystal X-ray diffraction samples were collected at 296 K using a Bruker D8 VENTURE diffractometer (Mo / Kαλ radiation = 0.71073 Å). Table 2 shows the crystallographic data and structure refinement of Forms C and D.

[182] Table 2. Crystallographic data and structure refinement of Forms C and D of the single-crystal polymorph of Formula I Parameters Form C Form D Empirical formula C14H16F3N7 C14H16F3N7 Formula weight 339.34 339.34 Temperature 150.2(2) K 150% Wavelength Cu / Kcí (À = 1.54178 Â) Cu / Kα (Â = 1.54178 Â) Crystal system, space group Monoclinic, C2 / c Orthorhombic, Pca2i Unit cell dimensions a = 13.7032(3) Â b = 17.5697(4) Â c = 27.4196(6) Â α = 90° / 3 = 91.982 (2) ° Y = 90° a = 17.63410(10) Â b = 14.03430 (10) Â c = 26, 2102 (2) Â α = 90° 0 = 90° = = 90° Volume 6597, 6(3) Â3 64 8 6, 56(8) Â3 Z, calculated density 16, 1.3 67 g / cm3 16, 1.390 g / cm3 Absorption coefficient 0, 964 mm“1 0, 980 mm'1 F(000) 2816.0 2816.0 Crystal size 0.4 x 0.4 x 0.3 mm3 0.6 x 0.5 x 0.2 mm3 Range 2 Theta for data collection 6.45° to 140.532° 6.744° to 141.124° Limiting indices -13 < h < 16 -21 < k < 15 -31 < l < 33 -21 < h < 21 -16 < k < 14 -23 < l < 31 Collected Reflections / Reflections 12836 / 6205 [Rint = 0.0208, 47670 / 11179 [Rint = 0.0269,Rsigma=0.0214] Petition 870210111193, dated 11 / 30 / 2021, pp. 200 / 267 45 / 65 Independent Rsigma=0.0267] Integrity 98.24% 89.80% Refinement Method Full Matrix Least Squares in F2 Full Matrix Least Squares in F2 Data / Constraints / Parameters 6205 / 0 / 441 11179 / 1 / 881 Good fit in F2 1.038 1.031 Final R-indices [I> 2 si gma(I)] Ri = 0.0461, wR2 = 0.1241 Ri = 0.032, wR2 = 0.0857 Final R-indices [all data] Ri = 0.0518, wR2 = 0.1281 Ri = 0.0339, wR2 = 0.0872 Largest difference. Peak and trough 0.85 / -0.37 e.Â-3 0.19 / -0.21 e.Â-3

[183] ​​Simple crystals of Form C and Form D were prepared and analyzed by single crystal X-ray diffraction (SCXRD). The single crystal structures of Form C and Form D were successfully determined.

[184] The characterization of SCXRD confirmed that Forma C crystallized in a monoclinic crystal system and space group C2 / c with the unit cell parameters {a = 13.7032(3) Â, b = 17.5697(4) Â, c = 27.4196(6) Â; α = 90°, β = 91.982 (2)°, γ = 90°}. The cell volume V was calculated at 6597.6 (3) Â3. The asymmetric unit is composed of two molecules, indicating that Forma C is an anhydrate. The calculated density of Forma C is 1.367 g / cm3. The single crystal cell unit is composed of sixteen molecules.

[185] SCXRD characterization confirmed that Form D crystallized in an orthorhombic crystal system and space group Pca21 with unit cell parameters {a = 17.63410(10) Å, b = 14.03430(10) Å, c = 26.2102(2) Å; α = 90°, β = 90°, γ = 90°}. The cell volume V was calculated to be 6486.56(8) Å3. The asymmetric unit is composed of four molecules, indicating that Form D is an anhydrate. The calculated density of Form D is 1.390 Petition 870210111193, dated 11 / 30 / 2021, pp. 201 / 267 46 / 65 g / cm3. The unit cell of a simple crystal is composed of sixteen molecules.

[186] The Form C polymorph of the Formula I compound exhibits an X-ray powder diffraction pattern with characteristic peaks expressed in degrees 2-theta at approximately 6.4, 15.1, 21.2, 25.7 and 27.8. The X-ray powder diffraction pattern of the Form C polymorph of the Formula I compound further comprises peaks at 16.5 and 22.1 ± 0.05 degrees 2-theta.

[187] The C-Form polymorph of the Formula I compound exhibits an X-ray powder diffraction pattern with characteristic peaks expressed in degrees 2-theta at approximately 6.4, 8.1, 8.6, 8.8, 9.9, 10.2, 12.9, 13.8, 15.1, 15.4, 16.5, 19.8, 21.2, 22.1, 23.7, 25.7 and 27.8.

[188] The C-Form polymorph of the Formula I compound exhibits a considerably peak-free X-ray powder diffraction pattern at 13.6 and 14.8 ± 0.05 degrees 2-theta.

[189] The Form D polymorph of the Formula I compound exhibits an X-ray powder diffraction pattern with characteristic peaks expressed in degrees 2-theta at approximately 9.2, 14.0, 14.8, 19.7 and 20.0.

[190] The D-Form polymorph of the Formula I compound exhibits an X-ray powder diffraction pattern with characteristic peaks expressed in degrees 2-theta at approximately 8.0, 8.7, 9.2, 9.8, 10.4, 12.9, 13.4, 14.0, 14.8, 16.4, 18.5, 19.7, 20.0, 20.8, 23.1, 23.3, 23.9, 25.5 and 25.7.

[191] The Form D polymorph of the compound of Formula I exhibits a considerably peak-free X-ray powder diffraction pattern at 13.6 ± 0.05 degrees 2-theta. Example 2 Formulation processes Part 1: Manufacturing of Immediate-Release (IR) Active Pharmaceutical Ingredient (API) Drug Pellets

[192] An initial polymer solution is made by mixing purified water, hypromellose, and polyvinylpyrrolidone. The compound of Formula I (active pharmaceutical ingredient - API) is added to the polymer solution and mixed. The mixture is then sieved to produce the drug dispersion. The spherical core of the seed of Petition 870210111193, dated 11 / 30 / 2021, pp. 202 / 267 47 / 65 microcrystalline cellulose is loaded into the fluidized bed processor bowl and the drug dispersion is sprayed onto the microcrystalline cellulose. After loss on drying (LOD) and in-process assay controls, the resulting particles are sized to produce the API drug core pellet.

[193] The IR coating solution is prepared by mixing purified water, hypromellose, and polyethylene glycol. The API core pellet is loaded into the fluidized bed processor bowl and the IR coating solution is sprayed onto the pellets until the desired weight gain (1.5-3.0%) is achieved. Following LOD process control, the resulting particles are sized to produce the IR API drug pellets which are packaged and tested. Part 2: Manufacturing of Modified-Release Active Pharmaceutical Ingredient (MUP) Pellets

[194] An initial modified-release polymer solution is prepared by mixing purified water, polyethylene glycol, and polyvinylpyrrolidone. Talc is added to the solution to produce a lump-free dispersion. A 30% polyvinyl acetate dispersion is added to the dispersion and mixed. The resulting dispersion is filtered to produce the MR coating dispersion. The IR API drug pellets are loaded into the fluidized bed, and the MR coating dispersion is sprayed onto the pellets until the required weight gain (3-60%) is achieved. The coated pellets are then cured for about 30 minutes to about 2 hours at a product temperature of about 40°C - 60°C. After loss in control of the drying process, the resulting particles are sized to produce the MR API drug pellets, which are packaged and tested. Part 3: Manufacturing of MUPS (Multiple Unit Pellet System) for API drugs

[195] The required quantity of IFA drug pellets (IR) (if required) followed by the required quantity of IFA drug pellets (if required) were individually and Petition 870210111193, dated 11 / 30 / 2021, pp. 203 / 267 48 / 65 manually weighed into each gelatin capsule. The capsule was sealed, visually assessed, weighed, and packaged. Example 3 Formulation of the compound of Formula I in Modified-Release Tablets 3.1.C Modified-release tablets with HPMC polymers

[196] Four tablet formulations with HPMC were prepared to control the release of API, the tablets containing the components in Table 3 below. The release rate can be adjusted with the addition of HPMC polymers. HPMC K100 LV results in faster release than with HPMC (Methocel K-15M CR) alone.

[197] Table 3. Modified-release tablets with HPMC polymers Material Low rapid dose High rapid dose Low slow dose High slow dose Quantity (%) Quantity (g) Quantity (%) Quantity (g) Quantity (%) Quantity (g) Quantity (%) Quantity (g) API 10.00 15.00 30.00 45.00 10.00 15.00 30.00 45.00 Mannitol 100SD 20.00 30.00 20.00 30.00 MCC PH102 45.70 68.55 25.70 38.55 65.70 98.55 45.70 68.55 HPMC (Methocel K-15M CR) 20.00 30.00 20.00 30,00 HPMC Kl 0 0 LV 20,00 30,00 20,00 30,00 Povidone (Kollidon 30) 3.00 4.50 3.00 4.50 3.00 4.50 3.00 4.50 Aerosil 200 0.50 0.75 0.50 0.75 0.50 0.75 0.50 0.75 Magnesium stearate 0.80 1.20 0.80 1.20 0.80 1.20 0.80 1.20 Petition 870210111193, dated 11 / 30 / 2021, pp. 204 / 267 49 / 65 Total 100, 0 150.00 100, 0 150.00 100, 0 150.00 100, 0 150.00

[198] The excess amount of hydrophilic pyrogenic silica Aerosil 200 was weighed and passed through a clean, dry 850 μM sieve, then transferred to a 1 L powder vial and the weight was recorded. The vial was placed in a Turbula mixer at 32 rpm for 1 minute. Excess amounts of MCC, IFA and mannitol were weighed and then passed through clean, dry 600 μM sieves. The required amounts of MCC, IFA and mannitol were transferred to the powder vial and the weights were recorded. The contents of the powder vial were manually mixed with a spatula for 30 seconds and the vial was placed in the Turbula mixer at 32 rpm for 5 minutes. The contents of the vial were sieved through a clean, dry 600 μM sieve. Excess amounts of HPMC and Povidone were weighed and then passed through clean, dry sieves of 600 μM. The required quantities of HPMC and Povidone were transferred to the powder vial and the weight was recorded.The contents of the powder vial were manually mixed with a spatula for 30 seconds, and the vial was placed in the Turbula mixer at 32 rpm for 5 minutes. The mixture was visually inspected and no lumps were observed; therefore, the mixture was not sieved. Next, the excess magnesium stearate was passed through a clean, dry 600 μm sieve. The required amount of sieved magnesium stearate was transferred to the powder vial, and the weight was recorded. The vial was placed in the Turbula mixer at 32 rpm for 3 minutes, and then the mixture was ready for tablet formation. Tablet formation was achieved in a Natoli tablet press with an oval tool to achieve a suitable filling depth for all four formulations.

[199] The dissolution profiles of the tablets determined using the method in Table 4 are shown in Figures 26 and 27. Petition 870210111193, dated 11 / 30 / 2021, pp. 205 / 267 50 / 65

[200] Table 4. Dissolution test method for HPMC tablets Medium: McIlvaine buffer pH 3.0 USP Apparatus Apparatus II (Paddles) Paddle speed: 7.5 rpm Medium volume: 900 mL Temperature: 37 °C ± 0.5 °C Weight: None used Sampling time instant (h): 0.50, 1.00, 2.00, 4.00, 6.00, 8.00, 10.00, 12.00, 18.00, 24.00, 25.00 Sampling type: Automatic (through a 10 µm free-flow filter) Sampling volume: 1.5 mL Autosampler parameters: Flow 3.0 mL Displacement: 2.0 mL Medium recycling: Enabled Medium replacement: Disabled Number of flow times: 2 Continuous washing: 1 Pump flow rates (collection, sampling, other) (rates): 10.0 mL / min 3.2. Modified-release tablets with PARTECK® polymers

[201] Two batches (SR PVA matrix tablets, 40 mg and SR PVA matrix tablets, 120 mg) were manufactured for the SR PVA matrix tablets according to Table 5.

[202] Table 5. Petition 870210111193, dated 11 / 30 / 2021, pp. 206 / 267 51 / 65 Component Function SR PVA Matrix Tablets, 40 mg formulation SR PVA Matrix Tablets, 120 mg formulation % w / w mg / tablet Quantity (g) % w / w mg / tablet Quantity (g) API Drug Substance 10.0 40.0 20.00 30.0 120.0 60.00 Microcrystalline cellulose (Avicel PH102) Filler 53.0 212.0 106.00 33.0 132.0 66.00 Povidone K30 Binder 3.0 12.0 6.00 3.0 12.0 6.00 Colloidal silicon dioxide (Aerosil 200 Pharma) Glidant 0.5 2.0 1.00 0.5 2.0 1.00 Lubricating Talc 1.0 4.0 2.00 1.0 4.0 2.00 Magnesium Stearate Lubricant 0.5 2.0 1.00 0.5 2.0 1.00 Intragranular Weight _ 68.0 272.0 136.00 68.0 272.0 136.00 Polyvinyl Alcohol (Parteck SRP80) Release Modifier 30.0 120.0 60.00 30.0 120.0 60.00 Colloidal Silicon Dioxide (Aerosil 200 Pharma) Glidant 0.5 2.0 1.00 0.5 2.0 1.00 Lubricating Talc 1.0 4.0 2.00 1.0 4.0 2.00 Lubricant Stearate 0.5 2.0 1.00 0.5 2.0 1.00 Petition 870210111193, dated 11 / 30 / 2021, pp. 207 / 267 52 / 65 Magnesium Total 100.0 400.0 200.0 100.0 400.0 200.0

[203] Fifty percent of the total Microcrystalline Cellulose PH102 plus IFA, Talc and Aerosil 200 were passed through the same 600 μm sieve and collected in a 1 LO flask. The flask was placed in the Turbula mixer and mixed for 5 minutes at 23 rpm. The remaining 50% of Microcrystalline Cellulose PH102 plus Povidone K30 were passed through the same 600 μm sieve and collected in a 1 LO flask. The flask was placed in the Turbula mixer and mixed for 5 minutes at 23 rpm. An excess amount of magnesium stearate was passed separately through clean, dry 600 μm sieves. The required amount of magnesium stearate was added to the 1 LO flask. The flask was placed in the Turbula mixer and mixed for 5 minutes at 23 rpm. The required amount of mixture was inserted into the cartridge instrument mold (round flat instrument of 22.00 mm) for compression into a cartridge.The necessary compression force was applied to achieve an acceptable solid fraction (0.60 to 0.70) using the following equation (Weight / ((Thickness x 380.13)) / 1.4). The solid fraction was calculated for all cartridges. The desired weight range was 2000 mg ± 5%. Hardness was recorded for the first two cartridges, and the entire mixture was fragmented. The cartridges were placed in a mortar and gently crushed with the pestle until granules were formed, taking care not to generate fine particles. The crushed cartridges were passed through a 1.18 mm sieve followed by an 850 μm sieve receiving plate. Oversized material was returned to the mortar and crushed as needed for further size reduction. This step was performed on a 1.18 μm sieve first followed by an 850 μm sieve. The fraction retained on the screen was crushed as described above until all... granules passed through the 850 μM screen.The ground granules were weighed and collected in an appropriately sized amber glass vial, and the yield was 85.98% for the 40 mg low-dose formulation and 69.07% for the [previous formulation]. Petition 870210111193, dated 11 / 30 / 2021, pp. 208 / 267 53 / 65 high-dose formulation. PVA (Parteck SRP80), Anhydrous Colloidal Silica 200 (Aerosil), and talc were passed through the same 600 μm sieve and collected in the vial. The vial was placed in the Turbula mixer and mixed for 5 minutes at 23 rpm. Approximately 110% of the magnesium stearate was passed through a 250 μm sieve and collected with the weights recorded. An excess amount of magnesium stearate was passed separately through clean, dry 600 μm sieves. The required amount of magnesium stearate was added to the 1 L vial, which was placed in the Turbula mixer and mixed for 5 minutes at 23 rpm. The required amount of tablet mixture was inserted into the cartridge instrument mold (oval 15x7 mm) for compression into the first tablet. The filling depth was adjusted to achieve the desired filling weight (400 mg ± 5%). The compression force was adjusted to achieve the desired hardness (12kP ± 2kP).The weights and thicknesses of the tablets were checked and recorded (weight range: 400 mg ± 5%). The hardness was recorded for the first two tablets. The mixture was compressed to obtain approximately 30 tablets, and the hardness was obtained from two additional tablets at the end of production. Acceptable tablets were packaged in a 60 mL Duma container.

[204] The dissolution profiles of the tablets determined according to Table 6 are shown in Figures 28 and 29.

[205] Table 6. Dissolution test method for PARTECK® tablets. Medium: McIlvaine buffer pH 3.0 USP Apparatus Apparatus II (Paddles) Paddle speed: 75 rpm. Infinite rotation at 250 rpm Medium volume: 900 mL Temperature: 37 °C ± 0.5 °C Weight: QSS2 Number of coils: 6 (Stainless steel) Internal length: ~23.66 mm Petition 870210111193, dated 11 / 30 / 2021, pp. 209 / 267 54 / 65 Internal diameter: ~9.49 mm Maximum width: ~11.79 mm Sampling times: 0.50, 1.00, 2.00, 4.00, 6.00, 8.00, 10.00, 12.00, 18.00, 24.00 + 1h in infinite rotation Sampling type: Automatic (through a 10 µm free-flow filter) Sampling volume: 1.5 mL Autosampler parameters: Flow: 3.0 mL Displacement: 2.0 mL Media recycling: Enabled Media replacement: Disabled Number of flow times: 2 Continuous washing: 2 Pump flow rates (collection, sampling, other rates): 10.0 mL / min Example 4: Formulation of the compound of Formula I in modified-release coated MUPS.

[206] EUDRAGIT® RS 30 D and EUDRAGIT® RL 30 D in a 9:1 ratio were used as modified-release polymers. The drug-coated suspension was prepared by first preparing a uniform dispersion of API (250 g) and water (2.1 L) to which a clear solution of PEG 6000 (8.33 g), HPMC E5 (83.33 g) and water (~1 L) was then added. Stratification of microcrystalline drug spheres (CP 102, 500 g) was obtained after pulverization for 10 h 30 minutes. The drug-coated product was maintained at 42 °C during the sealing coating process with HPMC E5. The sealing coating solution was prepared by slowly adding HPMC E5 powder (22.5 g) to water (258.8 g) with stirring until the polymer was completely dissolved. The pellets were dried by 10 minutes, then selected to retain granules between 300-425μM, and resulted in 762.3 g of the product with a sealed coated drug layer.

[207] The anti-adherent agent, talc (35.0 g, 50% based on Petition 870210111193, dated 11 / 30 / 2021, pp. 210 / 267 55 / 65 dry polymer) and the plasticizer triethyl citrate (TEC) (24.0 g, 50% based on dry polymer) were added to water (312.7 g) and then homogenized for 10 minutes using a homogenizer. EUDRAGIT® RS 30 D (210.0 g) and EUDRAGIT® RL 30 D (23.3 g) were stirred for 10 minutes at low shear rate. The excipient suspension was slowly poured into the EUDRAGIT® dispersion while gently stirring with a conventional stirrer for 30 minutes. The final suspension was filtered using a 0.25 mm sieve mesh. The suspension was kept under low-speed stirring throughout the coating process. This process was used to prepare pellets with 5%, 10%, and 15% w / w coating. The formulations with 15% w / w coating were fed to mini-pigs.

[208] The drug release over time was then measured. The Formula I compound formulation was dissolved in McIlvaine buffer composed of citric acid and disodium hydrogen phosphate, also known as phosphate-citrate buffer, at pH 3. Comparisons of the dissolution rates of the API (80 mg), pellets with drug layers coated with sealing, pellets with 5%, 10% and 15% w / w coating are shown in figure 31. Example 5: Studies with Cyno PK

[209] Cynomolgus monkeys with a surgically implanted CSF collection port were housed and cared for in accordance with IACUC Guidelines and SOPs for Testing Facilities.

[210] Whole blood collection and processing to plasma (pharmacokinetics): Blood samples were collected from a peripheral vein by direct needle puncture at appropriate times (see below). Whole blood was placed on moist ice until processed to plasma according to the Test Facility SOP. Plasma was stored at -80°C until shipment to the analytical laboratory on dry ice at the conclusion of the study.

[211] Whole blood collection for pharmacodynamics: Blood samples were collected from a peripheral vein by direct needle puncture at appropriate times. 100 pL (microliters) of Petition 870210111193, dated 11 / 30 / 2021, pp. 211 / 267 56 / 65 of whole blood was pipetted into a 1.5 mL pressure-capped tube, flash-frozen in liquid nitrogen, and stored at -80°C until shipment to the responsible party on dry ice upon completion of the study.

[212] CSF Collection: CSF samples were collected from a permanent intrathecal catheter accessed subcutaneously using sterile technique. The port was accessed and ~180 μL of fluid was removed from the line before CSF collection. The CSF was rapidly assessed for the presence of red blood cells, centrifuged in a microcentrifuge at 2,000g, 10 minutes, room temperature, and the supernatant aliquoted, frozen in LN2 and stored at -80°C until it was sent to the responsible party on dry ice at the end of the study. After CSF collection, the port / catheter was blocked with ~140 μL of sterile 0.9% sodium chloride solution.

[213] Pharmacokinetic Study in Cynomolgus Monkeys Obtained from CSF: Before the first day of dosing, all animals (n=16) received, orally, vehicle (0.5% w / v methylcellulose, 0.1% w / v Tween 80 in reverse osmosis water) once daily for 5 days. Starting on the first day of dosing, 10 animals received an oral dose once daily of the Formula I compound formulation for three or seven days, while the remaining animals continued to receive a daily dose of vehicle for three or seven days. Feeding was withheld from the animals overnight before dosing and for at least one hour after dosing (not exceeding 3 hours).

[214] Three MUPS capsule formulations were evaluated in cynomolgus monkeys (body weight approximately 5 kg). The MUPS formulations contained the compound of Formula I formulated as pellets with drug layers coated with the polymer KOLLICOAT® SR 30D at various levels (3%, 5%, and 8% w / w) designed to provide different drug release rates. In vitro dissolution results supported further characterization with in vivo PK studies. The MUPS formulations were evaluated in cynomolgus monkeys using a crossover design with a minimum elimination period of one Petition 870210111193, dated 11 / 30 / 2021, pp. 212 / 267 57 / 65 week. The uncoated pellet and the API in capsule formulations served as comparators with immediate release rates. A single dose (2 mg / kg of Formula I compound) of each formulation was administered to fasted animals (n=4) and timed blood samples were obtained over 24 hours after dosing. Figure 20A shows the PK study for formulations in Cynomolgus monkeys. 1. IR pellet in capsule; 2. 8% Kollicoat® pellet in capsule; 3. Pure API (Formula I compound) in capsule; 4. Enteric-coated pellet in capsule; 5. 5% Kollicoat® pellet in capsule; 6. 3% Kollicoat® pellet in capsule.

[215] After oral administration to fasted monkeys, the uncoated pellet and PIC formulations achieved similar Tmax, Cmax, and AUCc-inf. Formulations containing coated pellets of KOLLICOAT® SR 30D showed slower absorption of the Formula I compound compared to the two immediate-release formulations, as shown by a longer Tmax and reduced Cmax. Figure 20B shows time-to-mean concentrations of the Formula I compound in monkeys (N=4) after a single oral administration of the Formula I compound (2 mg / kg) as immediate-release and MUPS formulations. The mean Tmax for the API in the capsule formulation was 1.25 h compared to 2.0, 1.75, and 7.5 h for the KOLLICOAT® 3%, 5%, and 8% formulations, respectively, while the corresponding mean Cmax values ​​were 1.14, 0.585, 0.190, and 0.0660 μM, respectively.The relative bioavailabilities, based on AUC ratios compared to the API in capsules, of the KOLLICOAT® formulations at 3%, 5%, and 8% were 84%, 40%, and 20%, respectively, indicating that the lower Cmax for the two formulations with higher polymer content was due to a combination of slower absorption rate and a decrease in the extent of absorption. Example 6: PK studies of minipigs

[216] Blood collection from minipig subjects was similar to cyno subjects in Example 5. Petition 870210111193, dated 11 / 30 / 2021, pp. 213 / 267 58 / 65

[217] Uncoated drug pellets and 5% and 8% KOLLICOAT® formulations in capsules were evaluated using a crossover design in fasted Göttingen minipigs (N=3). Figure 17A shows time-to-mean oral concentration graphs for Formulations 1-5 in minipigs. Kollicoat® pellets exhibit a slower absorption rate. Enteric-coated pellets achieved similar exposure to IR pellets. 1. IR pellet in capsule; 2. 8% Kollicoat® pellet in capsule; 3. IV (0.5 mg / kg); 4. Enteric-coated pellet in capsule; 5. Kollicoat® 5% pellet in capsule form. The KOLLICOAT® 5% and 8% formulations at 1 mg / kg exhibited slower absorption of the compound from Formula I. The mean Tmax values ​​were 2.0, 2.5, and 4.0 h for the uncoated pellet and the KOLLICOAT® 5% and 8% formulations, respectively, while the corresponding Cmax values ​​were 0.197, 0.0940, and 0.0469 μM, respectively.Figure 17B shows time graphs of mean concentrations of the Formula I compound in minipigs (N=3) after a single oral administration of the Formula I compound (1 mg / kg) as immediate-release and MUPS formulations. Example 7: MUPS Pellet

[218] MUPS pellets containing 80 mg of the compound of Formula I were prepared according to the previous examples. Pellets with KOLLICOAT® SR 30D coatings at 5%, 7% and 9% weight gain relative to the uncoated pellet were found to have the dissolution profiles shown in Table 7. The dissolution profile of uncoated MUPS pellets with a modified-release polymer is shown in Table 8. The drug components and stratification steps of the KOLLICOAT® SR 30D coatings at 5% and 7% are shown in Tables 9 and 10. Petition 870210111193, dated 11 / 30 / 2021, pp. 214 / 267 59 / 65

[219] Table 7. Dissolution of modified-release MUPS pellets coated with KOLLICOAT® for different weight gains. USPII apparatus; 900 mL; 100 rpm; 37°C McIlvaine buffer pH 3.0 % Dissolved (average) Time (h) 5% weight gain 7% weight gain 9% weight gain 0.5 8 2 2 1 19 5 4 2 35 11 8 4 56 22 14 6 72 31 21 8 82 39 27 10 88 46 33 12 92 52 38 18 97 65 51 24 98 76 64

[220] Table 8. Dissolution of instant-release MUPS pellets Time (min.) % Dissolved (average) 5 9 10 48 15 82 20 90 30 93 45 95 60 96 120 98

[221] Table 9. MUPS pellet with 80 mg API and KOLLICOAT® SR 30D coatings with a 5% weight gain. Step Ingredients %w / w mg / unit 1 MCC Spheres 56.91 160.00 2 API 28.46 80.00 Petition 870210111193, dated 11 / 30 / 2021, pp. 215 / 267 60 / 65 3 Hydroxypropyl methylcellulose 5.34 15.00 4 Povidone 2.67 7.50 Subtotal 93.37 262.50 Sealing coating (weight gain 2%) 5 Spheres with medicated coating 93.37 262.50 6 Hydroxypropyl methylcellulose 1.68 4.73 7 Polyethylene glycol 0.18 0.52 Subtotal 95.24 267.75 MR coating (5% weight gain) 8 Sealing coated spheres 95.24 267.75 9 Kollicoat SR30D 3.50 9.84 10 Polyethylene glycol 0.28 0.79 11 Talc 0.28 0.79 12 Povidone 0.70 1.97 Total 100 281.14

[222] Table 10. MUPS pellet with 80 mg API and KOLLICOAT® SR 30D coatings with a weight gain of 7%. Step Ingredients %w / w mg / unit 1 MCC Spheres 55.85 160.00 2 API 27.92 80.00 3 Hydroxypropyl methylcellulose 5.24 15.00 4 Povidone 2.62 7.50 Subtotal 91.63 262.50 Sealing coating (2% weight gain) 5 Drug-coated spheres 91.63 262.50 6 Hydroxypropyl methylcellulose 1.65 4.73 7 Polyethylene glycol 0.18 0.52 Subtotal 93.46 267.75 MR coating (7% weight gain) 8 Sealing coated spheres 93.46 267.75 9 Kollicoat SR30D 4.81 13.78 10 Polyethylene glycol 0.38 1.10 11 Talc 0.38 1.10 12 Povidone 0.96 2.76 Petition 870210111193, dated 11 / 30 / 2021, pp. 216 / 267 61 / 65 Total 100 286.49 Example 8 Modified-release tablets

[223] Tablets containing 80 mg of the compound of Formula 1 (API) were prepared with PVA or HPMC release-modifying agents as shown in Tables 11 and 12. Their dissolution profiles are shown in Table 13. In comparison, the dissolution profile of the API in the capsule formulation (80 mg of the compound of Formula 1 in a gelatin capsule without any added excipients) is shown in Table 14.

[224] Table 11. 80 mg sustained-release tablets based on polyvinyl alcohol Petition 870210111193, dated 11 / 30 / 2021, pp. 217 / 267 62 / 65 Ingredients %w / w IFA 20 Microcrystalline cellulose 43 Polyvinylpyrrolidone 3 Polyvinyl alcohol 30 Colloidal silica, anhydrous 1 Talc 2 Magnesium stearate 1 Total 100

[225] Table 12. 80 mg sustained-release tablets based on HPMC Ingredients %w / w IFA 20.0 Mannitol 10.0 Microcrystalline cellulose 45.7 HPMC K15M 10 HPMC K100LV 10 Povidone 3 Colloidal silica, anhydrous 0.5 Magnesium stearate 0.8 Total 100

[226] Table 13. Dissolution profile of HPMC tablets and PVA Time (h) % Dissolved API 80 mg (PVA) API 80 mg (HPMC) 0.5 9.1 18.7 1 18.1 24.9 2 33.8 33.2 4 62.2 47.2 6 85.9 60.4 8 97.9 72.0 10 99.8 81.2 12 99.8 87.7 14 99.8 92.4 Petition 870210111193, dated 11 / 30 / 2021, pp. 218 / 267 63 / 65 18 99, 6 97,0 24 99, 6 98,4

[227] Table 14. API dissolution profile in the capsule Time (min.) % Dissolved 0 0 5 4 10 24 20 65 30 87 45 100 Example 9 Pharmacokinetic (PK) and Bioavailability Study to Investigate Modified-Release Formulations in Humans:

[228] The in vivo human bioavailability of some of the modified-release (MR) formulations described in the Examples above was evaluated in a pharmacokinetic and bioavailability study of healthy volunteers using a crossover design with a minimum elimination period of one week. The immediate-release (IR) formulation of the compound of Formula I as a capsule-based API formulation was used as a comparator and reference. A single 80 mg dose of the compound of Formula I was given to fasting human subjects as the capsule-based API, KOLLICOAT® SR 30D 5% pellets, or KOLLICOAT® SR 30D 7% pellets in capsule formulation. Timed blood samples were obtained 72 hours after dosing. The above dosing periods were repeated to acquire pharmacokinetic and bioavailability data for each of the above formulations as desired.Blood samples from individuals were collected at regular intervals. PK parameters were measured using standard techniques. Additional measurements were made related to post-dosage safety, including evaluation of laboratory safety tests (hematology, clinical chemistry, and urinalysis), vital signs, ECGs, physical examinations, and any adverse events (AEs). The PK properties of the tested formulations are shown in the tables below. Petition 870210111193, dated 11 / 30 / 2021, pp. 219 / 267 64 / 65

[229] Table 15. Pharmacokinetic properties of MUPS capsules compared with the API in the capsule Formulation (single dose: 80 mg) Observed Cmax / C12hr ratio Reduction in Cmax vs. API in capsule API in capsule 10.0 NA MUPS Kollicoat 5% 7.77 -39.8% MUPS Kollicoat 7% 4.39 -69.6%

[230] The MUPS KOLLICOAT® SR 30D 5% and 7% capsule pellet formulations showed reduced Cmax and Cmax / C12hr compared to the immediate-release formulation and were considered well tolerated and bioavailable.

[231] Two tablet formulations were evaluated in healthy human volunteers in a similar study design. HPMC (80 mg) and PVC (80 mg) tablets were studied in a crossover fashion with timed blood samples obtained over 72 hours after dosing. The API in the capsule formulation (80 mg) served as a comparator. Oral administration of HPMC and PVC tablets achieved reduced Cmax compared to healthy fasting subjects and was considered well tolerated and bioavailable.

[232] Table 16. Pharmacokinetic properties of modified-release tablets compared with API in capsules Formulation (single dose: 80 mg) Observed Cmax / C12hr ratio Reduction in Cmax vs. API in capsule API in capsule 8.02 NA HPMC 2.19 -75% PVA 1.67 -80%

[233] Overall, the clinical study demonstrated that the capsules and modified-release tablets were well tolerated and achieved lower Cmax and reduced Cmax / C12hr, while maintaining oral bioavailability (relative oral bioavailability in Petition 870210111193, dated 11 / 30 / 2021, pp. 220 / 267 65 / 65 comparison with IFA in capsules greater than 30%). No clinically significant impact on pulse rate or blood pressure was observed. Formulations that reduce Cmax while retaining oral bioavailability may allow for a higher and / or lower dosing frequency and allow for greater tolerability and safety.

[234] Although the prior invention has been described in some detail by way of illustration and example for the sake of clarity, the descriptions and examples should not be construed as limiting the scope of the invention. Consequently, all suitable and equivalent modifications may be considered as within the scope of the invention, as defined by the claims that follow. Disclosures of all patents and scientific literature cited in this document are expressly incorporated in their entirety by reference. Petition 870210111193, dated 11 / 30 / 2021, pp. 221 / 267

Claims

1 / 4 Claims 1. A modified-release formulation characterized in that it comprises 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1yl)propanenitrile and at least one release-modifying agent, wherein (i) the release-modifying agent is polyvinyl acetate, wherein the release-modifying agent comprises 3% to 10% by weight of the formulation; (ii) the release-modifying agent is hydroxypropylmethylcellulose (HPMC) or polyvinyl alcohol (PVA) polymer, wherein the release-modifying agent comprises 20-30% by weight of the formulation; or (iii) the release-modifying agent is poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate-co-chloride), wherein the release-modifying agent comprises 3 to 20% by weight of the formulation.

2. Modified release formulation of claim 1, characterized by comprising pellets containing 2-methyl-2-(3methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and coated with at least one release-modifying agent.

3. Modified release formulation of claim 1 or 2, characterized in that the modified release formulation comprises 10% to 50% by weight of 2-methyl-2-(3-methyl-4-(4(methylamino)-5-(trifluoromethyl)pyrimidine-2-ylamino)-1H-pyrazol-1-yl)propanenitrile.

4. Modified release formulation of claims 1-3, characterized in that 2-methyl-2-(3-methyl-4-(4)(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1Hpyrazol-1-yl)propanenitrile is crystalline.

5. Modified release formulation of claim 4, characterized in that the crystalline 2-methyl-2-(3-methyl-4-(4(methylamino)-5-(trifluoromethyl)pyrimidine-2-ylamino)-1Hpyrazol-1-yl)propanenitrile is milled or micronized.

6. Modified release formulation of claims 1-5, characterized in that it is a tablet.

7. Modified-release formulation of claim 6, characterized in that the tablet comprises 10 to 500 mg, preferably 40 to 120 mg, or more preferably 30 to 80 mg of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1yl)propanenitrile.

8. Modified release formulation of claim 6, characterized in that the release modifier is HPMC or a polyvinyl alcohol polymer.

9. Modified release formulation of claim 8, characterized in that the release modifier comprises 20-30% w / w of the formulation.

10. A modified release formulation of any one of claims 1-9, characterized in that the formulation is a capsule containing pellets.

11. Modified release formulation of claim 10, characterized in that (i) the capsule is a combination of particles from various units of immediate release pellets and modified release pellets contained in the capsule; and / or Petition 870260041418, dated 04 / 05 / 2026, page 22 / 24 3 / 4 (ii) the modified release formulation is selected from a delayed release pellet formulation, a controlled release pellet formulation, a prolonged release pellet formulation and a pulsed release pellet formulation.

12. Modified release formulation of claim 11, characterized in that the formulation comprises a coating agent, and the coating agent comprises a poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride) polymer in up to 20% w / w.

13. Modified release formulation of claim 11, characterized in that the formulation comprises a coating agent, wherein the coating agent is a polyvinyl acetate polymer stabilized with povidone and sodium lauryl sulfate, wherein the polymer contains about 27% polyvinyl acetate, about 2.7% povidone K30, about 0.3% sodium lauryl sulfate and about 70% water.

14. Modified release formulation of claim 13, characterized in that the polyvinyl acetate polymer provides a weight gain of 5-9%, 5%, 7% or 8% of the pellets.

15. Method for preparing a modified-release formulation of claim 1, characterized in that it comprises: (a) coating an inert core selected from the group consisting of sugar, polyols, carnauba wax, silicon dioxide, MCC and tartaric acid, with 2-methyl-2-(3-methyl-4-(4(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile to form an API core pellet; Petition 870260041418, dated 04 / 05 / 2026, page 23 / 24 4 / 4 (b) coating the API core pellet with a cosmetic and non-functional sealing coating to form a sealing-coated pellet; and (c) coating the sealing-coated pellet with a release-modifying agent to form the modified-release formulation.

16. Method of claim 15, characterized in that (a) the inert core is selected from a sugar, microcrystalline cellulose (MCC), tartaric acid, polyols, carnauba wax, silicon dioxide and combinations thereof; (b) the cosmetic and non-functional sealing coating is selected from hydroxypropyl methylcellulose (HPMC) and a mixture of hypromellose and ethylcellulose; and / or (c) the release modifier agent is selected from the group consisting of polyvinyl acetate polymer, poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), hydroxypropyl methylcellulose (HPMC) and a mixture of hypromellose and ethylcellulose. Petition 870260041418, dated 04 / 05 / 2026, p. 24 / 24

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