Modified release formulation of pyrimidinylamino-pyrazole compound, and methods of treatment

Abstract

To provide 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 with the modified release formulations.SOLUTION: An embodiment of the present disclosure includes 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.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to 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 modified release formulations. [Background technology]

[0003] Parkinsonism is a term that encompasses several conditions, including Parkinson's disease (PD) and other conditions with similar symptoms, collectively known as Parkinsonism, such as slow movement, stiffness, 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, stiffness, and slow movement. The exact cause of Parkinson's disease is unknown, but it is believed that a combination of genetic and environmental factors contribute to the etiology of the disease. Drugs approved to treat 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 These include a receptor agonist (pimavanserin), and a dopamine transporter for imaging (iofulpane I-123). However, these medications provide symptomatic benefit to Parkinson's disease patients and do not reduce disease progression.

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

[0005] LRRK2 kinase inhibitors represent a new class of therapeutic agents with the potential to address the underlying biology of Parkinson's disease, ALS, and other neurodegenerative diseases (Estrada, AA et al (2015) Jour. Med. Chem. 58(17):6733-6746, Estrada, AA et al (2013) Jour. Med. Chem. 57:921-936, Chen, H. et al (2012) Jour. Med. Chem. 55:5536-5545; Estrada, AA et al (2015) Jour. Med. Chem. 58:6733-6746, Chan, BK et al (2013) ACS Med. Chem. Lett. 4:85-90, US Patent (U.S. Pat. Nos. 8354420, 8569281, 8791130, 8796296, 8802674, 8809331, 8815882, 9145402, 9212173, 9212186, 9932325, WO 2011 / 151360, WO 2012 / 062783, WO 2013 / 079493). LRRK2 activity is linked to a central mechanism of Parkinson's disease pathology through its role in lysosomal function. Inhibitors of the LRRK2 kinase, a genetically validated target, can improve lysosomal function in LRRK2-PD and potentially in idiopathic Parkinson's disease. Thus, LRRK2 inhibition may mediate a key disease pathway in Parkinson's disease and prevent or attenuate the accumulation of motor and non-motor impairments that define the progression of Parkinson's disease. There is a need for new therapies aimed at reducing or slowing disease progression and postponing the occurrence of late motor complications for neurodegenerative disorders. Additionally, there is a need for solid oral dosage forms of pharmaceutical compositions that are effective in achieving optimal blood concentrations between the maximum tolerated dose and the minimum effective dose. Optimized solid oral dosage forms modulate the release and pharmacokinetic profile, minimize dosing frequency, and minimize pill burden in patients with limited swallowing ability and other compliance factors. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 8,354,420 [Patent Document 2] U.S. Pat. No. 8,569,281 [Patent Document 3] U.S. Patent No. 8,791,130 Summary of the Invention [Means for solving the problem]

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

[0008] An embodiment of the present disclosure includes 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] An exemplary embodiment of the formulation comprises a pellet 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 pellet contains in its core 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile. In another exemplary embodiment, the pellet contains 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 demonstrates that the release of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is 6% in 2 hours when tested at 37° C. in a pH 3 McIlvaine buffer using a USP Type II apparatus at 50-75 rpm. 0% at 8 hours and greater than 60% at 8 hours, and wherein the formulation is a tablet.

[0011] An exemplary embodiment of the formulation is one in which the release of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is less than 60% at 1 hour and more than 70% at 8 hours when tested at 37° C. in McIlvaine buffer, 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] An exemplary embodiment of the formulation is one in which 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile has a reduced C after administration to a subject (e.g., a human subject) compared to an immediate release formulation. max It is an embodiment having the following.

[0014] An exemplary embodiment of the formulation is max is reduced by at least 20% (e.g., 20-80%, 40-80%, 60-80%, and 65-75%).

[0015] An exemplary embodiment of the formulation is a method for determining the steady-state C max / C min In an embodiment, the ratio ranges from about 1.5 to about 4.5 during the first 12 hours after administration to a subject.

[0016] An exemplary embodiment of the formulation is one in which the modified release formulation comprises 10% to 50% by weight of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile.

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

[0018] An exemplary embodiment of the formulation is one 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 those in which the release modifying agent comprises between 3% and 60% by weight (e.g., between 3% and 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 include those in which the release modifier is selected from the group consisting of MCC (microcrystalline cellulose), HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), PEG (polyethylene glycol glycerides), PVA (polyvinyl alcohol), PVP (polyvinylpyrrolidone), CAP (cellulose acetate phthalate), CMC-Na (sodium carboxymethylcellulose), HPMCAS (hydroxypropyl methylcellulose acetate succinate), HPMCP (hydroxypropyl methylcellulose phthalate), poly(methyl ac In some embodiments, the poly(methacrylic acid-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 include those in which the release modifying agent 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® polymers, 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 those in which the release modifying agent is selected from the group consisting of microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, KOLLICOAT®, CARBOPOL®, and AQUACOAT.

[0023] An exemplary embodiment of the formulation is one in which the release modifying agent 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% on 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% on the pellets. In some embodiments, the mixture provides a coating weight gain of about 6% on the pellets. In some embodiments, the mixture provides a coating weight gain of about 7% on the pellets. In some embodiments, the mixture provides a coating weight gain of about 8% on the pellets. In some embodiments, the mixture provides a coating weight gain of about 9% on 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% on the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 5% on the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 6% on the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 7% on the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 8% on the pellets. In an exemplary embodiment of the formulation, KOLLICOAT® SR30D provides a coating weight gain of about 9% on 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, polyvinylpyrrolidone, purified talc, colloidal silicon dioxide, and magnesium stearate, and a coating.

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

[0028] An exemplary embodiment of the formulation is one in which the tablet contains 10 to 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 one in which the tablet contains 40 to 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 one in which the tablet contains 30 to 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 one in which the release modifying agent is HPMC.

[0032] An exemplary embodiment of the formulation is one in which the release modifying agent is a PARTECK® polymer.

[0033] An exemplary embodiment of the formulation is one in which the release modifying agent comprises 20-30% w / w of the formulation.

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

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

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

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

[0038] Exemplary embodiments of the formulations are those in which the modified release formulation is selected from a delayed release pellet formulation, a controlled release pellet formulation, a sustained release pellet formulation, and a pulsatile release pellet formulation.

[0039] An exemplary embodiment of the formulation is one in which the formulation comprises a coating that is EUDRAGIT®.

[0040] An exemplary embodiment of the formulation is one in which the coating comprises between 3% and 60% EUDRAGIT® by weight of the formulation.

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

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

[0043] An aspect of the present disclosure is a method of preparing a modified 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 pellets with a cosmetic, non-functional seal coating to form seal coated pellets; (c) coating the seal coated pellets with a release modifying agent to form a modified release formulation. The present invention includes a method comprising the steps of:

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

[0045] An exemplary embodiment of the method of preparing a modified release formulation is one 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 modified release formulation is one 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] An aspect of the present disclosure is a method of preparing a modified release formulation, comprising: (a) roller compacting 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, thereby forming pellets; (b) polymer-coating the pellets with a dispersion of a coating agent selected from KOLLICOAT®, CARBOPOL®, AQUACOAT®, and OPADRY® White; The present invention includes a method comprising the steps of:

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

[0049] An exemplary embodiment of the method of preparing the modified release formulation further comprises filling a soft or hard capsule shell with the coated pellets.

[0050] An aspect of the present disclosure is a method of preparing a modified release formulation 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 a dry granulation of the dry mixture as a granule by roller compaction; (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 extragranular mixture into a tablet; (f) coating the tablets with a coating agent selected from KOLLICOAT®, CARBOPOL®, AQUACOAT®, and EUDRAGIT®; The present invention includes a method comprising the steps of:

[0051] Aspects of the present disclosure include methods of treating an LRRK2-mediated disease comprising administering to a subject in need thereof a formulation of the present disclosure.

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

[0053] An exemplary embodiment of the method of treating a LRRK2-mediated disease is one in which the formulation is administered to the subject twice daily.

[0054] An exemplary embodiment of the method of treating a LRRK2-mediated disease is one in which the LRRK2-mediated disease is a neurodegenerative disease.

[0055] An exemplary embodiment of the method of treating a LRRK2-mediated disease is one in which the LRRK2-mediated disease is Parkinson's disease.

[0056] According to an embodiment of the present invention, consistent steady state blood levels of the modified release formulation of the compound of formula I within the therapeutic range of about 0.2 μM to about 1.2 μM are provided over a period of at least 12 hours. The blood concentration can be measured as an average plasma or serum concentration from multiple subjects or studies. The blood concentration can be measured at the time of administration and at various time points to establish a time profile of the subject's blood concentration after administration of the modified release formulation of the compound of formula I.

[0057] The controlled release method of delivery of the present invention can be accomplished by administering multiple single unit dosage forms of equal or varying concentrations of the compound of formula I. Each such unit can be designed to release its contents at various times over a period of at least 12 hours so as to maintain blood levels of the compound of formula I within the therapeutic range previously described.

[0058] A preferred embodiment of the present invention provides that the patient to be treated ingests at a single time point a dosage form containing the compound of formula I capable of maintaining a blood concentration in the patient of about 0.2 μM to about 1.2 μM over a period of at least 12 hours. Such a dosage form can consist of one or more units having the same or different concentrations of the compound of formula I designed to release their contents at different times to maintain the blood concentration level of the compound of formula I within the therapeutic range over the previously described periods of time.

[0059] One embodiment may include one single dosage form that contains multiple units therein and can release their contents at various times (US Pat. No. 5,326,570). Another embodiment of the single dosage form may consist of one unit that can immediately release a concentration of the compound of formula I, and then modulate release the compound of formula I at other times as needed to maintain blood levels within the therapeutic range. In another embodiment, the dosage form may be in multiple separate units that can release the compound of formula I at various times, and said multiple separate units may all be taken at the same time by the patient to be treated. Multiparticulates allow flexible adjustment of the therapeutic dose. Capsules can be filled with various amounts of microparticles or pellets without any further processing or formulation. [Brief description of the drawings]

[0060] [Figure 1] FIG. 1 shows the ideal blood concentrations of the compound of formula I after dosing with the minimum effective dose of an immediate release (IR) formulation, a modified release (MR-I) formulation, and a reduced dose modified release formulation (MR-II).

[0061] [Diagram 2] Figure 2 shows the cerebrospinal fluid (CSF):plasma concentration ratios of the compound of formula I in healthy (non-PD) young and healthy elderly patients on day 10 of various twice-daily (BID) dose regimens of an immediate release capsule formulation of the compound of formula I. The mean CSF:unbound plasma ratio was approximately 1.0. Data shown is from multiple dose cohorts of 25 mg, 80 mg, and 100 mg BID.

[0062] [Diagram 3] FIG. 3 shows a modified release tablet containing a pore former, in which the compound of formula I and other excipients comprise a core with a coating comprising povidone K30 and polyvinyl acetate.

[0063] [Figure 4]FIG. 4 shows a modified release matrix tablet in which the compound of formula I and other excipients are formulated in a matrix with polyvinylpyrrolidone and polyvinyl acetate.

[0064] [Diagram 5] 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 layer of drug to be seal coated. The outer layer is a polymer coating, such as KOLLICOAT® (approximately 5-12% weight gain compared to the mass of the material to be coated) or EUDRAGIT® for modified release.

[0065] [Figure 6] FIG. 6 shows a table of comparative formulations of matrix modified release (MR) 80 mg tablets batch numbers 1-3 using 30% w / w, 40% w / w, and 50% w / w of PARTECK® polymer.

[0066] [Figure 7] Figure 7 shows comparative dissolution data of MR tablets of the compound of formula I of Figure 6. A modified release effect is observed over a 12 hour period for each of batches 1-3. A higher RSD% (relative standard deviation) is observed throughout the release profile of batches 1 and 2, respectively. The release profiles of all three batches are similar regardless of the amount of PARTECK® SRP80 used. Batch No. 3, containing 50% w / w PARTECK® SRP80, shows a lower RSD% compared to batches Nos. 1 and 2, containing 30% and 40% PARTECK® SRP80, respectively.

[0067] [Figure 8] FIG. 8 shows MR matrix tablets with 10% w / w, 15% w / w, and 20% w / w HPMC K-15M (intragranous by direct compression).

[0068] [Figure 9] FIG. 9 shows comparative dissolution data for the MR tablets of FIG.

[0069] [Figure 10] FIG. 10 shows MR matrix tablets with PARTECK® SRP80 (extragranular by direct compression).

[0070] [Figure 11] FIG. 11 shows comparative dissolution data for the MR matrix tablets of FIG.

[0071] [Figure 12] FIG. 12 shows the composition of MR (MUPS) pellets, 80 mg.

[0072] [Figure 13] FIG. 13 shows comparative drug release data for batches with various pore former (povidone) levels.

[0073] [Figure 14] Figure 14 shows comparative dissolution profiles of multiple unit pellet system (MUPS) capsules with various MR pellets and IR+MR pellets in 900 mL (37°C) of McIlvaine buffer at pH 3 at a paddle speed of 50 rpm with sinker. Samples: 12.02% w / w MR pellets, 5.2% w / w MR pellets, 8.2% w / w MR pellets, and 40 mg IR pellets + 40 mg 12.02% w / w MR pellets.

[0074] [Figure 15]Figure 15 shows the dose-normalized mean concentration-time profiles of formulations 1-5 in minipigs. The modified release (MR) formulations show lower dose-normalized Cmax and generally slower absorption than the compound of formula I in capsules (API, active pharmaceutical ingredient) or IR tablets. Samples: API in gelatin capsules (1 mg / kg), (4 mg / kg), PARTECK® 40% MR tablets (80 mg, 4 mg / kg), PARTECK® 30% MR tablets (80 mg, 4 mg / kg), and EUDRAGIT® RS / RL MUPS capsules (1 mg / kg).

[0075] [Figure 16] FIG. 16 shows a summary of dose-normalized data for Formulations 1-5 shown in FIG. 15 in minipigs.

[0076] [Figure 17A] Figure 17A shows the mean oral concentration time plots of pellet formulations 1-5 in minipigs. KOLLICOAT® pellets show a slower absorption rate. The enteric coated pellets achieved similar exposure to the IR pellets. Samples: 1. Uncoated pellets in capsules (immediate release), 2. KOLLICOAT® 8% pellets in capsules, 4. Enteric coated pellets in capsules, and 5. KOLLICOAT® 5% pellets in capsules.

[0077] [Figure 17B] FIG. 17B shows the mean concentration time plots of the compound of Formula I in minipigs (N=3) following a single oral dose of the compound of Formula I (1 mg / kg) as uncoated pellets in a capsule (immediate release) and as a MUPS formulation.

[0078] [Figure 18]Figure 18 shows the PK in minipigs of the 1 mg / kg modified release formulation. KOLLICOAT® pellets show a slower absorption rate and reduced Cmax versus IR pellets. Bioavailability of KOLLICOAT® 8% compared to IR was 73%. Bioavailability of KOLLICOAT® 5% compared to IR was 86%. Enteric coated pellets achieved similar Cmax and AUC (area under the curve) to IR pellets.

[0079] [Figure 19] FIG. 19 shows the PK in cynomolgus monkeys of the 2 mg / kg modified release (MR) formulation.

[0080] [Figure 20A] Figure 20A shows a PK study for the formulations in cynomolgus monkeys. Samples: 1. Uncoated pellets in capsule (immediate release), 2. KOLLICOAT® 8% pellets in capsule, 3. API (compound of formula I) in capsule, 4. Enteric coated pellets in capsule, 5. KOLLICOAT® 5% pellets in capsule, 6. KOLLICOAT® 3% pellets in capsule.

[0081] [Figure 20B] FIG. 20B shows the mean concentration time plots of the compound of formula I in monkeys (N=4) following a single oral administration of the compound of formula I (2 mg / kg) as an uncoated pellet in a capsule and API in a capsule (both immediate release with no polymer coating) and a MUPS formulation.

[0082] [Figure 21] FIG. 21 shows a modified release (MR) pellet formulation in a capsule with EUDRAGIT® L30D55 ​​and CARBOPOL® applied in a coating step.

[0083] [Figure 22] FIG. 22 shows a modified release (MR) pellet formulation in a capsule with AQUACOAT® and CARBOPOL® applied in the coating step.

[0084] [Diagram 23] FIG. 23 shows the modified release (MR) pellet formulation in a capsule with KOLLICOAT® and CARBOPOL® applied in a coating step.

[0085] [Figure 24] FIG. 24 shows the composition of 40 mg, 80 mg, 100 mg, 106.68 mg and 160 mg compound of formula I tablets.

[0086] [Diagram 25] FIG. 25 shows the steps of the manufacturing process for preparing 40 mg, 80 mg, 100 mg, 106.68 mg and 160 mg tablets of the compound of formula I.

[0087] [Figure 26] FIG. 26 shows the average dissolution profiles of four modified release tablets using HMPC polymer formulations, expressed as percent drug release versus time.

[0088] [Figure 27] FIG. 27 shows the average dissolution profiles of four modified release tablets using HMPC polymer formulations, expressed as percent drug release (mg) versus time.

[0089] [Figure 28] FIG. 28 shows the average dissolution profiles of 40 mg low dose (1A) and 120 mg high dose (2A) tablets using the PARTECK® polymer formulation, expressed as percent drug release versus time.

[0090] [Figure 29]FIG. 29 shows the mean dissolution profiles of 40 mg low dose (1A) and 120 mg high dose (2A) tablets using the PARTECK® polymer formulation, expressed as cumulative drug release versus time.

[0091] [Diagram 30] FIG. 30 shows the average dissolution profiles from MR pellets with various polymer coatings expressed as drug release versus time in McIlvaine buffer at pH 3 (900 mL, USP Type II apparatus, 100 rpm, 37° C., with sinker).

[0092] [Diagram 31] FIG. 31 shows the mean dissolution profiles for the EUDRAGIT® coated MUPS of Example 4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0093] definition 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," when used in this specification and claims, are intended to specify the presence of stated features, integers, components, or steps, but do not exclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0095] Defined parameters, e.g., the amount of ingredients in the formulation, water content, C max , t maxThe term "about" or "approximately" referring to, for example, AUC, intrinsic dissolution rate, temperature, and time, indicates the inherent variability in measuring or achieving a parameter. Those skilled in the art having the benefit of this disclosure will understand the variability of a parameter implied by the use of the term "about" or "approximately". The term "about" or "approximately", when used in conjunction with a numerical value, includes a range of + / - (plus or minus) 10% of that numerical value.

[0096] "Polymorphism," as used herein, refers to the occurrence of various crystalline forms of a compound that differ in packing or conformation / configuration but have the same chemical composition. Crystalline forms have molecules in various arrangements and / or conformations within the crystal lattice. Thus, a single compound may give rise to various polymorphs, each form having various distinct physical properties, such as solubility profile, melting point temperature, hygroscopicity, particle shape, morphology, density, flowability, compactibility, and / or X-ray diffraction peaks. The solubility of each polymorph may vary, and therefore identifying the presence of pharmaceutical polymorphs is essential to provide a pharmaceutical product with a predictable solubility profile. It is desirable to characterize and investigate all solid states of a drug, including any polymorphs, and determine the stability, dissolution, and flowability properties of each polymorph. Polymorphs of a compound can be distinguished in the laboratory by X-ray diffraction and other methods, such as infrared or Raman or solid-state NMR spectroscopy. For a general review of polymorphism and pharmaceutical applications of polymorphism, see GM Wall, Pharm Manuf. 3:33 (1986), JK 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 JK Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.

[0097] A "solvate" is a crystal form that contains either stoichiometric or non-stoichiometric amounts 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 with the same solvent content but different lattice packing or conformation.

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

[0099] The phrase "pharmaceutical acceptable salt" as used herein refers to pharmaceutical acceptable organic or inorganic salts of the compounds 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, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Other salts include acid salts such as the aforementioned coformers. Pharmaceutically acceptable salts may involve the inclusion of another molecule such as acetate, succinate or other counter ions. Counter ions may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, pharmaceutically acceptable salts may have more than one charged atom in their structure. When multiple charged atoms are part of the pharmaceutically acceptable salt, it can have multiple counter ions. Thus, pharmaceutically acceptable salts can have one or more charged atoms and / or one or more counter ions.

[0100] The desired pharma- ceutically acceptable salts can be prepared by any suitable method available in the art.For example, treatment of the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, methanesulfonic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl 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 that are generally considered suitable for the formation of pharma- ceutically useful or acceptable salts from basic pharmaceutical compounds are described, for example, in Stahl PH, Wermuth CG, editors. Handbook of Pharmaceutical Salts; Properties, Selection and Use, 2 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) 1 19, P. Gould, International J. of Pharmaceutics (1986) 33 201 217, Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York, Remington's Pharmaceutical Sciences, 18 th ed., (1995) Mack Publishing Co., Easton PA, and The Orange Book (Food & Drug Administration, Washington, DC, on its website). No. 6,393,962, the disclosures of which are incorporated herein by reference.

[0101] The phrase "pharmacologically 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" refers to an amount of drug that is small enough to be non-toxic, but sufficient to achieve therapeutic results, including eliminating, reducing, and / or slowing the progression of a condition or its symptoms.Therapeutically effective amounts may vary depending on biological factors.The achievement of therapeutic results can be measured by a physician or other qualified medical personnel using objective assessments known in the art, or by subjective assessment by individual patients.

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

[0104] The term "chiral" refers to molecules that possess the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0105] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0106] "Diastereomer" refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures, such as electrophoresis and chromatography.

[0107] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0108] The stereochemical definitions and conventions used herein are generally those of SP Parker, Ed., According to 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 therefore exist in various stereoisomeric forms. It is contemplated that all stereoisomers of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, e.g., racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing 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 a compound, with (-) or l meaning that the compound is levorotatory. Compounds with a (+) or d prefix are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific 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, which can occur when there has been 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 is devoid of optical activity.

[0109] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by rearrangement of some of the bonding electrons.

[0110] "Solid oral dosage form" refers to a formulation that is ready to be administered 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 pelleted 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 any substance that is intended to provide long-term stabilization, bulking up, or providing therapeutic enhancement to the active ingredient in the final dosage form of a solid formulation containing a small amount of potent active ingredient. Excipients refer to substances formulated with the active pharmaceutical ingredient (API) of a therapeutic agent that are included to impart strength, for example, to facilitate drug absorption, reduce viscosity, or enhance solubility. Excipients can also be useful in the manufacturing process to aid in handling of the active agent in question, such as by promoting powder flow or non-stick properties, in addition to aiding in in vitro stability, such as preventing denaturation or aggregation over the expected shelf life. The selection of appropriate excipients also depends on the route of administration and dosage form, as well as the active ingredient and other factors. In some formulations, excipients can be a critical determinant 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, flavorings, glidants, lubricants, preservatives, adsorbents, sweeteners, and vehicles.

[0112] The term "pellets" encompasses particles of any shape, including beads, granules, irregularly shaped particles, and / or spherical particles. Granules may be of any suitable size, for example, from about 0.1 mm to about 1.0 mm. In 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 pharmaceutical products into globules, and typically involves wetting a dry mixture with API, fillers, spheronization agents, binders, superdisintegrants, or other excipients, such as a granulation fluid (e.g., water mixed with alcohol, if necessary), granulating the wet mixture, extruding the resulting granulated mass, spheronizing the extrudate to provide beads, and drying the beads. The flow characteristics of the globules make them suitable for transportation and transfer. The globules offer the smallest surface area:volume ratio, and therefore the pharmaceutical compound can be coated with a minimum of coating material.

[0114] The term "modified release" refers to a dosage form in which the drug release is different from immediate release, i.e., releases about 60% or more of the drug 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, slow release, delayed release, and pulsatile release.

[0115] A "release modifier" is a composition comprising a polymeric material, which may be a mixture of various polymer backbones, chain lengths, and branching, that has the property of modulating the release rate of a drug in a formulation. A release modifier alters the release rate of a drug from a dosage form, such that the release rate of a dosage form that includes a release modifier differs from the release rate of an otherwise identical dosage form under the same conditions without the release modifier. Examples of release modifiers include MCC (microcrystalline cellulose), HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), PEG (polyethylene glycol glyceride), PVA (polyvinyl alcohol), PVP (polyvinylpyrrolidone), Carbopol, (a)CAP (cellulose acetate phthalate), e.g., AQUACOAT®; CMC-Na (sodium carboxymethylcellulose), e.g., WALOCEL®; HPMCAS (hydroxypropyl methylcellulose), e.g., ...b)CAP (cellulose acetate phthalate), e.g., AQUACOAT®; CMC-Na (sodium carboxymethylcellulose), e.g., WALOCEL®; poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), such as EUDRAGIT® FS30D; poly(methacrylic acid-co-ethyl acrylate), such as EUDRAGIT® L30D-55 / L100-55, or KOLLICOAT® MAE30DP / 100P, or Eastacryl 30D; polymers for enteric coating, including poly(methacrylic acid-co-methyl methacrylate), such as EUDRAGIT® L12,5 / EUDRAGIT® L100, or EUDRAGIT® S12,5 / EUDRAGIT® S100, (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™, or AQUACOAT® ECD, or SURELEASE® (ready to use), or Glyceride GATTECOAT™;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;

[0116] Compounds of Formula I and Pharmaceutical Compositions The present disclosure relates to a structure [ka] and has the name 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile (WO 2012 / 062783, U.S. Pat. No. 8,815,882, U.S. Pat. Appl. No. 2012 / 0157427, each of which is incorporated by reference), including polymorphs and amorphous forms of the compound of formula I (CAS Registry No. 1374828-69-9). As used herein, the compound of formula I includes its tautomers or pharma- ceutically acceptable salts. The compound of formula I is the API (active pharmaceutical ingredient) in the formulations described herein for use in treating Parkinson's disease and parkinsonism.

[0117] Pharmacokinetics The ingredients and composition of the dosage form can have large effects on dissolution rate and blood levels.

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

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

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

[0121] For API in a capsule formulation given at doses of 25 mg, 40 mg, 80 mg and 100 mg BID, the C of compound of formula I at steady state max / C min (C max / C trough The C ) ratio ranged from 2.6 to 12 (mean 5.3). Due to the parallel (non-crossover) nature of the study design, intrasubject variability in the ratio was observed. It was generally well tolerated, although modest changes in pulse rate and blood pressure were observed at higher doses. Physiologically based PK modeling was used to determine the C ) ratio for MUPS formulations containing various amounts of KOLLICOAT® polymer. max / C minThe predicted C ratios under BID for MUPS formulations containing 3%, 5% and 8% polymer KOLLICOAT® were max / C min The ratios ranged from 1.5 to 2.6.

[0122] Solid Oral Dosage Forms The present invention surprisingly provides new modified release formulations of the discovered compounds of formula I, and new methods for preparing them, which achieve desirable modified release profiles.

[0123] Solid oral dosage forms of the compound of formula I include delivery systems broadly classified as single unit dosage forms (capsules or tablets) and multiple unit dosage forms or pelleted dosage forms (one or more pellets in a capsule or tablet). Pellets impart certain therapeutic advantages since they are uniformly distributed throughout the gastrointestinal tract. Pellets also have less intra- and inter-individual variability since they can be gradually emptied from the stomach, thus providing better predictability of the administered dose. With pellets, the risk of high local drug concentrations and toxicity associated with locally restricted tablet ingestion can be avoided. Premature drug release from enteric coated tablets in the stomach, which can potentially result in drug degradation or gastric mucosal irritation, can also be reduced with coated pellets due to their rapid transit time. Better distribution of pellets in the gastrointestinal tract can also improve the bioavailability of the drug they contain, resulting in reduced drug doses and adverse effects (Kushare, S et al., 2003). al (2011) Asian J Pharm, 5:203-8).

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

[0125] Modified release (MR) achieves a slower release of drug than conventional immediate release dosage forms. Advantages of modified release dosage forms include reduced dosing frequency, better patient tolerance and compliance, fewer gastrointestinal (GI) side effects, and less fluctuation in plasma drug levels (C). max / C min These include improved efficacy / safety parameters (as measured by the β-blocker ratio), as well as a well-characterized, reproducible dosage form. An optimized modified release profile may place patients in a therapeutic window above the minimal effective concentration of the drug but below the maximum tolerated dose for a longer period following administration. Modified release (MR) formulations achieve a constant concentration of To maintain the drug, a delay in the release of the drug into the patient's blood after administration can be achieved.

[0126] A multiple unit pellet system (MUPS) is a multiphasic or programmed release dosage form used as an alternative to conventional 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 drug release for oral administration. These multiple units are composed of tablets or capsules containing uncoated or coated pellets that allow controlled drug release. Advantages of these systems include reduced irritation to the gastric mucosa due to drug degradation of the simple units compared to simple tablets or capsules, and improved dose titration. The system also offers the possibility of administering incompatible drugs with multiparticulate systems. The pellets in MUPS tablets or capsules may be uncoated or coated. The drug may be included in the core or as a layer applied to the inert core of the pellet. The inert core may be a neutral starting pellet composed of sugar, microcrystalline cellulose (MCC), polyol, carnauba wax, or silicon dioxide. In addition, the pellets can have one or more layers that may 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 suitable polymer and amount to form a coating film. The strength, ductility and thickness properties of the polymer affect the pellets' ability to break and deform when compressed. Furthermore, the stability of the pellets' coating film varies depending on the compression force applied.

[0128] The polymers used to create the coating film of pellets include cellulosic and acrylic polymers. The advantage of acrylic polymers is their flexibility and the feature that allows the tableting process without destroying the coating film of pellets. The combination of two polymers can improve the flexibility of the coating film and the addition of a certain percentage of plasticizer, which is desirable for the refinement of coated pellets.

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

[0130] The excipients and binder liquids used to produce the pellet cores can affect the deformation and viscoelastic properties of the pellets during compression, thus causing changes in the drug release profile. The use of other components such as carrageenan polysaccharides in the production / manufacturing of pellets allows the pellets to disintegrate rapidly and therefore 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 coated pellets can be divided into two steps: making pellets and making pellet-containing tablets. First, the drug pellet manufacturing process starts by blending the pellet components, e.g., drug, cushioning excipients such as microcrystalline cellulose, glyceryl monostearate (GMS) and lactose monohydrate (LM), which are widely used in this type of formulation. Binder liquid, e.g. For example, water or glycerol can be used for wet mixing. The resulting mass proceeds to an extrusion-spheronization process and drying of the currently formed pellets can be carried out in a fluidized bed dryer. The next step, coating of the pellets, forms a coating film to obtain the desired drug release (Bashaiwoldu AB et al.: Advan. Powder Technol. (2011) 22:340-353).

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

[0133] The pellet-containing tablet with specific features of shape, weight, thickness, and hardness then proceeds to a tablet film coating process. Tablet film coating is applied to improve the stability and appearance of the pharmaceutical composition.

[0134] Film coatings are frequently applied in pharmaceutical drug delivery of solid oral dosage forms. The motivation for coating a dosage form varies from cosmetic considerations (color, gloss) to improving stability (protection from light, barrier against moisture and gases) and making the tablet easier to swallow. In addition, functional coatings can be used to modulate the drug release behavior from the dosage form. Depending on the polymer used, the use of coatings to delay drug release (such as in enteric coatings) or to sustain the release of the drug from the dosage form over an extended period of time is possible.

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

[0136] Multiple unit pellet systems (MUPS) are designed to obtain a controlled release profile of a drug. This controlled release can be considered as delayed release or modified release. Delayed release can be achieved, for example, by enteric coating pellets. Enteric coating allows active pharmaceutical ingredients that may be unstable in the gastric medium or cause gastric irritation to be protected by the enteric coating. Methacrylic acid copolymers, 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 dosing intervals, and reduce side effects. Pellets coated with different polymers and different film thicknesses allow for the regulation of the release rate from the pellets. The polymers used may be, inter alia, cellulose derivatives, such as ethyl cellulose and hydroxypropyl methylcellulose (HPMC). Non-coated pellets may 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, inter alia, are frequently used.

[0138] FIG. 3 shows a modified release (MR) tablet containing a pore former, in which the compound of Formula I and other excipients comprise a core with a coating comprising 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 in 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, covered with a layer of drug that is seal coated. 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 effective and useful properties.

[0142] PARTECK® SRP80 (EMD Millipore) is a functional excipient based on the hydrophilic polymer polyvinyl alcohol (PVA). It is used in the formulation of pharmaceutical oral dosage tablet forms that form a swellable and erodible matrix and exhibit a controlled API release. PARTECK® SRP80 contains PVA40-88 as a single component, does not contain any further additives, has a viscosity (mPa) of 4% aqueous solution at 20°C, and a degree of hydrolysis (saponification) of 88 (mol%). PARTECK® SRP80 is a milled polyvinyl alcohol (PVA40-88) with a special particle size. CAS registration number 9002-89-5

[0143] KOLLICOAT® SR30D (BASF) is an aqueous dispersion of polyvinyl acetate stabilized with povidone and SLS (sodium lauryl sulfate). KOLLICOAT® SR30D contains about 27% polyvinyl acetate, about 2.7% povidone K30, about 0.3% sodium lauryl sulfate, and about 70% water (CAS Registry Number 9003-20-7). The polyvinyl acetate, povidone (polyvinylpyrrolidone), and sodium lauryl sulfate are present in a ratio of about 90:9:1. The PVA forms an insoluble matrix and reduces drug release. The povidone added to the aqueous dispersion is highly soluble in nature and dissolves when the tablet is brought into contact with the dissolution medium, acting as a pore former. The drug dissolves at a controlled rate and diffuses through the pores, leaving behind an empty polymer shell. Both the viscosity of povidone (PVP K30 vs. PVP K90) and its concentration affect drug release. Increasing the viscosity and concentration of PVP increases drug release.

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

[0145] Hypromellose, also known as hydroxypropyl methylcellulose and HPMC, is a semi-synthetic, 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 uses, 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, a new inner layer replaces it, but the inner layer is sufficiently viscous and continuous to retard water influx and control drug diffusion. The rate-limiting polymer for forming a protective gelatinous layer around the matrix requires rapid hydration followed by rapid gelation and polymer / polymer coalescence. This is because the matrix is ​​too fast to form a gelatinous layer. Prevents immediate tablet disintegration resulting in drug release. Optimized amount of polymer content, e.g. HPMC, in 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 is ​​eventually diluted to a point where individual chains detach from the matrix and diffuse into the bulk solution. The polymer chains are dispersed at the surface concentration due to macromolecular disentanglement or surface disentanglement. Above a critical polymer concentration for face erosion, it disintegrates away from the matrix. 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., that are frequently used for controlled release drug formulations. Methocel products vary by their viscosity at certain concentrations in water. K15M refers to high molecular weight HPMC with about 19-24% methoxyl, about 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 about 19-24% methoxyl, about 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 either delayed or sustained release. These polymers allow drugs to be formulated in enteric, protective or sustained release formulations to prevent the drug from disintegrating until it reaches 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 modifiers in tablet or pellet formulations.

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

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

[0151] A buffering agent, such as polyethylene glycol, may be used to prevent deformation of the pellets during compression.

[0152] Non-functional "coatings," such as OPADRY®, provide a cosmetic effect, such as color, without modulating the release rate of the drug within the formulation.

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

[0154] The formulations can be prepared using conventional dissolving, 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 allow patient compliance with the prescribed regimen.

[0155] The pharmaceutical composition (or formulation) for application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, the 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 FIG. 15 shows the dose-normalized mean concentration-time profiles of formulations 1-5 in minipigs. The modified release (MR) formulations had a 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] FIG. 17A shows the mean oral concentration time plots for formulations 1-5 in minipigs. Uncoated drug pellets in capsules (IR) and KOLLICOAT® 5% and 8% formulations were evaluated using a crossover design in fasted Gottingen minipigs (N=3). KOLLICOAT® pellets show a slower absorption rate. Enteric coated pellets achieved similar exposure 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. 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.

[0159] Figure 17B shows the mean concentration time plots of the compound of formula I in minipigs (N=3) following a single oral dose of the compound of formula I (1 mg / kg) in immediate release and MUPS formulations. In contrast to monkeys, the bioavailability of the KOLLICOAT® formulation was similar to or lower than the uncoated pellet formulation, with relative bioavailability of the KOLLICOAT® 5% and 8% formulations being 86% and 73%, respectively. Overall, the MUPS formulations exhibited a slower absorption rate and lower C than the immediate release formulation. max showed.

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

[0161] Figure 19 shows the PK in cynomolgus monkeys of the 2 mg / kg modified release (MR) formulation. The KOLLICOAT® pellet formulation showed a slower absorption rate. Bioavailability was reduced compared to the immediate release capsule formulation. The degree of reduction was dependent on the pellet coating percentage, with higher coating percentages resulting in lower F. The enteric coated pellet formulation did not provide any improvement compared to the immediate release formulation (IR).

[0162] FIG. 20A shows PK studies for the formulations in cynomolgus monkeys (body weight approximately 5 kg). 1. IR pellets in capsule, 2. KOLLICOAT® 8% pellets in capsule, 3. API (compound of formula I) in capsule, 4. enteric coated pellets in capsule, 5. KOLLICOAT® 5% pellets in capsule, 6. KOLLICOAT® 3% pellets in capsule. 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. The in vitro dissolution results supported further characterization by in vivo PK studies. The MUPS formulations were evaluated in cynomolgus monkeys using a crossover design with a minimum washout period of 1 week. The uncoated pellets (IR) and API in capsule formulations served as comparators with immediate release rates. 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 a 24 hour period following dosing.

[0163] After oral administration to fasted monkeys, the uncoated pellets and API in the capsule formulation had similar T max , C max and AUC 0-inf The formulation containing KOLLICOAT® SR30D coated pellets achieved a longer T max and reduced C max As shown by the slower absorption of the compound of formula I compared to the two immediate release formulations, Figure 20B shows the mean concentration time plots of the compound of formula I in monkeys (N=4) following a single oral dose of the compound of formula I (2 mg / kg) in the immediate release and MUPS formulations. T for the API in the capsule formulation max The median 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 The values ​​were 1.14 μM, 0.585 μM, 0.190 μM, and 0.0660 μM, respectively. The relative bioavailability based on the AUC ratio for the KOLLICOAT® 3%, 5%, and 8% formulations compared to the API in the capsule was 84%, 40%, and 20%, respectively, thereby indicating a lower C for the two formulations with higher polymer content due to a combination of a slower absorption rate and a reduced extent of absorption. max was shown to be lower.

[0164] FIG. 21 shows a modified release (MR) pellet formulation in a capsule with EUDRAGIT® L30D55 ​​and CARBOPOL® applied in a coating step.

[0165] FIG. 22 shows a modified release (MR) pellet formulation in a capsule with AQUACOAT® and CARBOPOL® applied in the coating step.

[0166] FIG. 23 shows the modified release (MR) pellet formulation in a capsule with KOLLICOAT® and CARBOPOL® applied in a coating step.

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

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

[0169] Methods of Treating Parkinson's Disease and Parkinsonism In another aspect, the disclosure relates to a method of treating a disease or condition mediated at least in part by leucine-rich repeat kinase 2 (LRRK2) with a modified release formulation comprising a therapeutically effective amount of a compound of formula I and one or more of the excipients described herein. In particular, the disclosure provides a method for preventing or treating a disorder associated with LRRK2 in a mammal, comprising administering to said 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, e.g., a central nervous system (CNS) disorder, e.g., 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, e.g., transition from mild cognitive impairment to Alzheimer's disease), argyrophilic grain disease, lysosomal disorders (e.g., Niemann-Pick C disease, Gaucher disease), corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal / 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, hi some embodiments, the disease is Crohn's disease. EXAMPLES

[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 give 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 min it started to crystallize. The temperature was gradually increased (at a rate of 2° C. / min). Complete dissolution was achieved only at 69° C. More heptane (4 volumes, 80 ml) was added at 70° C., and a clear solution was observed visually 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, same batch) were added, but they did not dissolve. The temperature was then reduced to 20° C. over 8 hours. It was stirred overnight at 20° C. The solid was filtered and washed twice with 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 at RT by liquid vapor diffusion in 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 a mylar loop 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. Lorentz 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 is 0.964 mm at this wavelength (λ=1.54178 Å). -1 where 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 solved by direct methods using the ShelXS™ structure solution program to be in space group C2 / c (Sheldrick, GM (2008). Acta Cryst. A64:112-122) and was refined using the ShelXS™, Version 2014 / 7 refinement package to find the F structure contained in OLEX2. 2 The full matrix least squares method was used to refine the data (Dolomanov, OV, et al, (2009) J. Appl. Cryst. 42:339-341). All non-hydrogen atoms were refined anisotropically. The positions of hydrogen atoms present on carbon atoms were geometrically calculated and refined using the riding model, whereas the positions of hydrogen atoms present on nitrogen atoms were refined using the riding model. The hydrogen atoms present were freely refined according to the Fourier map.

[0177] Data collection details for the Form D single crystal are as follows: Cell parameters and orientation matrices for data collection were retrieved and refined by CrysAlisPro® software using set angles of 30349 reflections in the range 4.0180°<θ<70.5190°. Data were collected at 150 K up to a maximum diffraction angle (θ) of 70.562°. The data set was 89.9% complete with an average I / σ of 29.3 and a D min(Cu) of 0.82 Å.

[0178] Data reduction details for Form D single crystal are as follows: Frames were integrated with CrysAlisPro®, 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 corrections were performed using spherical harmonics implemented in the SCALE3 ABSPACK scaling algorithm. The absorption coefficient μ for this material is 0.980 mm at this wavelength (λ=1.54178 Å). -1where the minimum and maximum transmission are 0.83622 and 1.00000. The intensities of the equivalent reflections were averaged. The agreement factor for the averaging was 2.69% based on the intensity.

[0179] The structure of form D was solved by direct methods using the ShelXS structure solving program in space group Pca2. 1 It was found that F contained in OLEX2 was a nucleotide sequence of 1,000 bp, and 1,000 bp was a nucleotide sequence of 1,000 bp. 2 The structure was refined using full matrix least squares fitting to . All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using the riding model. [Table 1]

[0180] Polymorphs of the compound of formula I were determined using ShelXT (Sheldrick, GM (2015). Acta Cryst. A71, 3-8) Solved using a structure solving program (eigenphase method) and included in OLEX2 The SHELXL-2015 refinement package (Sheldrick, GM (2015). Acta Cryst. A71, 3-8) (F 2 The full-matrix least-squares method for the 10-kDa structure was used to refine the 10-kDa structure (Dolomanov, OV et al, "OLEX2: a complete structure solution, refinement and analysis program". J. Appl. Cryst. 2009, 42, 339-341). Calculated XRPD patterns were obtained from Mercury (Macrae, CF, et al, Appl. Cryst. (2006) 39:453-457) and crystal structure representations were generated 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 refinement for forms C and D. [Table 2]

[0181] Single crystals of Forms C and D were prepared and analyzed by single crystal X-ray diffraction (SCXRD). The single crystal structures of Forms C and D were successfully determined.

[0182] SCXRD characterization confirmed that Form C crystallized in the monoclinic system and 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°}. The cell volume, V, was calculated to be 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 a single crystal consists of 16 molecules.

[0183] SCXRD characterization revealed that form D is orthorhombic and Pca2 1 It was determined to crystallize in space group 100 with unit cell parameters {a = 17.63410(10) Å, b = 14.03430(10) Å, c = 26.2102(2) Å; α = 90°, β = 90°, γ = 90°}. The cell volume, V, was calculated to be 6486.56(8) Å. 3The asymmetric unit consists of four molecules, indicating that form D is anhydrous. The calculated density of form D is 1.390 g / cm 3 The unit cell of a single crystal consists of 16 molecules.

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

[0185] The Form C polymorph of the compound of formula I exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.4, 8.1, 8.6, 8.8, 9.9, 10.2, 12.9, 13.8, 15.1, 15.4, 16.5, 19.8, 21.2, 22.1, 23.7, 25.7, and 27.8.

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

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

[0188] The Form D polymorph of the compound of formula I exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.0, 8.7, 9.2, 9.8, 10.4, 12.9, 13.4, 14.0, 14.8, 16.4, 18.5, 19.7, 20.0, 20.8, 23.1, 23.3, 23.9, 25.5, and 25.7.

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

[0190] Example 2: Formulation Process Part 1: Manufacturing of API drug IR (immediate release) pellets An initial polymer solution is made by mixing purified water, hypromellose and polyvinylpyrrolidone. A compound of formula I (API drug substance) is added to the polymer solution and mixed. The mixture is then sieved to produce a drug dispersion. Microcrystalline cellulose spherical seed cores are loaded into a fluid bed processor bowl and the drug dispersion is sprayed onto the microcrystalline cellulose. The resulting particles are sized according to loss on drying (LOD) and assay in-process control 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 loaded 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 resulting particles are sized according to the LOD in-process control to produce the API drug IR pellets, which are packaged and tested.

[0192] Part 2: Manufacturing of API drug modified release pellets (MUPS) An initial modified release polymer solution is prepared by mixing purified water, polyethylene glycol, and polyvinylpyrrolidone. Talc is added to the solution to produce a lump-free dispersion. Poly(vinyl acetate) dispersion 30% is added to the dispersion and mixed. The resulting dispersion is filtered to produce the MR coated dispersion. API drug IR pellets are loaded into a fluidized bed and the MR coating dispersion is sprayed onto the pellets until the required weight gain (3-60%) is achieved. The coated pellets are then cured at a production temperature of about 40°C-60°C for about 30 minutes to about 2 hours. The resulting particles are sized according to loss on drying in-process control to produce API drug MR pellets, which are packaged and tested.

[0193] Part 3: Manufacturing of API drug MUPS (multiple unit pellet system) capsules The required amount of API drug IR pellets (if required) followed by the required amount of API drug MR pellets (if required) were individually manually weighed into each gelatin capsule. The capsules were sealed, visually evaluated, weighed and packaged.

[0194] Example 3. Formulation of a compound of formula I into a modified release tablet. 3.1. Modified Release Tablets Containing HPMC Polymers Four tablet formulations with HPMC were prepared to control API release and contained the components in Table 3 below. The release rate can be adjusted by the addition of HPMC polymers. HPMC K100LV provided a more rapid release than HPMC (Methocel K-15MCR) alone. [Table 3]

[0195] An excess of hydrophilic fumed silica Aerosil 200 was weighed and passed through a clean, dry 850 μM sieve and 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 of MCC, API and mannitol was weighed and then 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 of HPMC and povidone was weighed and then 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 for 5 minutes at 32 rpm. 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 was recorded. The bottle was placed in a Turbula mixer for 3 minutes at 32 rpm and then the blend was ready for compression. Compression 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 Figures 26 and 27. [Table 4]

[0197] 3.2. MODIFIED RELEASE TABLETS CONTAINING PARTECK® POLYMERS Two batches (SR PVA matrix tablets, 40 mg and SR PVA matrix tablets, 120 mg) were produced for SR PVA matrix tablets according to Table 5.

[0198]

Table 5

[0199] Fifty percent of the total Microcrystalline Cellulose PH102, in addition to the API, talc, and Aerosil 200, 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 for 5 minutes at 23 rpm. The remaining 50% of the Microcrystalline Cellulose PH102, in addition to the Povidone K30, 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 for 5 minutes at 23 rpm. The excess 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 for 5 minutes at 23 rpm. The required amount of blend was overfilled into the die of a slug tool (22.00 mm circular flat tool) for compression into slugs. The necessary compression force was applied to achieve an acceptable solid fraction (0.60-0.70) using the following equation (weight / ((thickness x 380.13)) / 1.4). The solid fraction was calculated for all slugs. The targeted weight range was 2000mg ± 5%. The hardness was recorded for the first two slugs and the entire blend was formed into a slug. The slugs were placed in a mortar and gently ground into granules using a pestle, taking care not to produce fines. The ground slugs were passed through a 1.18mm sieve, followed by an 850μM sieve into a receiving pan. Oversized material was returned to the mortar and pestle for further size reduction if necessary. This step was performed first with the 1.18μM sieve, followed by the 850μM sieve. The fraction retained on the screens was ground as described above until all granules had passed through the 850μM screen. The milled granules were weighed and collected in appropriate size amber glass bottles and the yield was found to be 85.98% for the low dose formulation of 40mg and 69.07% for the high dose formulation. PVA (Parteck SRP80), colloidal anhydrous silica 200 (Aerosil) and talc were passed through the same 600μm 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 the magnesium stearate was passed through a 250 μm sieve and collected and the weight was recorded. The excess magnesium stearate was passed separately 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 for 5 minutes at 23 rpm. The required amount of tablet blend was filled to overflowing into a die (15×7 mm oval) of a tableting tool for compression into 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 tablet weight and thickness were checked and recorded (weight range: 400 mg±5%). The hardness for the first two tablets was recorded. The blend was compressed to give approximately 30 tablets and hardness was collected from a further two tablets at the end of production. Acceptable tablets were packaged in 60 mL Duma containers.

[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 a compound of Formula I in a modified release coating MUPS EUDRAGIT® RS30D and EUDRAGIT® RL30D were used as modified release polymers in a 9 to 1 ratio. The drug layer suspension was prepared by first preparing a homogeneous dispersion of API (250 g) and water (2.1 L), and then adding a clear solution of PEG6000 (8.33 g), HPMC E5 (83.33 g) and water (about 1 L) to it. Drug layering of microcrystalline beads (CP102, 500 g) was achieved after spraying for 10 hours and 30 minutes. The drug layered 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 pellet was dried for 10 min and then sorted to retain beads between 300-425 μM, yielding 762.3 g of seal-coated drug-layered product.

[0203] The antiblocking agent, talc (35.0 g, 50% based on dry polymer), and the plasticizer, triethyl citrate (TEC) (24.0 g, 50% based on dry polymer), were added to water (312.7 g) and then homogenized using a homogenizer for 10 minutes. EUDRAGIT® RS30D (210.0 g) and EUDRAGIT® RL30D (23.3 g) were mixed at low shear rate for 10 minutes. The excipient suspension was slowly poured into the EUDRAGIT® dispersion with gentle stirring for 30 minutes with conventional stirring equipment. The final suspension was filtered using a sieve mesh size of 0.25 mm. 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 formulations with a 15% w / w coating were administered to minipigs.

[0204] The drug release over time was then measured. Formulations of the compound of formula I were dissolved in McIlvaine buffer, composed of citric acid and disodium hydrogen phosphate, also known as citrate-phosphate buffer, pH 3. A comparison of the dissolution rates of API (80 mg), seal-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 Monkey PK Study Cynomolgus monkeys with surgically implanted CSF collection ports were housed and cared for in accordance with study facility IACUC guidelines and SOPs.

[0206] Whole Blood Collection and Plasma Processing (Pharmacokinetics): Blood samples were collected from a peripheral vein by direct needle puncture at the appropriate time points (see below). Whole blood was placed on wet ice until processing for plasma according to study facility SOPs. Plasma was stored at -80°C on dry ice at study completion until transported to the analytical laboratory.

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

[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. CSF was immediately assessed for the presence of red blood cells, spun in a microcentrifuge at 2000 g for 10 minutes at room temperature, and the supernatant was aliquoted, flash frozen in LN2, and stored at -80°C on dry ice at the end of the study until delivery 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 cynomolgus monkeys ported into CSF: Prior to the first day of dosing, all animals (n=16) were orally dosed once daily for 5 days with vehicle (0.5% w / v methylcellulose in reverse osmosis water, 0.1% w / v Tween® 80). Beginning on the first day of dosing, 10 animals received a once daily oral dose of a formulation of the compound of formula I for 3 or 7 days, while the remaining animals continued to be dosed daily with vehicle for 3 or 7 days. Animals were abstained from food overnight prior to dosing and for at least 1 hour (but not more than 3 hours) after dosing.

[0210] Three MUPS capsule formulations were evaluated in cynomolgus monkeys (body weight approximately 5 kg). The MUPS formulations contained the compound of formula I formulated as 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 minimum of 1 week washout period. Uncoated pellets and API in capsule formulation served as comparators with immediate release rate. A single dose (2 mg / kg 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 capsule, 2. KOLLICOAT® 8% pellets in capsule, 3. Intact API (compound of formula I) in capsule, 4. Enteric coated pellets in capsule, 5. KOLLICOAT® 5% pellets in capsule, 6. KOLLICOAT® 3% pellets in capsule.

[0211] After oral administration to fasted monkeys, the uncoated pellet and PIC formulations had similar T max , C max and AUC 0-infThe formulation containing KOLLICOAT® SR30D coated pellets achieved a longer T max and reduced C max As shown by the slower absorption of the compound of formula I compared to the two immediate release formulations, Figure 20B shows the mean concentration time plots of the compound of formula I in monkeys (N=4) following a single oral dose of the compound of formula I (2 mg / kg) in the immediate release and MUPS formulations. max The median 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 The 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, thereby indicating a lower C for the two formulations with higher polymer content. max was shown to be due to a combination of slower absorption rate and reduced extent of absorption.

[0212] Example 6 Minipig PK Study Blood collection from the minipig subjects was similar to that of 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 Gottingen minipigs (N=3). Figure 17A shows the mean oral concentration time plots of formulations 1-5 in minipigs. KOLLICOAT® pellets show a slower absorption rate. The enteric coated pellets achieved similar exposure 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 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) following 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 with PVA or HPMC release modifiers as shown in Tables 11 and 12. Their dissolution profiles are shown in Table 13. In comparison, the dissolution profile of the API in a capsule formulation (80 mg of the compound of formula I in a gelatin capsule without any added excipients) is shown in Table 14. [Table 11] [Table 12] [Table 13] [Table 14]

[0216] Example 9 Pharmacokinetic (PK) and Bioavailability Studies 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 a bioavailability and pharmacokinetic study in healthy volunteers using a crossover design with a minimum washout period of 1 week. An immediate release (IR) formulation of the compound of formula I as an API formulation in capsule was used as a comparison and reference. A single 80 mg dose of the compound of formula I was given to fasted human subjects as API in capsule, KOLLICOAT® SR30D 5% pellets in capsule, or KOLLICOAT® SR30D 7% pellets in capsule formulation. Timed blood samples were obtained over a 72 hour period after 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 measures of safety after dosing were performed, including safety laboratory tests (hematology, clinical chemistry and urinalysis), vital signs, ECG, physical examination and evaluation of any adverse events (AEs). The PK properties of the formulations tested are shown in the table below. [Table 15]

[0217] MUPS KOLLICOAT® SR30D 5% and 7% pellets in capsule formulations showed reduced C compared to immediate release formulations. max and C max / C 12hr and was found to be well tolerated and bioavailable.

[0218] The two tablet formulations were evaluated in healthy human volunteers in a similar study design. HPMC (80 mg) and PVC (80 mg) tablets were studied in a crossover fashion with timed blood samples obtained over 72 hours after dosing. API (80 mg) in the capsule formulation served as a comparator. C maxOral administration of HPMC and PVA tablets achieved a reduction in β-amyloides concentration and was found to be well tolerated and bioavailable. [Table 16]

[0219] Overall, clinical studies have demonstrated that the modified-release capsules and tablets are well tolerated and have a lower C max and decreased Cmax / C 12hr It was demonstrated that the drug achieves a 100% dose-reducing effect while maintaining oral bioavailability (>30% relative oral bioavailability compared to API in capsules). No clinically significant effects on pulse rate or blood pressure were observed. max Formulations that lower the dosage while maintaining oral bioavailability may allow for higher and / or reduced dosing frequency and provide greater tolerability and safety.

[0220] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the description and illustration should not be construed as limiting the scope of the invention. Accordingly, all suitable modifications and equivalents may be deemed to be within the scope of the invention as defined by the following claims. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein in their entirety by reference. 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) 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) The formulation of any of the preceding items, wherein 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% at 2 hours and greater than 60% at 8 hours when tested at 37° C. in McIlvaine buffer, pH 3, using a USP Type II apparatus at 50-75 rpm, and wherein the formulation is a tablet. (Item 4) 3. The formulation according to item 2, wherein 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 when tested at 37° C. in McIlvaine buffer, pH 3, using a USP Type II apparatus at 100 rpm, and the formulation is a capsule containing pellets. (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 after administration to a subject compared to an immediate release formulation. max The formulation of any one of the preceding items, having the formula: (Item 6) Said C max is reduced by at least 20%. (Item 7) The formulation of any one of the preceding items, wherein 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. (Item 8) The formulation of 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) 9. The method according to claim 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) The formulation of any one of the preceding items, wherein the release modifier comprises 3% to 60% by weight of the formulation. (Item 11) The release modifier is selected from the group consisting of MCC (microcrystalline cellulose), HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), PEG (polyethylene glycol glyceride), PVA (polyvinyl alcohol), PVP (polyvinylpyrrolidone), CAP (cellulose acetate phthalate), CMC-Na (sodium carboxymethylcellulose), HPMCAS (hydroxypropyl methylcellulose acetate succinate), HPMCP (hydroxypropyl methylcellulose phthalate), poly(methyl acrylate-co-methyl) acrylate, ... 3. The formulation of any one of the preceding claims, wherein the poly(methacrylic acid-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. (Item 12) The release modifying agent may be 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® polymers, Eastman CA, Eastman CAB, Eastman CAB, Ethocel™, Aquacoat® ECD, or Surelease®, or Glyceride GatteCoat™, EUDRAGIT® NE30D, EUDRAGIT® NM30D, EUDRAGIT® RL30D, EUDRAGIT® RL100 / RL The formulation of any one of the preceding items, selected from the group consisting of EUDRAGIT® RS30D, EUDRAGIT® RS100 / RS, Kollicoat® SR30D, Walocel® HM-PPA, Kollicoat® MAE30DP / 100P, and Eastacryl 30D. (Item 13) The formulation of any one of the preceding items, wherein the release modifying agent is selected from the group consisting of microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, KOLLICOAT®, CARBOPOL®, and AQUACOAT®. (Item 14) The formulation of any one of the preceding items, comprising 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, and a coating. (Item 15) The formulation of any one of the preceding items, which is a tablet. (Item 16) 16. The formulation according to item 15, wherein the tablet contains 10 to 500 mg of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile. (Item 17) 16. The formulation according to item 15, wherein the tablet contains 40 to 120 mg of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile. (Item 18) 16. The formulation according to item 15, wherein the tablet contains 30 to 80 mg of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile. (Item 19) 16. The formulation of claim 15, wherein the release modifier is HPMC. (Item 20) 16. The formulation of item 15, wherein the release modifier is a PARTECK® polymer. (Item 21) 21. The formulation according to item 19 or 20, wherein the release modifier constitutes 20-30% w / w of the formulation. (Item 22) 2. The formulation of any one of the preceding items, which is a capsule containing pellets. (Item 23) 23. The formulation of item 22, wherein the capsule is a combination of multiple unit particles of immediate release pellets and modified release pellets contained in the capsule. (Item 24) 24. The formulation according to items 22-23, wherein the pellets comprise a release modifier selected from KOLLICOAT®, CARBOPOL®, and AQUACOAT®. (Item 25) 25. The formulation according to items 22 to 24, which is a combination of multiple unit particles of immediate release pellets and delayed release pellets contained in a capsule. (Item 26) The formulation according to items 22 to 25, wherein the modified release formulation is selected from delayed release pellet formulations, controlled release pellet formulations, sustained release pellet formulations, and pulsed release pellet formulations. (Item 27) 27. The formulation according to items 22 to 26, comprising a coating agent which is EUDRAGIT®. (Item 28) 28. The formulation of item 27, wherein the coating agent comprises 3% to 60% EUDRAGIT® by weight of the formulation. (Item 29) 29. The formulation of item 28, wherein the coating comprises up to 20% w / w EUDRAGIT® RS30D. (Item 30) 30. The formulation of item 29, wherein the coating comprises up to 60% w / w EUDRAGIT® NM30D. (Item 31) 27. The formulation according to items 22 to 26, comprising a coating agent which is KOLLICOAT® SR30D. (Item 32) 32. The formulation according to item 31, wherein the KOLLICOAT® SR30D provides a weight gain of about 5%. (Item 33) 32. The formulation according to item 31, wherein the KOLLICOAT® SR30D provides a weight gain of about 7%. (Item 34) 32. The formulation according to item 31, wherein the KOLLICOAT® SR30D provides a weight gain of about 8%. (Item 35) 32. The formulation according to item 31, wherein the KOLLICOAT® SR30D provides a weight gain of 5 to 9%. (Item 36) 1. A method for preparing a modified release formulation comprising the steps of: (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 pellets with a cosmetic, non-functional seal coating to form seal coated pellets; (c) coating the seal-coated pellets with a release modifying agent to form the modified release formulation. A method comprising: (Item 37) 37. The method of claim 36, wherein the inert core is selected from sugar, microcrystalline cellulose (MCC), tartaric acid, polyols, carnauba wax, silicon dioxide, and combinations thereof. (Item 38) 37. The method of claim 36, wherein the cosmetic non-functional seal coating is selected from hydroxypropyl methylcellulose (HPMC) and a mixture of hypromellose and ethylcellulose. (Item 39) 39. The method of claim 38, wherein the release modifying agent is selected from the group consisting of KOLLICOAT®, EUDRAGIT®, hydroxypropyl methylcellulose (HPMC), and a mixture of hypromellose and ethylcellulose. (Item 40) 1. A method for preparing a modified release formulation comprising the steps of: (a) roller compacting 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, thereby forming pellets; (b) polymer-coating the pellets with a dispersion of a coating agent selected from KOLLICOAT®, CARBOPOL®, AQUACOAT®, and OPADRY® White; A method comprising: (Item 41) Further comprising one or more steps selected from extrusion, spheronization, and compression; The method according to item 40. (Item 42) 41. The method of claim 40, further comprising filling a soft or hard capsule shell with the coated pellets. (Item 43) 1. A method for preparing a modified release formulation 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 a dry granulation of the dry mixture as a granule by roller compaction; (c) milling the granules; (d) adding croscarmellose sodium, silicon dioxide, talc, and magnesium stearate to the milled granules to form an extragranular mixture; (e) compressing the extragranular mixture into a tablet; (f) coating the tablets with a coating agent selected from KOLLICOAT®, CARBOPOL®, AQUACOAT®, and EUDRAGIT®. A method comprising: (Item 44) A method of treating an LRRK2-mediated disease, comprising administering to a subject in need thereof a formulation described in any one of the preceding items. (Item 45) 45. The method of claim 44, wherein one or more of the formulations are administered to the subject once daily, twice daily, or three times daily. (Item 46) 46. ​​The method of claim 45, wherein the formulation is administered to the subject twice daily. (Item 47) 47. The method of claim 46, wherein the LRRK2-mediated disease is a neurodegenerative disease. (Item 48) 48. The method of claim 47, wherein the LRRK2-mediated disease is Parkinson's disease.

Claims

[Claim 1] The invention described in this specification.

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