Modified Release Formulations of Pyrimidinylaminopyrazole Compounds and Methods of Treatment

Abstract

The present disclosure relates to modified-release formulations of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile or solvates, tautomers, and pharmaceutically acceptable salts thereof, and methods of treatment using the modified-release formulations. Embodiments of the present disclosure include a modified-release formulation comprising a therapeutically effective amount of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and at least one release modifier.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 855,740, filed May 31, 2019, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] The present disclosure relates to formulations of 2 - methyl - 2-(3 - methyl - 4 - ((4-(methylamino)-5-(trifluoromethyl)pyrimidin - 2 - yl)amino)-1H - pyrazol - 1 - yl)propanenitrile for use in the treatment of peripheral and neurodegenerative diseases including Parkinson's disease. The present disclosure also relates to methods for obtaining controlled - release formulations.

Background Art

[0003] Parkinsonism is a term that encompasses several conditions, including Parkinson's disease (PD), as well as other conditions with similar symptoms collectively known as parkinsonism, such as slowness of movement, rigidity, and problems with walking. Most people with parkinsonism have idiopathic Parkinson's disease, also known as Parkinson's. Idiopathic means that the cause is unknown. The most common symptoms of idiopathic Parkinson's are tremors, rigidity, and slowness of movement. The exact cause of Parkinson's disease is unknown, but a combination of genetic and environmental factors is thought to contribute to the etiology of the disease. Drugs approved for treating Parkinson's disease include dopamine replacement therapy (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 inhibitors (rivastigmine), serotonin 5 - HT2A It includes a receptor agonist (pimavanserin), and a dopamine transporter for imaging (ioflupane I-123). However, these pharmaceuticals provide symptomatic benefits to patients with Parkinson's disease and do not reduce the progression of the disease.

[0004] The combination of genetic and biochemical evidence implicates certain kinase functions in the etiology of neurodegenerative disorders (Christensen, K.V. (2017) Progress in medicinal chemistry 56:37-80, Fuji, R.N et al (2015) Science Translational Medicine 7(273):273ra15, Taymans, J.M et al (2016) Current Neuropharmacology 14(3):214-225). Genes implicated in Parkinson's disease include Park8, which encodes leucine-rich repeat kinase 2 (LRRK2), a complex signaling protein that is a particularly important therapeutic target in Parkinson's disease (PD). Mutations in Park8 are found in both the familial and non-familial (sporadic) forms of Parkinson's disease, and increased kinase activity of LRRK2 is involved in the etiology of Parkinson's disease. Mutations in the LRRK2 gene are the most frequent genetic cause of familial Parkinson's disease and a major factor in lysosomal dysfunction that contributes to the formation of Lewy body protein aggregates and neurodegeneration. LRRK2 controls the generation and function of lysosomes that are impaired in Parkinson's disease and can be restored by LRRK2 inhibition, thereby potentially reducing the progression of the disease in patients with genetic LRRK2 mutations and in patients with sporadic or idiopathic Parkinson's disease.

[0005] 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 disorders (Estrada, A.A et al (2015) Jour. Med. Chem. 58(17):6733-6746, Estrada, A.A et al (2013) Jour. Med. Chem. 57:921-936, Chen, H. et al (2012) Jour. Med. Chem. 55:5536-5545; Estrada, A.A. et al (2015) Jour. Med. Chem. 58:6733-6746, Chan, B.K. et al (2013) ACS Med. Chem. Lett. 4:85-90, U.S. Patent No. 8354420, U.S. Patent No. 8569281, U.S. Patent No. 8791130, U.S. Patent No. 8796296, U.S. Patent No. 8802674, U.S. Patent No. 8809331, U.S. Patent No. 8815882, U.S. Patent No. 9145402, U.S. Patent No. 9212173, U.S. Patent No. 9212186, U.S. Patent No. 9932325, International Publication No. 2011 / 151360, International Publication No. 2012 / 062783, International Publication No. 2013 / 079493). LRRK2 activity is related to a central mechanism of Parkinson's disease pathology by virtue of its role in lysosomal function. Inhibitors of the genetically validated target, LRRK2 kinase, can improve lysosomal function in LRRK2-PD and potentially in idiopathic Parkinson's disease. Thus, LRRK2 inhibition can intervene in an important disease pathway of Parkinson's disease and prevent or suppress the accumulation of motor and non-motor disabilities that define the progression of Parkinson's disease. There is a need for new therapies that reduce or delay the progression of late motor complications associated with neurodegenerative disorders and delay the onset of such complications. Further, there is a need for a solid oral dosage form of a pharmaceutical composition that is effective in achieving an optimal blood concentration between the maximum tolerated dose and the minimum effective dose. The optimized solid oral dosage form modulates the release and pharmacokinetic profile, minimizes the dosing frequency, and minimizes the burden of tablets in patients with limited swallowing ability and other compliance factors.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0007] The present disclosure relates to a modified-release formulation of a pyrimidinylaminopyrazole kinase inhibitor, which inhibitor is referred to herein as a compound of Formula I and has the name 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, and has the structure

Chemical Formula

[0008] Aspects of the present disclosure include a modified-release formulation comprising a therapeutically effective amount of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and at least one release modifier.

[0009] Exemplary embodiments of the formulation include 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 modifier. In another exemplary 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 exemplary 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.

[0010] An exemplary embodiment of the formulation is an embodiment 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 2 hours and more than 60% in 8 hours when tested at 37 °C in McIlvaine buffer at pH 3 using a USP type II apparatus at 50 - 75 rpm, and the formulation is a tablet.

[0011] An exemplary embodiment of the formulation is an embodiment 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 1 hour and more than 70% in 8 hours when tested at 37 °C in McIlvaine buffer at pH 3 using a USP type II apparatus at 100 rpm, and the formulation is a capsule containing pellets.

[0012] Exemplary embodiments of the formulation are those 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 1 hour and the formulation is a capsule containing pellets. In some embodiments, less than 60% (e.g., 5 - 40% and 5 - 15%) of the compound of formula I is released in 2 hours. In some embodiments, less than 60% (e.g., 15 - 60% and 15 - 25%) of the compound of formula I is released in 4 hours. In some embodiments, less than 60% (e.g., 35 - 55% and 40 - 60%) of the compound of formula I is released in 12 hours.

[0013] Exemplary embodiments of the formulation are those in which 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile has a reduced C max compared to an immediate release formulation after administration to a subject (e.g., a human subject).

[0014] Exemplary embodiments of the formulation are those in which C max is reduced by at least 20% (e.g., 20 - 80%, 40 - 80%, 60 - 80%, and 65 - 75%).

[0015] Exemplary embodiments of the formulation are those in which the steady state C max / C min ratio of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile in the blood is in the range of about 1.5 to about 4.5 during the first 12 hours after administration to the subject.

[0016] Exemplary embodiments of the formulation are embodiments 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-1-yl)propanenitrile.

[0017] Exemplary embodiments of the formulation are embodiments in which 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is crystalline.

[0018] Exemplary embodiments of the formulation are embodiments in which crystalline 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is milled or micronized.

[0019] Exemplary embodiments of the formulation are embodiments in which the release modifier constitutes 3% to 60% by weight (e.g., 3 to 10% by weight, about 5% by weight, about 7% by weight, or about 9% by weight) of the formulation.

[0020] Exemplary embodiments of the formulation are embodiments selected from the group consisting of MCC (microcrystalline cellulose), HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), PEG (polyethylene glycol glyceride), PVA (polyvinyl alcohol), PVP (polyvinyl pyrrolidone), CAP (cellulose acetate phthalate), CMC-Na (sodium carboxymethyl cellulose), HPMCAS (hydroxypropyl methylcellulose acetate succinate), HPMCP (hydroxypropyl methylcellulose phthalate), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), CA (cellulose acetate), CAB (cellulose acetate butyrate), EC (ethyl cellulose), poly(ethyl acrylate-co-methyl methacrylate), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), PVAc (polyvinyl acetate), and HPMC / CMC.

[0021] Exemplary embodiments of the formulation are embodiments in which the release regulator is selected from the group consisting of Aquacoat®, Walocel®, HP50 / HP55, Aqoat®, EUDRAGIT® FS30D, EUDRAGIT® L30D-55 / L100-55, EUDRAGIT® L12,5 / EUDRAGIT® L100, EUDRAGIT® S12,5 / EUDRAGIT® S100, Carbopol® polymer, Eastman CA, Eastman CAB, Eastman CAB, Ethocel™, Aquacoat® ECD, or Surelease®, or Glyceride GatteCoat™, EUDRAGIT® NE30D, EUDRAGIT® NM30D, EUDRAGIT® RL30D, EUDRAGIT® RL100 / RL PO, EUDRAGIT® RS30D, EUDRAGIT® RS100 / RS, Kollicoat® SR30D, Kollidon®, Walocel® HM-PPA, Kollicoat® MAE30DP / 100P, and Eastacryl 30D.

[0022] Exemplary embodiments of the formulation are embodiments in which the release regulator is selected from the group consisting of microcrystalline cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrrolidone, KOLLICOAT®, CARBOPOL®, and AQUACOAT.

[0023] An exemplary embodiment of the formulation is an embodiment in which the release regulator is polyvinyl acetate.

[0024] In an exemplary embodiment, the release modifier is a mixture of polyvinyl acetate, polyvinylpyrrolidone, and sodium lauryl sulfate. In some embodiments, the mixture of polyvinyl acetate, polyvinylpyrrolidone, and sodium lauryl sulfate is present in a ratio of about 90:9:1. In some embodiments, the mixture provides a coating weight gain of about 5-9% to pellets containing 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile. In some embodiments, the mixture provides a coating weight gain of about 5% to the pellets. In some embodiments, the mixture provides a coating weight gain of about 6% to the pellets. In some embodiments, the mixture provides a coating weight gain of about 7% to the pellets. In some embodiments, the mixture provides a coating weight gain of about 8% to the pellets. In some embodiments, the mixture provides a coating weight gain of about 9% to the pellets.

[0025] In an exemplary embodiment of the formulation, the release modifier is KOLLICOAT® SR30D. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 5-9% to the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 5% to the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 6% to the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 7% to the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 8% to the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 9% to the pellets.

[0026] Exemplary embodiments of the formulation include one or more excipients selected from the group consisting of microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrrolidone, purified talc, colloidal silicon dioxide, and magnesium stearate, and a coating.

[0027] An exemplary embodiment of the formulation is an embodiment in which the formulation is a tablet.

[0028] An exemplary embodiment of the formulation is an embodiment in which the tablet contains 10 - 500 mg of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile.

[0029] An exemplary embodiment of the formulation is an embodiment in which the tablet contains 40 - 120 mg of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile.

[0030] An exemplary embodiment of the formulation is an embodiment in which the tablet contains 30 - 80 mg of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile.

[0031] An exemplary embodiment of the formulation is an embodiment in which the release regulator is HPMC.

[0032] An exemplary embodiment of the formulation is an embodiment in which the release regulator is a PARTECK (registered trademark) polymer.

[0033] An exemplary embodiment of the formulation is an embodiment in which the release regulator constitutes 20 - 30% w / w of the formulation.

[0034] An exemplary embodiment of the formulation is an embodiment in which the formulation is a capsule containing pellets.

[0035] An exemplary embodiment of the formulation is an embodiment in which the capsule is a multi-unit particulate combination of immediate-release pellets and modified-release pellets contained in the capsule.

[0036] An exemplary embodiment of the formulation is an embodiment in which the pellets contain a release modifier selected from KOLLICOAT®, CARBOPOL®, and AQUACOAT®.

[0037] An exemplary embodiment of the formulation is an embodiment in which the formulation is a multi-unit particulate combination of immediate-release pellets and delayed-release pellets contained in the capsule.

[0038] An exemplary embodiment of the formulation is an embodiment in which the modified-release formulation is selected from delayed-release pellet formulations, controlled-release pellet formulations, sustained-release pellet formulations, and pulsatile-release pellet formulations.

[0039] An exemplary embodiment of the formulation is an embodiment in which the formulation contains a coating agent that is EUDRAGIT®.

[0040] An exemplary embodiment of the formulation is an embodiment in which the coating agent contains 3 wt% to 60 wt% of EUDRAGIT® of the formulation.

[0041] An exemplary embodiment of the formulation is an embodiment in which the coating agent contains up to 20% w / w of EUDRAGIT® RS30D.

[0042] An exemplary embodiment of the formulation is an embodiment in which the coating agent contains up to 60% w / w of EUDRAGIT® NM30D.

[0043] Aspects of the present disclosure are methods of preparing a controlled release formulation, comprising: (a) coating an inert core selected from the group consisting of sugar, 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; (b) coating the API core pellet with a cosmetic non-functional seal coating to form a seal-coated pellet; (c) coating the seal-coated pellet with a release modifier to form a controlled release formulation and a method comprising the same.

[0044] An exemplary embodiment of the method of preparing a controlled release formulation is an embodiment in which the inert core is selected from sugar, microcrystalline cellulose (MCC), tartaric acid, polyol, carnauba wax, silicon dioxide, and combinations thereof.

[0045] An exemplary embodiment of the method of preparing a controlled release formulation is an embodiment in which the cosmetic non-functional seal coating is selected from hydroxypropyl methylcellulose (HPMC), and a mixture of hypromellose and ethylcellulose.

[0046] An exemplary embodiment of the method of preparing a controlled release formulation is an embodiment in which the release modifier is selected from the group consisting of KOLLICOAT®, EUDRAGIT®, hydroxypropyl methylcellulose (HPMC), and a mixture of hypromellose and ethylcellulose.

[0047] Aspects of the present disclosure are methods of preparing a controlled release formulation, comprising: (a) 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, hydroxypropyl methylcellulose, croscarmellose sodium, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, purified talc, colloidal silicon dioxide, and magnesium stearate are roller-compressed, thereby forming pellets; (b) polymer-coating the pellets with a dispersion of a coating agent selected from KOLLICOAT®, CARBOPOL®, AQUACOAT®, and OPADRY® White comprising a method.

[0048] Exemplary embodiments of a method for preparing a controlled-release formulation further comprise one or more steps selected from extrusion, spheronization, and compression.

[0049] Exemplary embodiments of a method for preparing a controlled-release formulation further comprise filling a soft or hard capsule shell with coated pellets.

[0050] Aspects of the present disclosure are methods for preparing controlled-release formulation tablets, (a) blending a dry mixture of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, povidone, croscarmellose sodium, silicon dioxide, talc, microcrystalline cellulose, and magnesium stearate; (b) preparing as granules by roller-compressing a dry granulate of the dry mixture; (c) milling the granules (d) Adding croscarmellose sodium, silicon dioxide, talc, and magnesium stearate to the milled granules to form an extra-granular mixture; (e) Compressing the extra-granular mixture into tablets; (f) Coating the tablets with a coating agent selected from KOLLICOAT (registered trademark), CARBOPOL (registered trademark), AQUACOAT (registered trademark), and EUDRAGIT (registered trademark). A method comprising the above steps is provided.

[0051] Aspects of the present disclosure include a method for treating LRRK2-mediated diseases, which includes administering a formulation of the present disclosure to a subject in need thereof.

[0052] Exemplary embodiments of the method for treating LRRK2-mediated diseases are those in which one or more of the formulations are administered to the subject once, twice, or three times a day.

[0053] Exemplary embodiments of the method for treating LRRK2-mediated diseases are those in which the formulation is administered to the subject twice a day.

[0054] Exemplary embodiments of the method for treating LRRK2-mediated diseases are those in which the LRRK2-mediated disease is a neurodegenerative disease.

[0055] Exemplary embodiments of the method for treating LRRK2-mediated diseases are those in which the LRRK2-mediated disease is Parkinson's disease.

[0056] In accordance with aspects of the present invention, a consistent steady state blood level of a modified release formulation of a compound of Formula I within a therapeutic range of about 0.2 μM to about 1.2 μM is provided over a period of at least 12 hours. The blood concentration can be measured as the average plasma or serum concentration from a plurality of subjects or studies. The blood concentration can be measured at the time of administration and at various time points to establish the time-dependent profile of the blood concentration of the compound of Formula I in a subject after administration of the modified release formulation.

[0057] The modified release method of delivery of the present invention can be achieved by administering multiple single unit dosage forms of the compound of Formula I at equal or varying concentrations. Each such unit can be designated to release its contents at various time points over a period of at least 12 hours so as to maintain the blood level of the compound of Formula I within the therapeutic range already described.

[0058] A preferred embodiment of the present invention provides for a treated patient to ingest a dosage form containing a compound of Formula I that can maintain a patient blood concentration of about 0.2 μM to about 1.2 μM over a period of at least 12 hours at a single point in time. Such a dosage form can consist of one or more units having the same or varying concentrations of the compound of Formula I that are designed to release their contents at various times so as to maintain the blood concentration level of the compound of Formula I within the therapeutic range over the period already described.

[0059] One embodiment can include one single dosage form that contains a plurality of units therein and is capable of releasing their contents at various times (U.S. Patent No. 5,326,570). Another embodiment of the single dosage form can consist of one unit that immediately releases a certain concentration of the compound of Formula I and then can adjustably release the compound of Formula I at other times as needed to maintain the blood level within the therapeutic range. In another embodiment, the dosage form may exist as a plurality of discrete units capable of releasing the compound of Formula I at various times, and the aforementioned plurality of discrete units can all be ingested at the same time by the patient being treated. Multiparticulates allow for flexible adjustment of the therapeutic dose. Capsules can be filled with various amounts of microparticles or pellets without the use of any further processing or formulation. BRIEF DESCRIPTION OF THE DRAWINGS

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DETAILED DESCRIPTION OF THE INVENTION

[0093] Definitions Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and are consistent with the following.

[0094] The terms "comprise", "comprising", "include", "including", and "includes", as used herein and in the claims, are intended to specify the presence of the described features, integers, components, or steps, but do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0095] Defined parameters, for example, the amounts of components in the formulation, water content, C max , t maxThe terms "about" or "approximately" when referring to AUC, intrinsic dissolution rate, temperature, and time indicate, for example, the inherent variability in the measurement of the parameter or the achievement of the parameter. One of ordinary skill in the art having the benefit of this disclosure would understand the variability of the parameter implied by the use of the terms "about" or "approximately". When used with a numerical value, the terms "about" or "approximately" include a range of + / -(plus or minus) 10% of that numerical value.

[0096] "Polymorphs", as used herein, refer to the occurrence of various crystalline forms of a compound having the same chemical composition but different packing or three-dimensional structures / arrangements. The crystalline forms have molecules in various arrangements and / or three-dimensional structures within the crystal lattice. Thus, a single compound may give rise to various polymorphs, each form having various distinct physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, morphology, density, flowability, compactibility, and / or X-ray diffraction peaks. The solubility of each polymorph may vary, and thus, it is essential to identify the presence of pharmaceutical polymorphs in order to provide a pharmaceutical with a predictable solubility profile. It is desirable to characterize and investigate all solid states of a drug, including any polymorphs, and to determine the stability, dissolution, and flow properties of each polymorph. Polymorphs of a compound can be distinguished in the laboratory by X-ray diffraction methods and other methods, such as infrared or Raman or solid-state NMR spectroscopy. For a general overview of polymorphs and their pharmaceutical applications, see G. M. 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 the Pharmaceutical Sciences)", Harry G. Brittain, Ed. (2011) CRC Press (2009), and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.

[0097] A "solvate" is a crystalline form that contains either a stoichiometric or non-stoichiometric amount of a solvent. When the incorporated solvent is water, the solvate is generally known as a hydrate. Hydrates / solvates can exist as polymorphs for compounds having the same solvent content but different lattice packings or three-dimensional structures.

[0098] The term "hydrate" refers to a complex in which the solvent molecule is water.

[0099] The phrase "pharmaceutically acceptable salt", as used herein, refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, mesylate (i.e., methanesulfonate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Other salts include acid salts such as the aforementioned coformers. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Further, a pharmaceutically acceptable salt may have two or more charged atoms within its structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, multiple counterions can be present. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0100] The desired pharmaceutically acceptable salts can 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, etc., or 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, pyranosidic acids such as glucuronic acid or galacturonic acid, alpha-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc. Acids generally regarded as suitable for the formation of pharmaceutically useful or acceptable salts from basic pharmaceutical compounds are, for example, Stahl PH, Wermuth CG, editors. Handbook of Pharmaceutical Salts; Properties, Selection and Use, 2 nd nd Revision (International Union of Pure and Applied Chemistry). 2012, New York: Wiley-VCH, S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 119, 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, 18 th th ed., (1995) Mack Publishing Co., Easton PA, and The Orange Book (Food & Drug Administration, Washington, D.C., website) are discussed. These disclosures are incorporated herein by reference.

[0101] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the mammal being treated therewith.

[0102] The term "therapeutically effective amount" means an amount of a drug that is sufficiently low to be non-toxic but sufficient to achieve a therapeutic result, including eliminating, reducing, and / or slowing the progression of a condition or its symptoms. A therapeutically effective amount can vary depending on biological factors. The achievement of a therapeutic result can be measured by a physician or other qualified medical practitioner using objective evaluations known in the art, or by subjective evaluations by an individual patient.

[0103] 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, cows, dogs, cats, rabbits, rats, mice, and aquatic mammals.

[0104] The term "chiral" refers to a molecule having the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that can be superimposed on its mirror image partner.

[0105] The term "stereoisomer" refers to compounds having the same chemical constitution but differing in the arrangement of atoms or groups in space.

[0106] "Diastereomers" refer to stereoisomers having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have various physical properties such as melting point, boiling point, spectral properties, and reactivity. A mixture of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis and chromatography.

[0107] "Enantiomers" refers to two stereoisomers of a compound that are mirror images that cannot be superimposed on each other.

[0108] The stereochemical definitions and conventions used herein generally follow S. P. 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 present invention may contain asymmetric or chiral centers and thus exist in various stereoisomers. All stereoisomers of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., have the ability to rotate the plane of plane-polarized light. In the description of optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to designate the sign of rotation of the plane of plane-polarized light by the compound, and (-) or l means that the compound is levorotatory. A compound with the prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer can also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and they can occur when there is no stereoselection or stereospecificity during a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that are not optically active.

[0109] The terms "tautomer" or "tautomeric form" refer to structural isomers of various energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversion via the movement of a proton, such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversion by rearrangement of some of the bonding electrons.

[0110] "Solid oral dosage form" refers to a formulation that is ready for administration to a subject via the oral route. Exemplary oral dosage forms include, but are not limited to, tablets, mini-tablets, capsules, caplets, powders, pellets, beads, granules, and pelletized tablets containing polymer-coated pellets. The dosage form may be a "unit dosage form" intended to deliver one therapeutic dose per administration.

[0111] The term "excipient" refers to a substance that is formulated with the active pharmaceutical ingredient (API) of a therapeutic agent for the purpose of long-term stabilization, bulking up of a solid formulation containing a small amount of a potent active ingredient, or imparting a therapeutic enhancement to the active ingredient in the final dosage form, for example to promote drug absorption, reduce viscosity, or enhance solubility. Excipients can also be useful in the manufacturing process to aid in the handling of the corresponding active substance, for example by promoting powder flowability or non-stick properties, in addition to helping with in vitro stability such as preventing degradation 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 formulations, excipients can be very important determinants of the performance of the dosage form, having an effect on pharmacodynamics and pharmacokinetics. Types of excipients for oral dosage formulations include antiadherents, binders, coatings, colorants, disintegrants, flavoring agents, glidants, lubricants, preservatives, adsorbents, sweeteners, and vehicles.

[0112] The term "pellet" encompasses particles of any shape, including beads, granules, irregularly shaped particles, and / or spherical particles. The granules may be of any suitable size, for example, from about 0.1 mm to about 1.0 mm. In one embodiment, the pellet size is from about 100 μM (microns) to about 1200 μM (microns), from about 100 μM to about 1100 μM, from about 150 μM to about 600 μM, or from about 100 μM to about 400 μM, as measured by methods well known in the art.

[0113] "Spheronization" is a rapid and flexible process of creating small spheres from a pharmaceutical product, and typically involves wetting a dry mixture comprising an API, filler, spheronization agent, binder, superdisintegrant, or other excipients, such as a granulating fluid (e.g., water optionally mixed with alcohol), granulating the wet mixture, extruding the resulting granulated mass, spheronizing the extrudate to provide beads, and drying the beads. Due to the flow characteristics of the small spheres, they are suitable for transportation and movement. The small spheres provide the smallest surface area: volume ratio, and thus the pharmaceutical compound can be coated with a minimal amount of coating material.

[0114] The term "modified release" means a dosage form in which drug release is different from immediate release, i.e., more than about 60% of the drug is released in vivo within 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, modified release, sustained release, delayed release, and pulsed release.

[0115] The "release regulator" is a composition containing a polymer material that may be a mixture of various polymer backbones, chain lengths, and branching, having the property of regulating the release rate of the drug in the formulation. The release regulator changes the release rate of the drug from the dosage form, and thus the release rate of the dosage form including the release regulator is different from the release rate of the same dosage form under the same conditions without the release regulator. Examples of release regulators include MCC (microcrystalline cellulose), HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), PEG (polyethylene glycol glyceride), PVA (polyvinyl alcohol), PVP (polyvinyl pyrrolidone), Carbopol, (a) CAP (cellulose acetate phthalate), such as AQUACOAT (registered trademark); CMC-Na (sodium carboxymethyl cellulose), such as WALOCEL (registered trademark); HPMCAS (hydroxypropyl methylcellulose acetate succinate), such as AQOAT (registered trademark); HPMCP (hydroxypropyl methylcellulose phthalate), such as HP50 / HP55; poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), such as EUDRAGIT (registered trademark) FS30D; poly(methacrylic acid-co-ethyl acrylate), such as EUDRAGIT (registered trademark) L30D-55 / L100-55, or KOLLICOAT (registered trademark) MAE30DP / 100P, or Eastacryl 30D; poly(methacrylic acid-co-methyl methacrylate), such as EUDRAGIT (registered trademark) L12,5 / EUDRAGIT (registered trademark) L100, or EUDRAGIT (registered trademark) S12,5 / EUDRAGIT (registered trademark) S100, etc., polymers for enteric coating, (b) polymers for time-controlled release, such as CA (cellulose acetate), such as Eastman CA and Eastman CAB; (cellulose acetate butyrate), such as Eastman CAB; EC (ethyl cellulose) ETHOCEL (trademark), or AQUACOAT (registered trademark) ECD, or SURELEASE (registered trademark) (ready-to-use), or Glyceride GATTECOAT (trademark);Poly(ethyl acrylate-co-methyl methacrylate), such as EUDRAGIT® NE30D, or EUDRAGIT® NM30D; poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), such as EUDRAGIT® RL30D, EUDRAGIT® RL100 / RLPO, EUDRAGIT® RS30D, or EUDRAGIT® RS100 / RS; PVAc (polyvinyl acetate), such as KOLLICOAT® SR30D; HPMC / CMC, such as WALOCEL® HM-PPA, and the like.

[0116] Compounds and pharmaceutical compositions of formula I This disclosure relates to the structure [Chemical formula] having the name 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile (International Publication No. WO 2012 / 062783, U.S. Patent No. 8,815,882, and U.S. Patent Application Publication No. 2012 / 0157427, each incorporated by reference), polymorphs and amorphous forms of the compound of formula I (CAS Registry Number 1374828-69-9). As used herein, the compound of formula I includes its tautomers or pharmaceutically acceptable salts. The compound of formula I is the API (active pharmaceutical ingredient) in the formulations described herein for use in the treatment of Parkinson's disease and parkinsonism.

[0117] Pharmacokinetics The components and composition of the dosage form can have a significant effect on the dissolution rate and blood concentration.

[0118] Figure 1 shows the ideal blood concentration of the compound of formula I after dosing with an immediate release (IR) formulation of the minimum effective dose, a modified release (MR) formulation, and a reduced dose MR formulation.

[0119] Figure 2 shows the cerebrospinal fluid (CSF): plasma concentration ratio of the compound of formula I in healthy (non-PD) young and healthy elderly patients on the 10th day of various twice-daily (BID) dosing regimens of an immediate-release capsule formulation of the compound of formula I. The mean CSF: unbound plasma ratio was approximately 1.0. The data shown were obtained from multiple dose cohorts of 25 mg, 80 mg, and 100 mg BID.

[0120] The compound of formula I was administered to healthy young human subjects as an API formulation in capsules at doses of 25 mg, 40 mg, 80 mg and 100 mg BID, and to healthy elderly subjects at 80 mg BID. The concentration of the compound of formula I was determined at day 1 and day 10, and at trough on selected days during the 10-day administration. Pharmacokinetic analysis of the plasma concentrations obtained after dosing on day 10 showed a terminal-phase half-life in plasma of 14 - 26 hours. A plateau of trough (minimum) concentrations demonstrated that steady state had been achieved by day 10. Plasma C max and AUC increased in a dose-proportional manner over the dose range of 25 - 100 mg BID. This terminal-phase half-life, as well as the plasma concentration and pS935 inhibition at trough (minimum), is consistent with twice-daily dosing as an effective regimen.

[0121] For the API in capsule formulations given at doses of 25 mg, 40 mg, 80 mg and 100 mg BID, the C max / C min (C max / C trough ) ratio was 2.6 - 12 (mean 5.3). Due to the parallel (non-cross-over) nature of the study design, within-subject variability of that ratio was seen. It was generally well tolerated, although at higher doses, mild changes in pulse rate and blood pressure were observed. Physiologically based PK modeling was used to determine C max / C minThe ratios were predicted. For MUPS formulations containing 3%, 5% and 8% polymer KOLLICOAT® (registered trademark), the C max / C min ratios were in the range of 1.5 - 2.6.

[0122] Solid oral dosage forms Surprisingly, the present invention provides new controlled release formulations of the compounds of formula I that achieve a desirable controlled release profile, and new methods for preparing them.

[0123] Solid oral dosage forms of the compounds of formula I include delivery systems that are broadly classified into single unit dosage forms (capsules or tablets) and multiple unit dosage forms or pelletized dosage forms (one or more pellets in capsules or tablets). Pellets provide certain therapeutic advantages as they spread uniformly in the gastrointestinal tract. Pellets can also be gradually discharged from the stomach, resulting in less intra - and inter - individual variability, and thus better predictability of the administered dose. The use of pellets can avoid the high local drug concentration and risk of toxicity associated with the ingestion of locally restricted tablets. The early drug release from enteric - coated tablets in the stomach, which may potentially cause drug degradation or gastric mucosal irritation, can also be reduced using coated pellets due to their rapid transit time. The better distribution of pellets in the gastrointestinal tract can also improve the bioavailability of the drugs contained in the pellets, potentially resulting in a reduction in drug dosage and adverse effects (Kushare, S et al (2011) Asian J Pharm, 5:203 - 8).

[0124] Immediate release (IR) dosage forms are formulated to achieve rapid or uncontrolled release of the drug into the patient's blood after administration.

[0125] Modified release (MR) achieves drug release that is slower than that of conventional immediate release dosage forms. The advantages of modified release dosage forms include reduced dosing frequency, better patient acceptability and compliance, reduced gastrointestinal (GI) side effects, decreased variability of plasma drug levels (as measured by the C max / C min ratio), improved efficacy / safety parameters, and a well-characterized and reproducible dosage form. With an optimized modified release profile, the patient can be placed in the therapeutic window, above the minimum effective concentration but below the maximum tolerated dose, for a longer period after administration. Modified release (MR) formulations can achieve a delay in drug release into the patient's blood after administration in order to maintain a constant concentration of the drug in the blood.

[0126] Multiple unit pellet systems (MUPS) are multiphasic or programmed-release dosage forms used as an alternative to traditional tablets or capsules. Multiple unit pellet system (MUPS) tablets or capsules are a type of multiparticulate system that has become an important and successful dosage form for immediate or controlled-release oral drug administration. These multiple units are composed of tablets or capsules containing uncoated or coated pellets that enable controlled drug release. Advantages of these systems include reduced gastric mucosal irritation due to drug degradation in the simple units and improved dose titration compared to simple tablets or capsules. The systems also offer the possibility of administering incompatible drugs via multiparticulate systems. The pellets in MUPS tablets or capsules may be uncoated or coated. The drug may be contained 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), polyol, carnauba wax, or silicon dioxide. Furthermore, the pellets can have one or more layers that can contain excipients suitable for controlled release, such as polymers for enteric coating or polymers for controlled release. Uncoated pellets are made from suitable pharmaceutical excipients, such as lactose and microcrystalline cellulose (MCC), among others. The pellets can be filled into capsules or compressed into tablets for oral administration.

[0127] The coated pellets are produced using a polymer and amount suitable for forming a coating film. The strength, ductility, and thickness properties of the polymer affect the pellet's ability to break and deform when compressed. Furthermore, the stability of the coating film on the pellets varies depending on the compression force applied.

[0128] The polymers used to create the coating film of the pellets include cellulose-based and acrylic polymers. The advantages of acrylic polymers are flexibility and the characteristic that enables the tableting process without breaking the coating film of the pellets. By combining the two polymers, it is possible to improve the flexibility of the coating film, which is desirable for the refinement of the coated pellets, and the addition of a specific proportion of plasticizer.

[0129] The pellet core can affect the drug release from the MUPS. The pellet porosity of both uncoated and coated pellets affects the modified drug release profile.

[0130] The excipients and binder solutions used to produce the pellet core may affect the deformation and viscoelastic properties of the pellets during compression and thus may cause changes in the drug release profile. The use of other components such as carrageenan polysaccharides in the production / manufacture of the pellets allows the pellets to disintegrate rapidly and thus release the drug rapidly (Kranz H. et al.: Eur. J. Pharm. Biopharm. 73: 302-309 (2009), Ghanam D. and Kleinebudde. P.: Int. J. Pharm. 409: 9-18 (2011).

[0131] The manufacturing process of the coated pellets can be divided into two steps: the manufacturing of the pellets and the manufacturing of the pellet-containing tablets. First, the drug pellet manufacturing process begins by blending pellet components, such as drugs, cushioning excipients widely used in this type of formulation, like microcrystalline cellulose, glyceryl monostearate (GMS), and lactose monohydrate (LM). A binder solution, such as water or glycerol, can be used for wet mixing. The resulting mass proceeds to an extrusion-spheronization process, and the drying of the pellets formed in recent years can be carried out in a fluidized bed dryer. The next step, the coating of the pellets, forms a coating film to obtain the desired drug release (Bashaiwoldu A.B et al.: Advan. Powder Technol. (2011) 22:340-353).

[0132] The tableting process can be carried out by a rotary tablet press using controlled parameters, such as the main compression force and speed. Pellets and cushioning excipients can be added to optimize certain properties, including the ability to withstand high compression forces, for tableting.

[0133] Next, the pellet-containing tablets with specific characteristics of shape, weight, thickness, and hardness proceed to the tablet film coating process. Tablet film coating is applied to improve the stability and appearance of the pharmaceutical composition.

[0134] Film coating is frequently applied in the pharmaceutical drug delivery of solid oral dosage forms. The motivations for coating the dosage form vary from cosmetic considerations (color, gloss) to improving stability (protection from light, barrier against moisture and gases) and facilitating the swallowing of tablets. Furthermore, functional coatings can be used to regulate the drug release behavior from the dosage form. Depending on the polymer used, it is possible to delay drug release (such as in enteric coatings) or use coatings to sustain the release of the drug from the dosage form over a long period of time.

[0135] Film coating is a thin polymer-based coating applied to solid dosage forms, such as tablets. The thickness of such coatings usually ranges between 20 and 100 μm. By using non-destructive analytical methods, it is possible to track the effect of dynamic hardening on the tablet coating structure.

[0136] Multiple unit pellet systems (MUPS) are designed to obtain a controlled drug release profile. This controlled release can be considered as either delayed release or modified release. Delayed release can be achieved, for example, by enteric-coated pellets. Enteric coatings enable the protection of active pharmaceutical ingredients that are unstable in the gastric medium or can cause gastric irritation by the enteric coating. Copolymer of methacrylic acid, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate are enteric coating polymers frequently used for this function.

[0137] MUPS tablets containing modified-release pellets can achieve sustained action, prolong pharmacological effects, increase dosage intervals, and reduce side effects. Pellets coated with various polymers and various film thicknesses allow for adjustment of the release rate from the pellets. The polymers used may be, inter alia, cellulose derivatives, such as ethyl cellulose and hydroxypropylmethylcellulose (HPMC). Uncoated pellets can be used as matrix polymer systems for the modified release of drugs. Among this group, hydrophilic matrix systems based on the use of cellulose polymers, carbomers, or xanthan gum, among others, are frequently used.

[0138] FIG. 3 shows a pore-forming modified-release (MR) tablet comprising a core with a coating comprising the compound of Formula I and other excipients KOLLICOAT® IR, povidone K30, and polyvinyl acetate.

[0139] FIG. 4 shows a modified-release matrix tablet in which the compound of formula I and other excipients are formulated into a matrix with polyvinylpyrrolidone and polyvinyl acetate.

[0140] Figure 5 shows a representation of a pellet for a multiple unit pellet system (MUPS) formulation, where the inner core of the pellet is an inert material, such as sugar, microcrystalline cellulose (MCC), or tartaric acid, coated with a seal-coated layer of drug. The outer layer is a polymer coating, such as KOLLICOAT® for modified release or EUDRAGIT® for sustained release.

[0141] excipients Suitable excipients are known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. Excipients can have a variety of multiple effects and useful properties.

[0142] PARTECK (registered trademark) SRP80 (EMD Millipore) is a functional excipient based on polyvinyl alcohol (PVA), a hydrophilic polymer. It forms a swellable and erodible matrix and is used in pharmaceutical oral dosage tablet formulations that exhibit controlled API release. PARTECK (registered trademark) SRP80 contains PVA40 - 88 as a single component, contains no further additives, has a viscosity (mPa) of a 4% aqueous solution at 20°C, and a degree of hydrolysis (saponification) of 88 (mol%). PARTECK (registered trademark) SRP80 is milled polyvinyl alcohol (PVA40 - 88) with a special particle size. CAS registration number 9002 - 89 - 5

[0143] KOLLICOAT (registered trademark) SR30D (BASF) is an aqueous dispersion of polyvinyl acetate stabilized with povidone and SLS (sodium lauryl sulfate). KOLLICOAT (registered trademark) SR30D contains approximately 27% polyvinyl acetate, approximately 2.7% povidone K30, approximately 0.3% sodium lauryl sulfate, and approximately 70% water (CAS registration number 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. The povidone added to the aqueous dispersion is highly soluble and dissolves when the tablet is brought into contact with the dissolution medium, acting as a pore - forming agent. The drug dissolves at a controlled rate and diffuses through the pores, leaving an empty polymer shell. Both the viscosity and its concentration of povidone (PVP K30 vs PVP K90) affect drug release. As the viscosity and concentration of PVP increase, drug release increases.

[0144] Povidone (polyvinylpyrrolidone, PVP) is a synthetic polymer vehicle used to disperse and suspend drugs. Povidone also acts as a disintegrant and tablet binder. Povidone appears as a white to off - white hygroscopic powder in its pure form and dissolves easily in water.

[0145] Hypromellose, also known as hydroxypropyl methylcellulose and HPMC, is a semisynthetic, inert, viscoelastic, water-soluble polymer used as an excipient and controlled-delivery component in oral pharmaceuticals and found in various commercial products. HPMC is used for its seal-coating effect, for example, to create a smooth surface. In other applications, HPMC can rapidly hydrate to form a gelatinous layer on the outer tablet skin. The rapid formation of the gelatinous layer prevents the interior of the tablet core from wetting and disintegrating. Once the original protective gel layer is formed, it controls further water penetration into the tablet. Once the outer gel layer is fully hydrated and dissolved, it is replaced by a new inner layer that is sufficiently viscous and continuous to delay water influx and control drug diffusion. The rate-controlling polymer for forming the protective gelatinous layer around the matrix requires rapid hydration followed by rapid gelation and polymerization / polymer coalescence. This prevents the tablet from immediately disintegrating, which would result in premature drug release. An optimized amount of polymer content, such as HPMC, in a matrix system forms a uniform barrier to protect the drug from immediate release into the dissolution medium. If the polymer level is too low, a complete gel layer may not be formed. Increasing the polymer level in the formulation reduces the drug release rate. As hydrophilic matrix tablets containing HPMC absorb water and swell, the polymer level in the outermost hydrated layer decreases over time. The outermost layer of the matrix eventually becomes diluted to the point where individual chains detach from the matrix and diffuse into the bulk solution. The polymer chains disintegrate and detach from the matrix when the surface concentration exceeds the critical polymer concentration for macromolecular disentanglement or surface erosion. The polymer concentration at the matrix surface can be defined as the polymer disentanglement concentration.

[0146] METHOCEL® (The Dow Chemical Co.) is a commercial line of HPMC products designated E, F, K, etc., frequently used for controlled-release drug formulations. Methocel products vary in viscosity at specific concentrations in water. K15M refers to high molecular weight HPMC with approximately 19-24% methoxyl, approximately 7-12% hydroxypropoxyl, and a viscosity of 10,000-18,000 cP (centipoise) (2% in water at 20°C). K100LV refers to low molecular weight HPMC with approximately 19-24% methoxyl, approximately 7-12% hydroxypropoxyl, and a viscosity of 80-120 cP (centipoise) (2% in water at 20°C).

[0147] EUDRAGIT® (Evonik) is a family of polymethacrylate polymers that are proprietary targeted drug-release coatings. EUDRAGIT® polymers can be acidic, neutral, or basic, and therefore either time-controlled or pH-dependent, and thus also either delayed- or sustained-release. These polymers allow drugs to be formulated in enteric, protective, or sustained-release formulations to prevent drug disintegration until they reach an area of the gastrointestinal (GI) tract with the appropriate pH. Once the drug reaches its target area of the GI tract (i.e., duodenum, stomach), it can be released from the polymer matrix and absorbed.

[0148] CARBOPOL® (Lubrizol) is a family of high molecular weight cross-linked polyacrylic acid polymers used as coating agents. Carbopols form hydrogels in water or alkaline solutions due to hydration of the carboxyl groups and can be used as release-modifying agents in tablet or pellet formulations.

[0149] Sodium croscarmellose, or croscarmellose sodium, is an internally cross-linked sodium carboxymethylcellulose for use as a disintegrant in pharmaceutical formulations to provide drug dissolution and disintegration characteristics.

[0150] AQUACOAT ECD (registered trademark) (FMC Biopolymer) is a 30% (w / w) aqueous dispersion of ethylcellulose (EC) polymer. Ethylcellulose is a hydrophobic coating material used in various coating applications to achieve sustained release, taste masking, and moisture barrier / sealant. AQUACOAT (registered trademark) ECD is a 30% by weight aqueous dispersion of ethylcellulose polymer.

[0151] Buffers, such as polyethylene glycol, can be used to prevent deformation of the pellets during compression.

[0152] Non-functional "coating agents", such as OPADRY (registered trademark), provide cosmetic effects, such as color, without regulating the release rate of the drug in the formulation.

[0153] Modified release formulations The compounds of formula I are formulated according to the procedure of Example 2 in accordance with standard pharmaceutical practice for use in the therapeutic treatment (including prophylactic treatment) of mammals, including humans. The present disclosure provides various formulations comprising a compound of formula I together with one or more pharmaceutically acceptable excipients. Modified release drug formulations release the active ingredient over several hours to maintain a constant concentration of the drug in the blood.

[0154] The formulations can be prepared using conventional dissolution, blending, and mixing procedures. The compounds of the present disclosure are typically formulated into pharmaceutical dosage forms to provide an easily controllable drug dosage and to enable patient compliance with the prescribed regimen.

[0155] Pharmaceutical compositions (or formulations) for application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container into which the pharmaceutical formulation is placed 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 tamper-evident constructions to prevent indiscreet access to the package contents. Additionally, the container has a label placed thereon that describes the contents of the container. The label may also include appropriate warnings.

[0156] Pharmacokinetics of MR formulations in monkeys and minipigs Figure 15 shows the dose-normalized mean concentration-time profiles of formulations 1-5 in minipigs. The modified-release (MR) formulations exhibited lower dose-normalized C max and generally exhibits slower absorption than the compound of Formula I in capsule (API) or IR tablet. Samples: API in gelatin 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).

[0157] FIG. 16 shows a summary of dose-normalized data for Formulations 1-5 shown in FIG. 15 in minipigs.

[0158] Figure 17A shows the mean oral concentration-time plots of Formulations 1-5 in minipigs. Uncoated drug pellets (IR) in capsules, as well as KOLLICOAT® 5% and 8% formulations, were evaluated using a crossover design in fasted Göttingen minipigs (N = 3). KOLLICOAT® pellets showed a slower absorption rate. The enteric-coated pellets achieved exposure similar to the IR pellets. 1. IR pellets in capsules, 2. KOLLICOAT® 8% pellets in capsules, 3. IV (0.5 mg / kg), 4. enteric-coated pellets in capsules, and 5. KOLLICOAT® 5% pellets in capsules. The KOLLICOAT® 5% and 8% formulations at 1 mg / kg showed slower absorption of the compound of formula I. T max The median was 2.0 hours, 2.5 hours, and 4.0 hours for the uncoated pellets, as well as the KOLLICOAT® 5% and 8% formulations, respectively, while the corresponding C max values were 0.197 μM, 0.0940 μM, and 0.0469 μM, respectively.

[0159] Figure 17B shows the mean concentration-time plot of the compound of formula I in minipigs (N = 3) after single oral administration of the compound of formula I as an immediate-release and MUPS formulation (1 mg / kg). In contrast to the case of monkeys, the bioavailability of the KOLLICOAT® formulations was similar to or lower than that of the uncoated pellet formulation, and the relative bioavailabilities of the KOLLICOAT® 5% and 8% formulations were 86% and 73%, respectively. Overall, the MUPS formulation showed a slower absorption rate and lower C max was shown.

[0160] Figure 18 shows the PK of minipigs with a 1 mg / kg modified-release formulation. The KOLLICOAT® pellets had a slower absorption rate and reduced C maxis shown. The bioavailability of KOLLICOAT® 8% compared to IR was 73%. The bioavailability of KOLLICOAT® 5% compared to IR was 86%. The enteric-coated pellets achieved a C max and AUC similar to the IR pellets.

[0161] Figure 19 shows the PK of cynomolgus monkeys for a 2 mg / kg modified release (MR) formulation. The KOLLICOAT® pellet formulation showed a slower absorption rate. The bioavailability was decreased compared to the immediate release capsule formulation. The degree of decrease was determined depending on the % of pellet coating, and the higher the coating rate, the lower the F. The enteric-coated pellet formulation did not provide an improvement compared to the immediate release formulation (IR).

[0162] Figure 20A shows the PK study for the formulations in cynomolgus monkeys (weighing approximately 5 kg). 1. IR pellets in capsules, 2. KOLLICOAT® 8% pellets in capsules, 3. API (compound of formula I) in capsules, 4. enteric-coated pellets in capsules, 5. KOLLICOAT® 5% pellets in capsules, 6. KOLLICOAT® 3% pellets in capsules. The MUPS formulation contained the compound of formula I formulated as drug-layered pellets coated with various levels (3% w / w, 5% w / w and 8% w / w) of KOLLICOAT® SR30D polymer designed to provide different drug release rates. The in vitro dissolution results were supported by further characterization by in vivo PK studies. The MUPS formulation was evaluated in cynomolgus monkeys using a crossover design with a washout period of at least 1 week. The non-coated pellets (IR) and API in the capsule formulation served as comparators with immediate release rates. Single doses (2 mg / kg of the compound of formula I) of each formulation were administered to fasted animals (n = 4), and timed blood samples were obtained over 24 hours after dosing.

[0163] After oral administration to fasting monkeys, the uncoated pellets and API in the capsule formulation achieved similar T max , C max and AUC 0-inf . Formulations containing KOLLICOAT® SR30D coated pellets showed slower absorption of the compound of formula I compared to two immediate release formulations, as indicated by a longer T max and a decreased C max . Figure 20B shows the mean concentration-time plot of the compound of formula I in monkeys (N = 4) after single oral administration of the compound of formula I (2 mg / kg) as an immediate release and MUPS formulation. The median T max for the API in the capsule formulation was 1.25 hours compared to 2.0 hours, 1.75 hours and 7.5 hours for the KOLLICOAT® 3%, 5% and 8% formulations respectively, while the corresponding mean C max values were 1.14 μM, 0.585 μM, 0.190 μM and 0.0660 μM respectively. The relative bioavailability based on the AUC ratio of the KOLLICOAT® 3%, 5% and 8% formulations compared to the API in the capsule was 84%, 40% and 20% respectively, indicating that C max was lower for the two formulations with higher polymer content due to a combination of a slower absorption rate and a reduced extent of absorption.

[0164] Figure 21 shows a modified release (MR) pellet formulation in a capsule having EUDRAGIT® L30D55 and CARBOPOL® applied at the coating stage.

[0165] Figure 22 shows a modified release (MR) pellet formulation in a capsule having AQUACOAT® and CARBOPOL® applied at the coating stage.

[0166] Figure 23 shows a modified release (MR) pellet formulation in capsules having KOLLICOAT® and CARBOPOL® applied at the coating stage.

[0167] Figure 24 shows the composition of MR tablets of formula I at 40 mg, 80 mg, 100 mg, 106.68 mg and 160 mg.

[0168] Figure 25 shows the steps of a manufacturing process for preparing tablets of the compound of formula I at 40 mg, 80 mg, 100 mg, 106.68 mg and 160 mg.

[0169] Methods for treating Parkinson's disease and parkinsonism 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 controlled release formulation comprising a therapeutically effective amount of a compound of Formula I and one or more of the excipients described herein. In particular, the present disclosure provides a method for preventing or treating an LRRK2-related disorder in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of Formula I. In some embodiments, the disease or condition mediated at least in part by LRRK2 is a neurodegenerative disease, such as 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 impairment, mild cognitive impairment (including, for example, the transition from mild cognitive impairment to Alzheimer's disease), argyrophilic grain disease, lysosomal disorders (such as Niemann-Pick type C disease, Gaucher's disease), corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms / relapse associated with drug addiction, L-dopa-induced dyskinesia, Huntington's disease (HD), and HIV-associated dementia (HAD). In other embodiments, the disorder is an ischemic disease of an organ, including but not limited to the brain, heart, kidney, and liver. In some embodiments, the disease is Crohn's disease.

Example

[0170] (Example 1 Isolation and Physicochemical Characterization of the Compound of Formula I) The compound of formula I, 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile (CAS Registry Number 1374828-69-9), prepared according to Example 394 of U.S. Pat. No. 8,815,882 and Compound 12 of Estrada, AA et al. (2013) J. Med. Chem. 57:921-936, each of which is specifically incorporated herein by reference, was dissolved in methyl tert-butyl ether (MTBE, 10 volumes, 200 ml) to obtain a brown solution. The solution was filtered through a 3M Zeta Plus activated carbon disk (R55SP, 5 cm diameter) at 3 ml / min. The filter was washed with MTBE (5 volumes, 100 ml). The clear, colorless solution (300 ml) was concentrated to 8 volumes (160 ml) and charged into a 500 ml reactor. n-Heptane (8 volumes, 160 ml) was added at 20°C. Initially, the solution remained clear, but after 2 minutes, it began to crystallize. The temperature was gradually increased (at a rate of 2°C / min). Complete dissolution was achieved only at 69°C. Further heptane (4 volumes, 80 ml) was added at 70°C, and a clear solution was visually observed at 70°C. The temperature was set to 65°C (1.0°C / min). At 65°C, the solution became clear, and seed crystals of the compound of Formula I (200 mg, from the same batch) were added, but they did not dissolve. The temperature was then reduced to 20°C over 8 hours. It was stirred at 20°C overnight. The solid was filtered and washed twice with the mother liquor. It was dried under vacuum at 40° C. for 2 hours to give 15.91 g (79.6% yield) of crystalline compound of Formula I. The mother liquor was evaporated to dryness to give an additional 3.47 g (17.4% recovery).

[0171] The Form C polymorph of the compound of formula I was obtained from block-like single crystals by liquid vapor diffusion at RT in an n-butyl acetate / cyclohexane solvent mixture system (n-butyl acetate was the solvent, while cyclohexane was the antisolvent).

[0172] The Form D polymorph of the compound of formula I was obtained from block-like single crystals by slow evaporation at RT in an acetone / n-heptane (1:10, v / v) solvent mixture system.

[0173] Single crystal structure determinations were performed from colorless, block-like single crystals selected from Form C or Form D single crystals and encased in Paratone-N (an oil-based cryoprotectant). The crystals were mounted on mylar loops in a random orientation and immersed in a nitrogen stream at 150 K. Preliminary examination and data collection were performed using an Agilent SuperNova® (Cu / K α λ = 1.54178 Å) diffractometer and analyzed with the CrysAlisPro® (Agilent, version 1.171.38.41) software package.

[0174] Data collection details for the Form C single crystal are as follows: Cell parameters and orientation matrices for data collection were retrieved and refined by CrysAlisPro® software using set angles of 6568 reflections in the range 4.0790°<θ<70.0660°. Data were collected at 150.2(2) K up to a maximum diffraction angle (θ) of 70.266°. The data set was 99.9% complete with an average I / σ of 19.4 and a D min(Cu) of 0.82 Å.

[0175] Data reduction details for Form C single crystal are as follows: Frames were integrated with CrysAlisPro®, version 1.171.38.41 software. A total of 12836 reflections were collected, of which 6205 were unique. Lorentzian and polarization corrections were applied to the data. Empirical absorption corrections were performed using spherical harmonics implemented in the SCALE3 ABSPACK scaling algorithm. The absorption coefficient μ for this material was 0.964 mm at this wavelength (λ = 1.54178 Å). -1 and the minimum and maximum transmission are 0.80956 and 1.00000. The intensities of the equivalent reflections were averaged. The agreement factor for the averaging was 2.08% based on the intensity.

[0176] The structure of Form C was elucidated to be in the space group C2 / c by using the direct method with the ShelXS (trademark) structure solution program (Sheldrick, G.M. (2008). Acta Cryst. A64:112-122) and refined using the full-matrix least-squares method for F contained in OLEX2 with the ShelXS (trademark), Version 2014 / 7 refinement package 2 (Dolomanov, O.V., et al, (2009) J. Appl. Cryst. 42:339-341). All non-hydrogen atoms were refined anisotropically. The positions of the hydrogen atoms present on carbon atoms were geometrically calculated and refined using the riding model, while the hydrogen atoms present on nitrogen atoms were freely refined according to the Fourier map

[0177] Details of the data collection for the Form D single crystal are as follows. The cell parameters and orientation matrix for data collection were read out and refined by CrysAlisPro (registered trademark) software using the setting angles of 30349 reflections in the range of 4.0180° < θ < 70.5190°. The data were collected at 150 K up to a maximum diffraction angle (θ) of 70.562°. The data set was 89.9% complete and had an average I / σ of 29.3 and a D min(Cu) of 0.82 Å

[0178] Details of the data reduction for the Form D single crystal are as follows. The frames were integrated with CrysAlisPro (registered trademark), version 1.171.38.41 software. A total of 47670 reflections were collected, of which 11179 were unique. Lorentz and polarization corrections were applied to the data. Empirical absorption correction was performed using spherical harmonic functions implemented in the SCALE3 ABSPACK scaling algorithm. The absorption coefficient μ of this material is 0.980 mm at this wavelength (λ = 1.54178 Å) -1 and the minimum and maximum transmissions are 0.83622 and 1.00000, respectively. The intensities of equivalent reflections were averaged. The agreement factor for averaging was 2.69% based on intensity

[0179] The structure of Form D was elucidated to be in the space group Pca21 using the direct method with the ShelXS structure solution program and refined using the full-matrix least-squares method for F contained in OLEX2 with the ShelXS™, Version 2014 / 7 refinement package. All non-hydrogen atoms were refined anisotropically. The positions of hydrogen atoms were geometrically calculated and refined using a riding model. 2 For the polymorphs of the compound of Formula I, they were elucidated using the ShelXT (Sheldrick, G.M. (2015). Acta Cryst. A71, 3-8) structure solution program (intrinsic phasing method) and refined using the SHELXL-2015 refinement package (Sheldrick, G.M. (2015). Acta Cryst. A71, 3-8) (full-matrix least-squares method for F) contained in OLEX2 (Dolomanov, O. V. et al, "OLEX2: a complete structure solution, refinement and analysis program". J. Appl. Cryst. 2009, 42, 339-341). The calculated XRPD patterns were obtained from Mercury (Macrae, C. F., et al, Appl. Cryst. (2006) 39:453-457), and the crystal structure representations were made by Diamond. Single-crystal X-ray diffraction data were collected at 296 K using a Bruker D8 VENTURE diffractometer (Mo / Kα radiation, λ = 0.71073 Å). Table 2 shows the crystallographic data and structure refinements for Forms C and D.

Table 1

[0180] For the polymorphs of the compound of Formula I, they were elucidated using the ShelXT (Sheldrick, G.M. (2015). Acta Cryst. A71, 3-8) structure solution program (intrinsic phasing method) and refined using the SHELXL-2015 refinement package (Sheldrick, G.M. (2015). Acta Cryst. A71, 3-8) (full-matrix least-squares method for F) contained in OLEX2 (Dolomanov, O. V. et al, "OLEX2: a complete structure solution, refinement and analysis program". J. Appl. Cryst. 2009, 42, 339-341). The calculated XRPD patterns were obtained from Mercury (Macrae, C. F., et al, Appl. Cryst. (2006) 39:453-457), and the crystal structure representations were made by Diamond. Single-crystal X-ray diffraction data were collected at 296 K using a Bruker D8 VENTURE diffractometer (Mo / Kα radiation, λ = 0.71073 Å). Table 2 shows the crystallographic data and structure refinements for Forms C and D. 2 For the polymorphs of the compound of Formula I, they were elucidated using the ShelXT (Sheldrick, G.M. (2015). Acta Cryst. A71, 3-8) structure solution program (intrinsic phasing method) and refined using the SHELXL-2015 refinement package (Sheldrick, G.M. (2015). Acta Cryst. A71, 3-8) (full-matrix least-squares method for F) contained in OLEX2 (Dolomanov, O. V. et al, "OLEX2: a complete structure solution, refinement and analysis program". J. Appl. Cryst. 2009, 42, 339-341). The calculated XRPD patterns were obtained from Mercury (Macrae, C. F., et al, Appl. Cryst. (2006) 39:453-457), and the crystal structure representations were made by Diamond. Single-crystal X-ray diffraction data were collected at 296 K using a Bruker D8 VENTURE diffractometer (Mo / Kα radiation, λ = 0.71073 Å). Table 2 shows the crystallographic data and structure refinements for Forms C and D.

Table 2

[0181] Single 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.

[0182] By SCXRD characterization, it was confirmed that Form C crystallizes in the monoclinic system and the C2 / c space group, with unit cell parameters {a = 13.7032(3) Å, b = 17.5697(4) Å, c = 27.4196(6) Å; α = 90°, β = 91.982(2)°, γ = 90°}. Calculating the cell volume V, it was 6597.6(3) Å 3 The asymmetric unit consists of two molecules, indicating that Form C is an anhydrate. The calculated density of Form C is 1.367 g / cm 3 The unit cell of the single crystal consists of 16 molecules.

[0183] By SCXRD characterization, it was confirmed that Form D crystallizes in the orthorhombic system and the Pca21 space group, 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°}. Calculating the cell volume V, it was 6486.56(8) Å 3 The asymmetric unit consists of four molecules, indicating that Form D is an anhydrate. The calculated density of Form D is 1.390 g / cm 3 The unit cell of the single crystal consists of 16 molecules.

[0184] The Form C polymorph of the compound of Formula I exhibits an X-ray powder diffraction pattern having characteristic peaks represented at approximately 2 theta degrees of 6.4, 15.1, 21.2, 25.7, and 27.8. The X-ray powder diffraction pattern of the Form C polymorph of the compound of Formula I further includes peaks at 16.5 and 22.1 ± 0.05 2 theta degrees.

[0185] Polymorph C of the compound of formula I exhibits an X-ray powder diffraction pattern having characteristic peaks represented at approximately 2 theta degrees of 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.

[0186] Polymorph C of the compound of formula I exhibits an X-ray powder diffraction pattern substantially free of peaks at 13.6 and 14.8 ± 0.05 2 theta degrees.

[0187] Polymorph D of the compound of formula I exhibits an X-ray powder diffraction pattern having characteristic peaks represented at approximately 2 theta degrees of 9.2, 14.0, 14.8, 19.7, and 20.0.

[0188] Polymorph D of the compound of formula I exhibits an X-ray powder diffraction pattern having characteristic peaks represented at approximately 2 theta degrees of 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.

[0189] Polymorph D of the compound of formula I exhibits an X-ray powder diffraction pattern substantially free of a peak at 13.6 ± 0.05 2 theta degrees.

[0190] (Example 2 Formulation Process) Part 1: Manufacture of API Drug IR (Immediate Release) Pellets An initial polymer solution is created by mixing purified water, hypromellose, and polyvinylpyrrolidone. The compound of formula I (API drug substance) is added to the polymer solution and mixed. Next, the mixture is sieved to produce a drug dispersion. Spherical seed cores of microcrystalline cellulose are charged into a fluid bed processor bowl, and the drug dispersion is sprayed onto the microcrystalline cellulose. The resulting particles are size classified according to loss on drying (LOD) and assay process controls to produce API drug core pellets.

[0191] The IR coating solution is prepared by mixing purified water, hypromellose and polyethylene glycol. The API drug core pellets are filled into a fluid bed processor bowl, and the IR coating solution is sprayed onto the pellets until the desired weight gain (1.5 - 3.0%) is achieved. The obtained particles are size classified according to the in - process control of the LOD process to produce API drug IR pellets, which are then packaged and tested.

[0192] Part 2: Manufacture of API drug modified - release pellets (MUPS) The 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. 30% of poly(vinyl acetate) dispersion is added to the dispersion and mixed. The obtained dispersion is filtered to produce an MR coating dispersion. The API drug IR pellets are filled into a fluid bed, and the MR coating dispersion is sprayed onto the pellets until the required weight gain (3 - 60%) is achieved. Next, the coated pellets are cured at a production temperature of about 40 °C to 60 °C for about 30 minutes to about 2 hours. The obtained particles are size classified according to the in - process control of the loss on drying process to produce API drug MR pellets, which are then packaged and tested.

[0193] Part 3: Manufacture of API drug MUPS (multiple - unit pellet system) capsules Following the required amount of API drug IR pellets (if required), the required amount of API drug MR pellets (if required) are individually weighed by hand and placed into each gelatin capsule. The capsules are sealed, visually evaluated, weighed and packaged.

[0194] (Example 3: Formulation of the compound of formula I into a modified - release tablet) Modified - release tablets containing HPMC polymer Four tablet formulations containing HPMC were prepared to control API release, and the tablets contained the components in Table 3 below. The release rate can be adjusted by the addition of HPMC polymer. HPMC K100LV provided a more rapid release than HPMC (Methocel K-15MCR) alone. [Table 3]

[0195] An excess amount of hydrophilic fumed silica Aerosil 200 was weighed and passed through a clean, dry 850 μM sieve, then transferred to a 1 L powder bottle, and the weight was recorded. The bottle was placed in a Turbula mixer at 32 rpm for 1 minute. An excess amount of MCC, API, and mannitol was weighed and passed through a clean, dry 600 μM sieve. The required amount of MCC, API, and mannitol was transferred to a powder bottle, and the weight was recorded. The contents of the powder bottle were mixed manually using a spatula for 30 seconds, and the bottle was placed in a Turbula mixer at 32 rpm for 5 minutes. The contents of the bottle were sieved through a clean, dry 600 μM sieve. An excess amount of HPMC and povidone was weighed and passed through a clean, dry 600 μM sieve. The required amount of HPMC and povidone was transferred to a powder bottle, and the weight was recorded. The contents of the powder bottle were mixed manually using a spatula for 30 seconds, and the bottle was placed in a Turbula mixer at 32 rpm for 5 minutes. Visual inspection of the blend revealed no lumps, so the blend was not sieved. The excess magnesium stearate was then passed through a clean, dry 600 μm sieve. The required amount of sieved magnesium stearate was transferred to the powder bottle and the weight recorded. The bottle was placed in a Turbula mixer at 32 rpm for 3 minutes, and then the blend was ready for tableting. Tableting was achieved on a Natoli tablet press using oval tooling to achieve the appropriate depth of fill for all four formulations.

[0196] The dissolution profiles of the tablets determined using the method of Table 4 are shown in FIGS. 26 and 27.

Table 4

[0197] 3.2. Modified-release tablets containing PARTECK (registered trademark) polymer Two batches (SR PVA matrix tablets, 40 mg and SR PVA matrix tablets, 120 mg) were manufactured for SR PVA matrix tablets according to Table 5.

[0198]

Table 5

[0199] In addition to the API, talc, and Aerosil 200, 50 percent of the fully microcrystalline cellulose PH102 was passed through the same 600 μm sieve and collected in a 1 L bottle. The bottle was placed in a Turbula mixer and mixed at 23 rpm for 5 minutes. In addition to the povidone K30, the remaining 50% of the microcrystalline cellulose PH102 was passed through the same 600 μm sieve and collected in a 1 L bottle. The bottle was placed in a Turbula mixer and mixed at 23 rpm for 5 minutes. An excess amount of magnesium stearate was passed separately through a clean, dry 600 μm sieve. The required amount of magnesium stearate was added to the 1 L bottle. The bottle was placed in a Turbula mixer and mixed at 23 rpm for 5 minutes. The required amount of blend was filled to overflow in the die of a slug tool (22.00 mm circular flat tool) for compressing the slug. The required compression force was applied to achieve the acceptable solid fraction (0.60 - 0.70) using the following equation: weight / ((thickness × 380.13)) / 1.4). The solid fraction was calculated for all slugs. The targeted weight range was 2000 mg ± 5%. The hardness was recorded for the first two slugs, and the entire blend was formed into slugs. The slugs were placed in a mortar and gently triturated to form granules, taking care not to produce fine particles, using a pestle. The triturated slugs were passed through a 1.18 mm sieve, followed by an 850 μM sieve and placed in a receptacle. Material that was too large was returned to the mortar and pestle for further size reduction as needed. This step was performed first with a 1.18 μM sieve, followed by an 850 μM sieve. The fraction retained on the screen was triturated as described above until all granules passed through the 850 μM screen. The milled granules were weighed and collected in amber glass bottles of appropriate size, and the yields were found to be 85.98% for the 40 mg low-dose formulation and 69.07% for the high-dose formulation. PVA (Parteck SRP80), colloidal anhydrous silica 200 (Aerosil), and talc were passed through the same 600 μm sieve and collected in a bottle. The bottle was placed in a Turbula mixer and mixed at 23 rpm for 5 minutes.Approximately 110% of magnesium stearate was passed through a 250 μm sieve, collected, and the weight was recorded. The excess magnesium stearate was separately passed through a clean, dry 600 μm sieve. The required amount of magnesium stearate was added to a 1 L bottle. The bottle was placed in a Turbula mixer and mixed at 23 rpm for 5 minutes. The required amount of tablet blend was filled to overflow the die (15×7 mm oval) of the tableting tool to compress the first tablet. The depth of filling was adjusted to achieve the desired fill weight (400 mg ± 5%). The compression force was adjusted to achieve the desired hardness (12 kP ± 2 kP). The weight and thickness of the tablets were checked and recorded (weight range: 400 mg ± 5%). The hardness of the first two tablets was recorded. The blend was tabletted to obtain approximately 30 tablets, and hardness was collected from an additional two tablets at the end of production. The acceptable tablets were packaged in a 60 mL Duma container.

[0200] The dissolution profiles of the tablets determined according to Table 6 are shown in Figures 28 and 29.

[0201]

Table 6

[0202] (Example 4 Formulation of the Compound of Formula I in a Modified Release Coated MUPS) EUDRAGIT® RS30D and EUDRAGIT® RL30D were used as the controlled release polymers in a 9:1 ratio. The suspension of the drug layer was prepared by first preparing a homogeneous dispersion of API (250 g) and water (2.1 L), and then adding thereto a clear solution of PEG6000 (8.33 g), HPMC E5 (83.33 g) and water (about 1 L). The drug layering of the microcrystalline beads (CP102, 500 g) was achieved after spraying for 10 hours and 30 minutes. The drug layering product was maintained at 42 °C during the seal coating process with HPMC E5. The seal coating solution was prepared by slowly adding HPMC E5 (22.5 g) powder to water (258.8 g) while stirring until the polymer was completely dissolved. The pellets were dried for 10 minutes and then sorted to retain beads between 300 - 425 μM, and 762.3 g of the drug layered product with seal coating was obtained.

[0203] The anti-adhesive agent, talc (35.0 g, 50% based on the dry polymer), and the plasticizer triethyl citrate (TEC) (24.0 g, 50% based on the dry polymer) were added to water (312.7 g) and then homogenized for 10 minutes using a homogenizer. EUDRAGIT® RS30D (210.0 g) and EUDRAGIT® RL30D (23.3 g) were stirred for 10 minutes at a low shear rate. The suspension of the excipients 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 size. The suspension was maintained under mixing at a slow rate throughout the coating process. Using this process, pellets with 5% w / w, 10% w / w, and 15% w / w coatings were prepared. The formulation with 15% w / w coating was administered to minipigs.

[0204] Next, the drug release over time was measured. The formulation of the compound of formula I was dissolved in McIlvaine buffer composed of citric acid and disodium hydrogen phosphate, also known as citric acid-phosphate buffer at pH 3. The comparison of the dissolution rates of API (80 mg), sealed-coated drug-layered pellets, 5% w / w, 10% w / w, and 15% w / w coated pellets is shown in Figure 31.

[0205] (Example 5 Cynomolgus PK Study) Cynomolgus monkeys with surgically implanted CSF collection ports were housed and cared for according to the test facility IACUC guidelines and SOP.

[0206] Whole blood collection and plasma processing (pharmacokinetics): Blood samples were collected from the peripheral vein at the appropriate time points by direct needle puncture (see below). The whole blood was placed on wet ice until processed into plasma according to the test facility SOP. The plasma was stored at -80 °C on dry ice at the end of the study until transported to the analytical laboratory.

[0207] Whole blood collection for pharmacodynamics: Blood samples were collected from the peripheral vein at the appropriate time points by direct needle puncture. 100 μL (microliters) of whole blood was pipetted into a 1.5 mL snap-cap tube, rapidly frozen in liquid nitrogen, and stored at -80 °C on dry ice at the end of the study until transported to the sponsor.

[0208] CSF collection: CSF samples were collected using aseptic technique from an indwelling intrathecal catheter accessed via a subcutaneous port. The port was accessed and approximately 180 μL of fluid was removed from the line prior to CSF collection. The CSF was immediately evaluated for the presence of red blood cells, spun at 2000 g for 10 minutes at room temperature in a microcentrifuge, the supernatant was aliquoted, rapidly frozen in LN2, and stored at -80 °C on dry ice at the end of the study until transported to the sponsor. After CSF collection, the port / catheter was locked with approximately 140 μL of sterile 0.9% sodium chloride solution.

[0209] Pharmacokinetic Study of Compounds in Cynomolgus Monkeys Ported to CSF: Before the first day of dosing, all animals (n = 16) were orally administered a vehicle (0.5 w / v% methylcellulose, 0.1 w / v% Tween® 80 in reverse osmosis water) once a day for 5 days. Starting on the first day of dosing, 10 animals received a formulation of the compound of Formula I at an oral dose once a day for 3 days or 7 days, while the remaining animals continued to be dosed with the vehicle daily for 3 days or 7 days. Food was withheld from the animals overnight before dosing and for at least 1 hour (not exceeding 3 hours) after dosing.

[0210] Three kinds of MUPS capsule formulations were evaluated in cynomolgus monkeys (body weight approximately 5 kg). The MUPS formulations contained the compound of Formula I formulated as drug-layered pellets coated with various levels (3% w / w, 5% w / w, and 8% w / w) of KOLLICOAT® SR30D polymer designed to provide different drug release rates. In vitro dissolution supported further characterization by in vivo PK studies. The MUPS formulations were evaluated in cynomolgus monkeys using a crossover design with a washout period of at least one week. The uncoated pellets and API in the capsule formulations served as comparators with an immediate release rate. A single dose (2 mg / kg of the compound of Formula I) 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 the formulations in cynomolgus monkeys. 1. IR pellets in capsules, 2. KOLLICOAT® 8% pellets in capsules, 3. API as such (compound of Formula I) in capsules, 4. enteric-coated pellets in capsules, 5. KOLLICOAT® 5% pellets in capsules, 6. KOLLICOAT® 3% pellets in capsules.

[0211] After oral administration to fasted monkeys, the uncoated pellets and PIC formulations had similar T max , C max and AUC 0-infwas achieved. Formulations containing KOLLICOAT® SR30D coating pellets showed a slower absorption of the compound of formula I compared to two immediate-release formulations, as indicated by a longer T max and a decreased C max . Figure 20B shows the mean concentration-time plot of the compound of formula I in monkeys (N = 4) after single oral administration of the compound of formula I (2 mg / kg) as an immediate-release and MUPS formulation. The T max median of the API in the capsule formulation was 1.25 hours compared to 2.0 hours, 1.75 hours, and 7.5 hours for the KOLLICOAT® 3%, 5%, and 8% formulations, respectively, while the corresponding mean C max values were 1.14, 0.585, 0.190, and 0.0660 μM, respectively. The relative bioavailability based on the AUC ratio of the KOLLICOAT® 3%, 5%, and 8% formulations compared to the API in the capsule was 84%, 40%, and 20%, respectively, indicating that the lower C max for the two formulations with higher polymer content was due to a combination of a slower absorption rate and a decrease in absorbance.

[0212] (Example 6 Mini-Pig PK Study) Blood sampling from the mini-pig subjects was the same as for the cynomolgus monkey subjects in Example 5.

[0213] Uncoated drug pellets in capsules and KOLLICOAT® 5% and 8% formulations were evaluated using a crossover design in fasted Göttingen minipigs (N=3). Figure 17A shows the mean oral concentration-time plots for Formulations 1-5 in minipigs. KOLLICOAT® pellets show a slower absorption rate. Enteric-coated pellets achieved exposure similar to IR pellets. 1. IR pellets in capsules, 2. KOLLICOAT® 8% pellets in capsules, 3. IV (0.5 mg / kg), 4. Enteric-coated pellets in capsules, and 5. KOLLICOAT® 5% pellets in capsules. The KOLLICOAT® 5% and 8% formulations at 1 mg / kg showed slower absorption of the compound of Formula I. T max The median values were 2.0, 2.5, and 4.0 hours for the uncoated pellets and the KOLLICOAT® 5% and 8% formulations, respectively, while the corresponding C max The values were 0.197 μM, 0.0940 μM, and 0.0469 μM, respectively. Figure 17B shows the mean concentration-time plots of the compound of Formula I in minipigs (N=3) after a single oral dose of the compound of Formula I (1 mg / kg) in immediate-release and MUPS formulations.

[0214] Example 7 MUPS Pellets MUPS pellets containing 80 mg of the compound of Formula I were prepared according to the previous examples. Pellets with KOLLICOAT® SR30D coatings of 5%, 7%, and 9% weight gain compared to uncoated pellets were found to have the dissolution profiles shown in Table 7. The dissolution profile of MUPS pellets not coated with a modified-release polymer is shown in Table 8. The components and drug layering steps of the 5% and 7% KOLLICOAT® SR30D coatings are shown in Tables 9 and 10. [Table 7]

Table 8

Table 9

Table 10

[0215] (Example 8 Modified Release Tablets) Tablets containing 80 mg of the compound of formula 1 (API) were prepared using PVA or HPMC release regulators as shown in Tables 11 and 12. Their dissolution profiles are shown in Table 13. For comparison, the dissolution profile of the API (80 mg of the compound of formula I in a gelatin capsule with no excipients added) in a capsule formulation is shown in Table 14.

Table 11

Table 12

Table 13

Table 14

[0216] (Example 9 Pharmacokinetics (PK) and Bioavailability Study to Investigate Modified Release Formulations in Humans) The in vivo human bioavailability of certain of the modified release (MR) formulations described in the above Examples was evaluated in healthy volunteer bioavailability and pharmacokinetic studies using a crossover design with a washout period of at least one week. Immediate release (IR) formulations of the compounds of Formula I as API formulations in capsules were used as comparators and references. A single 80 mg dose of the compound of Formula I was administered to fasted human subjects as the API in capsules, KOLLICOAT® SR30D 5% pellets in capsules, or KOLLICOAT® SR30D 7% pellets in capsule formulations. Timed blood samples were obtained over 72 hours post-dosing. The above dosing period was repeated as desired to obtain PK and bioavailability data for each of the above formulations. Blood samples were taken from the subjects at regular intervals. PK parameters were measured using standard techniques. Additional measurements regarding safety post-dosing were performed, including safety clinical examinations (hematology, clinical chemistry and urine tests), vital signs, ECG, physical examinations and the evaluation of any adverse events (AEs). The PK properties of the formulations tested are shown in the following table.

Table 15

[0217] The KOLLICOAT® SR30D 5% and 7% pellets of MUPS in capsule formulations showed decreased C max and C max / C 12hr compared to the immediate release formulation and were found to be well tolerated and bioavailable.

[0218] Two tablet formulations were evaluated in healthy human volunteers with a similar study design. HPMC (80 mg) and PVC (80 mg) tablets were studied in a crossover manner using timed blood samples obtained over 72 hours post-dosing. The API (80 mg) in capsule formulations served as the comparator. C maxOral administration of HPMC and PVA tablets that achieved a decrease was found to be well tolerated and bioavailable.

Table 16

[0219] Overall, clinical studies have shown that modified-release capsules and tablets are well tolerated and achieve lower C max and reduced Cmax / C 12hr while maintaining oral bioavailability (relative oral bioavailability greater than 30% compared to the API in capsules). No clinically significant effects on pulse rate or blood pressure were observed. Formulations that reduce C max while maintaining oral bioavailability can allow for a higher level and / or reduced dosing frequency, providing greater durability and safety.

[0220] The foregoing invention has been described in some detail by way of illustration and example for the purpose of clarity of understanding, but the description and examples should not be construed as limiting the scope of the invention. Accordingly, all suitable modifications and equivalents may be considered to be within the scope of the invention as defined by the following claims. The disclosures of all patent documents and scientific literature cited herein are hereby expressly incorporated by reference in their entirety. The present invention provides, for example, the following items. (Item 1) A modified-release formulation comprising a therapeutically effective amount of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and at least one release modifier. (Item 2) The modified-release formulation according to Item 1, comprising 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 modifier. (Item 3) When the release of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is tested at 37 °C in McIlvaine buffer at pH 3 using a USP Type II apparatus at 50 to 75 rpm, it is less than 60% in 2 hours and more than 60% in 8 hours, and the formulation is a tablet, the formulation according to any of the above items. (Item 4) When the release of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is tested at 37 °C in McIlvaine buffer at pH 3 using a USP Type II apparatus at 100 rpm, it is less than 60% in 1 hour, and the formulation is a capsule containing pellets, the formulation according to Item 2. (Item 5) The 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile has a reduced C max compared to an immediate-release formulation after being administered to a subject, the formulation according to any one of the above items. (Item 6) The C max is reduced by at least 20%, the formulation according to Item 5. (Item 7) The controlled-release formulation according to any one of the preceding items, wherein the controlled-release formulation contains 10% to 50% by weight of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile. (Item 8) The formulation according to any one of the preceding items, wherein the 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is crystalline. (Item 9) The method according to Item 8, wherein the crystalline 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is milled or micronized. (Item 10) [[ID= ​ ​ ​ The release regulator is any one of the following: Aquacoat (registered trademark), Walocel (registered trademark), HP50 / HP55, Aqoat (registered trademark), EUDRAGIT (registered trademark) FS30D, EUDRAGIT (registered trademark) L30D-55 / L100-55, EUDRAGIT (registered trademark) L12,5 / EUDRAGIT (registered trademark) L100, EUDRAGIT (registered trademark) S12,5 / EUDRAGIT (registered trademark) S100, Carbopol (registered trademark) polymer, Eastman CA, Eastman CAB, Eastman CAB, Ethocel (trademark), Aquacoat (registered trademark) ECD, or Surelease (registered trademark), or Glyceride GatteCoat (trademark), EUDRAGIT (registered trademark) NE30D, EUDRAGIT (registered trademark) NM30D, EUDRAGIT (registered trademark) RL30D, EUDRAGIT (registered trademark) RL100 / RL PO, EUDRAGIT (registered trademark) RS30D, EUDRAGIT (registered trademark) RS100 / RS, Kollicoat (registered trademark) SR30D, Walocel (registered trademark) HM-PPA, Kollicoat (registered trademark) MAE30DP / 100P, and Eastacryl 30D; the preparation according to any one of the above items. (Item 13) The release regulator is any one of the following: microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrrolidone, KOLLICOAT (registered trademark), CARBOPOL (registered trademark), and AQUACOAT (registered trademark); the preparation according to any one of the above items. (Item 14) One or more excipients selected from the group consisting of microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrrolidone, purified talc, colloidal silicon dioxide, and magnesium stearate, and a coating; the preparation according to any one of the above items. (Item 15) The preparation according to any one of the above items, which is a tablet. (Item 16) The preparation according to item 15, wherein the tablet contains 10 - 500 mg of 2 - methyl - 2 - (3 - methyl - 4 - (4 - (methylamino) - 5 - (trifluoromethyl)pyrimidin - 2 - ylamino) - 1H - pyrazol - 1 - yl)propanenitrile. (Item 17) The preparation according to item 15, wherein the tablet contains 40 - 120 mg of 2 - methyl - 2 - (3 - methyl - 4 - (4 - (methylamino) - 5 - (trifluoromethyl)pyrimidin - 2 - ylamino) - 1H - pyrazol - 1 - yl)propanenitrile. (Item 18) The preparation according to item 15, wherein the tablet contains 30 - 80 mg of 2 - methyl - 2 - (3 - methyl - 4 - (4 - (methylamino) - 5 - (trifluoromethyl)pyrimidin - 2 - ylamino) - 1H - pyrazol - 1 - yl)propanenitrile. (Item 19) The preparation according to item 15, wherein the release - controlling agent is HPMC. (Item 20) The preparation according to item 15, wherein the release - controlling agent is PARTECK (registered trademark) polymer. (Item 21) The preparation according to item 19 or 20, wherein the release - controlling agent constitutes 20 - 30% w / w of the preparation. (Item 22) The preparation according to any one of the above items, which is a capsule containing pellets. (Item 23) The preparation according to item 22, wherein the capsule is a combination of a plurality of units of particles of immediate - release pellets and modified - release pellets contained in the capsule. (Item 24) The preparation according to items 22 - 23, wherein the pellets contain a release - controlling agent selected from KOLLICOAT (registered trademark), CARBOPOL (registered trademark), and AQUACOAT (registered trademark). (Item 25) The preparation according to items 22 - 24, which is a combination of a plurality of units of particles of immediate - release pellets and delayed - release pellets contained in the capsule. (Item 26) The preparation according to items 22 - 25, wherein the modified - release preparation is selected from delayed - release pellet preparations, controlled - release pellet preparations, sustained - release pellet preparations, and pulsed - release pellet preparations. (Item 27) The preparation according to items 22 - 26, which contains a coating agent that is EUDRAGIT (registered trademark). (Item 28) The preparation according to item 27, wherein the coating agent contains 3 wt% - 60 wt% of EUDRAGIT (registered trademark) of the preparation. (Item 29) The preparation according to item 28, wherein the coating agent contains up to 20% w / w of EUDRAGIT (registered trademark) RS30D. (Item 30) The preparation according to item 29, wherein the coating agent contains up to 60% w / w of EUDRAGIT® NM30D. (Item 31) The preparation according to items 22 - 26, comprising a coating agent which is KOLLICOAT® SR30D. (Item 32) The preparation according to item 31, wherein the KOLLICOAT® SR30D brings about a weight increase of about 5%. (Item 33) The preparation according to item 31, wherein the KOLLICOAT® SR30D brings about a weight increase of about 7%. (Item 34) The preparation according to item 31, wherein the KOLLICOAT® SR30D brings about a weight increase of about 8%. (Item 35) The preparation according to item 31, wherein the KOLLICOAT® SR30D brings about a weight increase of 5 - 9%. (Item 36) A method for preparing a modified - release preparation, comprising: (a) Coating an inert core selected from the group consisting of sugar, 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 API core pellets; (b) Coating the API core pellets with a cosmetic non - functional seal coating to form seal - coated pellets; (c) Coating the seal - coated pellets with a release - controlling agent to form the modified - release preparation and including. (Item 37) The method according to item 36, wherein the inert core is selected from sugar, microcrystalline cellulose (MCC), tartaric acid, polyol, carnauba wax, silicon dioxide, and combinations thereof. (Item 38) The method according to item 36, wherein the cosmetic non - functional seal coating is selected from hydroxypropyl methylcellulose (HPMC), and a mixture of hypromellose and ethylcellulose. (Item 39) The method according to item 38, wherein the release - controlling agent is selected from the group consisting of KOLLICOAT®, EUDRAGIT®, hydroxypropyl methylcellulose (HPMC), and a mixture of hypromellose and ethylcellulose. (Item 40) A method for preparing a modified - release preparation, comprising: (a) 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, hydroxypropyl methylcellulose, croscarmellose sodium, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, purified talc, colloidal silicon dioxide, and magnesium stearate are roller-compressed, thereby forming pellets; (b) The pellets are polymer-coated with a dispersion of a coating agent selected from KOLLICOAT®, CARBOPOL®, AQUACOAT®, and OPADRY® White; A method comprising the above steps. (Item 41) The method according to Item 40, further comprising one or more steps selected from extrusion, spheronization, and compression. (Item 42) The method according to Item 40, further comprising the step of filling the coated pellets into soft or hard capsule shells. (Item 43) A method for preparing a modified-release pharmaceutical tablet, comprising: (a) Blending a dry mixture of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, povidone, croscarmellose sodium, silicon dioxide, talc, microcrystalline cellulose, and magnesium stearate; (b) Preparing granules by roller-compressing a dry granule of the dry mixture; (c) Milling the granules; (d) Adding croscarmellose sodium, silicon dioxide, talc, and magnesium stearate to the milled granules to form an extra-granular mixture; (e) Compressing the extra-granular mixture into tablets; (f) Coating the tablets with a coating agent selected from KOLLICOAT®, CARBOPOL®, AQUACOAT®, and EUDRAGIT®; A method comprising the above steps. (Item 44) A method for treating an LRRK2-mediated disease, comprising the step of administering to a subject in need thereof a formulation according to any one of the preceding items. (Item 45) The method according to item 44, wherein one or more of the formulations are administered to the subject once, twice, or three times a day. (Item 46) The method according to item 45, wherein the formulation is administered to the subject twice a day. (Item 47) The method according to item 46, wherein the LRRK2-mediated disease is a neurodegenerative disease. (Item 48) The method according to item 47, wherein the LRRK2-mediated disease is Parkinson's disease.

Claims

**Claim 1** A controlled-release formulation comprising a therapeutically effective amount of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and at least one release modifier, wherein (i) the release modifier is polyvinyl acetate and the release modifier constitutes 3% to 10% by weight of the formulation, (ii) the release modifier is an HPMC or polyvinyl alcohol (PVA) polymer and the release modifier constitutes 20% to 30% by weight of the formulation, or (iii) the release modifier is poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride) and the release modifier constitutes 3% to 20% by weight of the formulation, A controlled-release formulation. **Claim 2** The controlled-release formulation according to claim 1, comprising pellets containing 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and coated with the at least one release modifier. **Claim 3** The formulation according to any one of claims 1 or 2, wherein the controlled-release formulation comprises 10% to 50% by weight of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile. **Claim 4** The formulation according to any one of claims 1 to 3, wherein the 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is crystalline. **Claim 5** The formulation according to claim 4, wherein the crystalline 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is milled or micronized. **Claim 6** The formulation according to any one of claims 1 to 5, which is a tablet. **Claim 7** The tablet according to claim 6, wherein the tablet contains 10 - 500 mg, 40 - 120 mg, or 30 - 80 mg of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile.

8. The formulation according to claim 6, wherein the release control agent is HPMC or a PARTECK (registered trademark) polymer.

9. The formulation according to claim 8, wherein the release control agent constitutes 20 - 30% w / w of the formulation.

10. The formulation according to any one of claims 1 - 9, which is a capsule containing pellets.

11. (i) The capsule is a combination of a plurality of units of particles of immediate release pellets and modified release pellets contained in the capsule, and / or (ii) The modified release formulation is selected from a delayed release pellet formulation, a controlled release pellet formulation, a sustained release pellet formulation, and a pulsed release pellet formulation. The formulation according to claim 10.

12. The formulation according to claim 11, wherein the formulation contains a coating agent, and the coating agent is Kollicoat (registered trademark) SR30D.

13. The formulation according to claim 10, wherein the formulation contains a coating agent, and the coating agent contains 3% - 20% w / w of Eudragit (registered trademark) RS30D.

14. The formulation according to claim 12, wherein the Kollicoat (registered trademark) SR30D results in a weight increase of about 5%, about 7% or about 8% of the pellets.

15. A method for preparing a modified release formulation according to claim 1, comprising: (a) Coating an inert core selected from the group consisting of sugar, polyol, 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 API core pellets. (b) coating the API core pellet with a cosmetic non-functional seal coating to form a seal coating pellet, wherein the cosmetic non-functional seal coating is selected from hydroxypropyl methylcellulose (HPMC), and a mixture of hypromellose and ethylcellulose; (c) coating the seal coating pellet with the release regulator to form the modified release formulation; A method comprising the above steps.

16. The method according to claim 15, wherein the inert core is selected from sugar, microcrystalline cellulose (MCC), tartaric acid, polyols, carnauba wax, silicon dioxide, and combinations thereof.

17. A formulation according to any one of claims 1 to 14 for treating an LRRK2-mediated disease in a subject in need of treatment for an LRRK2-mediated disease, wherein the disease is a neurodegenerative disease.

18. The formulation according to claim 17, wherein one or more of the formulations are administered to the subject once, twice, or three times a day.

19. The formulation according to claim 18, wherein the formulation is administered to the subject twice a day.

20. The formulation according to claim 17, wherein the neurodegenerative disease is Parkinson's disease.

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