Cocrystals

Abstract

Cocrystals of itanapraced; methods for preparing the cocrystals; uses of the cocrystals as APIs; formulations comprising the cocrystals; uses of the cocrystals and formulations for the prevention and treatment of neurodegenerative disorders, infections, dementia, inflammation, and injury; and methods of preventing and treating neurodegenerative disorders, infections, dementia, inflammation, and injury are described.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 238,928, filed Aug. 31, 2021, which is incorporated herein by reference.

[0002] The present invention relates generally to cocrystals; methods for preparing cocrystals; use of cocrystals as active pharmaceutical ingredients (APIs); dosage forms comprising cocrystals; methods for preparing dosage forms; use of cocrystals, and dosage forms comprising cocrystals, for the prevention and treatment of neurodegenerative disorders, infections, dementia, inflammation, and injury; and methods of preventing and treating neurodegenerative disorders, infections, dementia, inflammation, and injury. [Background technology]

[0003] An active pharmaceutical ingredient (API) is an ingredient in a pharmaceutical dosage form (i.e., a drug) that is biologically active. Traditionally, the free base, salt, solvate, hydrate, or polymorph of this ingredient has been used as the API.

[0004] A salt is a chemical formed by the reaction of an acid and a base.

[0005] Solvates are multicomponent, crystalline solid molecular adducts formed by solvation (i.e., the combination of solvent molecules or ions with molecules of a solute). Solvates include molecules of the solute or ions and molecules of the solvent in a crystal lattice structure.

[0006] Hydrates are multicomponent, crystalline solid molecular adducts formed by hydration (i.e., the combination of water molecules with solute molecules or ions). Hydrates contain solute molecules or ions and water molecules incorporated into a crystal lattice structure.

[0007] Polymorphs are single-component crystalline forms that have different arrangements or conformations of the molecules of a compound in the crystal lattice.

[0008] Unlike salts, solvates, hydrates, and polymorphs, cocrystals are crystalline materials that contain molecules of two or more different compounds in a defined stoichiometric ratio in a crystal lattice. The molecules of the two or more different compounds are not covalently bonded and do not interact ionically. Rather, the molecules of the two or more different compounds interact with each other non-ionically in a cocrystal.

[0009] Cocrystals are distinguishable from salts because the components of a cocrystal interact non-ionically rather than ionically.

[0010] Cocrystals are distinguishable from polymorphs because cocrystals contain molecules of two or more different compounds rather than molecules of one compound.

[0011] Cocrystals are distinguishable from solvates because the second component of a cocrystal (the co-crystal former) is not a solvent and is usually non-volatile.

[0012] Cocrystals are distinguishable from hydrates because the second component of a cocrystal (the cocrystal former) is not water and is usually non-volatile.

[0013] Cocrystals are also distinguishable from the individual compounds in the crystal lattice because they have physicochemical properties that are different from the physicochemical properties of each of the compounds in the crystal lattice. For example, the melting point, solubility, bioavailability, hygroscopicity, stability, and / or permeability of a cocrystal may be different from the melting point, solubility, bioavailability, hygroscopicity, stability, and permeability of each component of the cocrystal.

[0014] Amyloid precursor protein (APP) is a widely expressed transmembrane protein. APP is expressed in neurons, astrocytes, and microglia, for example. The expression of APP and its metabolism change under various neuropathological conditions, especially in response to oxidative stress.

[0015] Cleavage of APP by the sequential action of gamma- and beta-secretase generates a series of fragments that include, for example, the amyloid-β (Aβ) peptide and the APP intracellular domain (AICD).

[0016] AICD is a transcriptional regulator that is involved in various physiological processes, including synaptic plasticity and cytoskeleton organization. However, under conditions of severe oxidative stress, AICD interacts with the transcriptional coactivator FOXO3a to promote cell death. Furthermore, AICD and FOXO3a have been shown to cooperate to control mitochondrial function by regulating the transcription of PTEN-induced putative kinase 1 (PINK1) and to regulate the expression of leucine-rich repeat kinase 2 (LRRK2). LRRK2 mutations adversely affect multiple physiological processes, including synaptic activity and plasticity, and the maintenance of normal dendritic spine morphology. Several lines of evidence indicate that overactive LRRK2 interferes with autophagy processes, including mitophagy. Therefore, based on these properties, inhibition of AICD activity is expected to show beneficial effects in the treatment of several diseases.

[0017] Although Aβ accumulation has received the most attention, there is growing recognition that the concomitant production of AICD likely plays a major role in the pathogenesis of Alzheimer's disease (AD) and numerous other neurodegenerative disorders, such as Parkinson's disease (PD), multiple sclerosis (MS), juvenile neuronal ceroid lipofuscinosis (JNCL) (Batten disease type 3), age-related macular degeneration (AMD); amyotrophic lateral sclerosis (ALS), mild cognitive impairment (MCI), neuronal injury (traumatic brain injury (TBI)), and neuroinflammation. Summary of the Invention

[0018] It is an object of the present invention to provide co-crystals that include moieties that bind to APP within its intracellular domain.

[0019] An object of the present invention is to provide a cocrystal containing a component that inhibits the nuclear translocation of AICD.

[0020] It is an object of the present invention to provide co-crystals comprising components that modulate the transcriptional activity of AICD.

[0021] It is an object of the present invention to provide co-crystals comprising components capable of modulating microglia.

[0022] An object of the present invention is to provide a cocrystal containing a component capable of inhibiting inflammation.

[0023] It is an object of the present invention to provide a co-crystal comprising itanapraced (also known as CSP-1103, formerly known as CHF5074) and a co-crystal former, such as nicotinamide.

[0024] It is a further object of the present invention to provide co-crystals of itanapraced which are more water soluble than itanapraced.

[0025] It is a further object of the present invention to provide a co-crystal comprising itanapraced and a co-crystal former, wherein the co-crystal is less hygroscopic than itanapraced.

[0026] Another object of the present invention is to provide methods for preventing, inhibiting, reducing, eliminating, protecting against, or delaying the onset of acute and chronic neurodegenerative disorders, mild cognitive impairment, dementia, neuronal injury, and neuroinflammation.

[0027] It is another object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

[0028] In accordance with the above and other objects, the present invention relates to a pharmaceutical formulation comprising a co-crystal, the co-crystal comprising a crystal lattice comprising molecules of an active ingredient and a co-crystal former, the active ingredient interacts non-ionically with the co-crystal former in the crystal lattice, the active ingredient comprises a carboxylic acid moiety, the co-crystal former is a non-volatile heterocyclic organic compound, the active ingredient and the co-crystal former are bound only by non-ionic and non-covalent bonds, and the co-crystal former is not a solvent. The stoichiometric ratio of active ingredient to co-crystal former can be from about 0:5:1.5 to about 1.5:0.5. The co-crystal former can be included in an amount sufficient to exhibit an improvement in a physical property of the active ingredient compared to the physical property of the active ingredient without the co-crystal former. The improved physical property can be, for example, hygroscopicity. In a particular embodiment, the active ingredient is praced (e.g., itanapraced) and the co-crystal former is a heterocyclic organic compound having a pyridinyl moiety. Heterocyclic organic compounds having a pyridinyl moiety include, for example, nicotinamide, picolinamide, isonicotinamide, isonicotinic acid, and nicotinic acid.

[0029] The present invention further relates to a pharmaceutical formulation comprising a therapeutically effective amount of an active ingredient (preferably an AICD inhibitor in certain embodiments), the active ingredient being in the form of a co-crystal, the co-crystal comprising molecules of the active ingredient and a co-crystal former in a crystal lattice, the active ingredient interacting non-ionically with the co-crystal former in the crystal lattice, the active ingredient and the co-crystal former being bound only by non-ionic and non-covalent bonds, and the co-crystal former being non-volatile and not a solvent. The co-crystal former may be included in an amount sufficient to exhibit improved physical properties (e.g., hygroscopicity, solubility, etc.) and / or improved bioavailability and / or improved dissolution rate, and / or improved time to Cmax of the active ingredient compared to the physical properties, bioavailability, dissolution rate, and time to Cmax of the active ingredient without the co-crystal former (i.e., not interacting non-ionically with the co-crystal former and not bound only by non-ionic and non-covalent bonds with the co-crystal former). When the co-crystal former separates from the active pharmaceutical ingredient, the active ingredient becomes available to exhibit a pharmacological effect.

[0030] The present invention also relates to a pharmaceutical formulation comprising a therapeutically effective amount of an AICD inhibitor, wherein the AICD inhibitor is in the form of a co-crystal, the co-crystal comprises a crystal lattice comprising molecules of the AICD inhibitor and a co-crystal former, the AICD inhibitor interacts non-ionically with the co-crystal former in the crystal lattice, the AICD inhibitor and the co-crystal former are bound only by non-ionic and non-covalent bonds, and the co-crystal former is non-volatile and is not a solvent. The co-crystal former may be included in an amount sufficient to show improved physical properties of the AICD inhibitor compared to the physical properties of the AICD inhibitor without the co-crystal former. Thus, in some embodiments, the co-crystal former may be included in an amount sufficient to show improved hygroscopicity of the AICD inhibitor compared to the hygroscopicity of the AICD inhibitor without the co-crystal former.

[0031] The present invention also relates to a pharmaceutical formulation comprising a therapeutically effective amount of an AICD inhibitor, wherein the AICD inhibitor is in the form of a co-crystal, the co-crystal comprises molecules of the AICD inhibitor and a co-crystal former in a crystal lattice, the AICD inhibitor interacts non-ionically with the co-crystal former in the crystal lattice, and the AICD inhibitor and the co-crystal former are bound only by non-ionic and non-covalent bonds, and the co-crystal former is non-volatile, is not a solvent, and is included in an amount sufficient to show improved bioavailability and / or dissolution rate of the AICD inhibitor and / or reduced time to Cmax compared to the bioavailability, dissolution rate, and time to Cmax of the AICD inhibitor without the co-crystal former. In certain embodiments, when the pharmaceutical formulation is administered to a human, the co-crystal former is separable from the AICD inhibitor. When the co-crystal former is separated from the AICD inhibitor, the AICD inhibitor is available to exhibit a pharmacological effect, for example, to bind to the intracellular domain of APP and inhibit the transcriptional activity of the APP intracellular domain (AICD). The AICD inhibitor can regulate the transcriptional activity of AICD. Thus, in some of these embodiments, the AICD inhibitor is capable of inducing the transcriptional activity of AICD, hi other embodiments, the AICD inhibitor is capable of inhibiting the transcriptional activity of AICD.

[0032] The present invention also relates to a pharmaceutical formulation comprising a therapeutically effective amount of an AICD inhibitor, wherein the AICD inhibitor is in the form of a co-crystal, the co-crystal comprising molecules of the AICD inhibitor and a co-crystal former in a crystal lattice, wherein the AICD inhibitor interacts non-ionically with the co-crystal former in the crystal lattice, and wherein the AICD inhibitor and the co-crystal former are bound only by non-ionic and non-covalent bonds, and wherein the co-crystal former is a non-volatile organic compound, is not a solvent, and is included in an amount sufficient to exhibit enhanced physical properties (e.g., hygroscopicity, solubility, etc.) and / or bioavailability and / or dissolution rate, and / or reduced time to Cmax of the AICD inhibitor compared to the physical properties, bioavailability, dissolution rate, and time to Cmax of the AICD inhibitor without the co-crystal former (i.e., does not interact non-ionically with the co-crystal former and is not bound to the co-crystal former by non-ionic and non-covalent bonds), whereby the co-crystal former dissociates from the AICD inhibitor when the pharmaceutical formulation is administered to a human. In some of these embodiments, the AICD inhibitor is placid and the co-crystal former is selected from the group consisting of nicotinamide, picolinamide, isonicotinamide, isonicotinic acid, and nicotinic acid. In some of these embodiments, the co-crystal comprises itanapraced and a co-crystal former, wherein the co-crystal former is nicotinamide, and the co-crystal comprises an X-ray powder diffraction pattern (XRPD) having specific peaks at about 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (all ±0.2 degrees 2θ) expressed from a Cu source (λ=1.54 Å after Ni filtering). For example, the XRPD can be substantially identical to the X-ray powder diffraction pattern (XRPD) shown in Figure 3 A. In some of these embodiments, the stoichiometric ratio of itanapraced to nicotinamide is about 0.8:1.2 to about 1.2:0.8 (e.g., about 1:1).In some of these embodiments, the stoichiometric ratio of itanapraced to nicotinamide is about 1: 1. In all of these embodiments, the pharmaceutical formulation may be less hygroscopic than itanapraced.

[0033] The present invention also relates to a pharmaceutical formulation comprising a therapeutically effective amount of an AICD inhibitor, wherein the AICD inhibitor is in the form of a co-crystal, the co-crystal comprises molecules of the AICD inhibitor and a co-crystal former in a crystal lattice, the AICD inhibitor interacts non-ionically with the co-crystal former in the crystal lattice, the AICD inhibitor and the co-crystal former are bound only by non-ionic and non-covalent bonds, the co-crystal former is a non-volatile organic compound, is not a solvent, and is bound only by non-ionic and non-covalent bonds with the AICD inhibitor, the co-crystal former is included in an amount sufficient to exhibit improved physical properties and / or bioavailability and / or dissolution rate, and / or reduced time to Cmax of the AICD inhibitor compared to the physical properties, bioavailability, dissolution rate, and time to Cmax of the AICD inhibitor without the co-crystal former, the AICD inhibitor is praced and the co-crystal former is selected from the group consisting of nicotinamide, picolinamide, isonicotinamide, isonicotinic acid, and nicotinic acid.

[0034] The present invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of an AICD inhibitor, wherein the AICD inhibitor is in the form of a co-crystal, the co-crystal comprising molecules of the AICD inhibitor and a co-crystal former in a crystal lattice, the AICD inhibitor non-ionically interacts with the co-crystal former in the crystal lattice, the AICD inhibitor and the co-crystal former are bound only by non-ionic and non-covalent bonds, the co-crystal former is a heterocyclic organic compound and is not a solvent, and the co-crystal former enhances the physical properties and / or bioavailability of the AICD inhibitor as compared to the physical properties, bioavailability, dissolution rate, and time to Cmax of the AICD inhibitor without the co-crystal former. and wherein the AICD inhibitor is praced and the co-crystal former is selected from the group consisting of nicotinamide, picolinamide, isonicotinamide, isonicotinic acid, and nicotinic acid; the praced is itanapraced and the co-crystal former is nicotinamide, and the stoichiometric ratio of itanapraced to nicotinamide is from about 0:8:1.2 to about 1.2:0.8, and the co-crystal comprises an X-ray powder diffraction pattern (XRPD) substantially identical to the X-ray powder diffraction pattern (XRPD) shown in FIG. 3A.

[0035] The present invention also relates to a pharmaceutical formulation comprising a therapeutically effective amount of Praced, wherein Praced is in the form of a co-crystal, the co-crystal comprises molecules of Praced and a co-crystal former in a crystal lattice, Praced interacts non-ionically with the co-crystal former in the crystal lattice, Praced and the co-crystal former are bound only by non-ionic and non-covalent bonds, the co-crystal former is a non-volatile heterocyclic organic compound having a pyridinyl moiety and is bound only by non-ionic and non-covalent bonds with Praced, the co-crystal former is included in an amount sufficient to show increased bioavailability and / or increased dissolution rate and / or decreased time to Cmax of Praced compared to the bioavailability, dissolution rate and time to Cmax of Praced without the co-crystal former, whereby when the pharmaceutical formulation is administered to a human, the co-crystal former separates from Praced. When the co-crystal former separates from Praced, Praced becomes available to show a pharmacological effect.

[0036] The present invention also relates to a pharmaceutical formulation comprising a therapeutically effective amount of Praced, wherein Praced is in the form of a co-crystal, the co-crystal comprising molecules of Praced and a co-crystal former in a crystal lattice, Praced interacts non-ionically with the co-crystal former in the crystal lattice, Praced and the co-crystal former are bound only by non-ionic and non-covalent bonds, the co-crystal former is a non-volatile heterocyclic organic compound having a pyridinyl moiety and is not a solvent, and the co-crystal former is included in an amount sufficient to reduce the hygroscopicity of the co-crystal compared to the hygroscopicity of Praced without the co-crystal former, whereby the co-crystal former separates from Praced when the pharmaceutical formulation is administered to a human.

[0037] The hygroscopicity of the pharmaceutical formulation of the present invention may be such that the weight of the pharmaceutical formulation increases or decreases by about 0.01% to 0.20% w / w, about 0.08% to 0.20% w / w, or about 0.1% to 0.20% w / w, all at 25° C. and 5 to 95% RH (relative humidity), and the hygroscopicity of Plased without a co-crystal former may be such that the weight of Plased increases or decreases by more than 0.20% w / w, but less than 2% w / w, or more than about 0.5% w / w, but less than 2% w / w, or more than about 0.8% w / w, but less than 2% w / w, all at 25° C. and 5 to 95% RH (relative humidity). The reduction in the hygroscopicity of the pharmaceutical formulation may result in increased stability and / or increased shelf life and / or easier incorporation of the pharmaceutical formulation into a pharmaceutical dosage form, for example, compared to Plased without a co-crystal former.

[0038] The present invention further relates to a pharmaceutical formulation comprising a therapeutically effective amount of Praced, wherein Praced is in the form of a co-crystal, the co-crystal comprises molecules of Praced and a co-crystal former in a crystal lattice, Praced interacts non-ionically with the co-crystal former in the crystal lattice, Praced and the co-crystal former are bound only by non-ionic and non-covalent bonds, the co-crystal former is a non-volatile heterocyclic organic compound having a pyridinyl moiety and is not a solvent, and the co-crystal former is included in an amount sufficient to increase the water solubility of the co-crystal compared to the water solubility of Praced without the co-crystal former, such that the co-crystal former separates from Praced when the pharmaceutical formulation is administered to a human. For example, the co-crystal may be water soluble, while Praced without the co-crystal former may be water soluble or less water soluble. The increased water solubility of the pharmaceutical formulation may result in improved bioavailability and / or a more rapid onset of action and / or a longer T time, compared to administration of Praced without the co-crystal former. max and / or plasma concentrations (e.g., C max ) and / or AUC may increase.

[0039] The present invention encompasses pharmaceutical formulations comprising a therapeutically effective amount of an AICD inhibitor having a carboxylic acid moiety, wherein the AICD inhibitor is in the form of a co-crystal, the co-crystal comprises a crystal lattice comprising molecules of the AICD inhibitor and a co-crystal former, the AICD inhibitor interacts non-ionically with the co-crystal former in the crystal lattice, the AICD inhibitor and the co-crystal former are bound only by non-ionic and non-covalent bonds, and the co-crystal former is a non-volatile heterocyclic organic compound having a pyridinyl moiety and is not a solvent. The co-crystal former may be included in an amount sufficient to exhibit an improved physical property of the AICD inhibitor compared to the physical property of the AICD inhibitor without the co-crystal former. The improved physical property may be, for example, hygroscopicity.

[0040] In certain embodiments, the invention relates to a pharmaceutical formulation comprising a co-crystal, wherein the co-crystal comprises a crystal lattice comprising molecules of an AICD inhibitor and a co-crystal former, wherein the AICD inhibitor interacts non-ionically with the co-crystal former in the crystal lattice, wherein the AICD inhibitor comprises a carboxylic acid moiety, wherein the co-crystal former is a non-volatile heterocyclic organic compound, and wherein the AICD inhibitor and the co-crystal former are bound only by non-ionic and non-covalent bonds, and not by a solvent.

[0041] The present invention further relates to a pharmaceutical formulation comprising a therapeutically effective amount of an AICD inhibitor, wherein the AICD inhibitor is in the form of a co-crystal, the co-crystal comprising a crystal lattice comprising molecules of the AICD inhibitor and a co-crystal former, the AICD inhibitor interacts non-ionically with the co-crystal former in the crystal lattice, the AICD inhibitor comprises a carboxylic acid moiety, the co-crystal former is a non-volatile heterocyclic organic compound having a pyridinyl moiety, the AICD inhibitor and the co-crystal former are bound only by non-ionic and non-covalent bonds, and the co-crystal former is not a solvent.

[0042] The AICD inhibitor in the pharmaceutical formulation of the present invention can be, for example, praced. In some of these embodiments, the praced is itanapraced and the co-crystal former is selected from the group consisting of nicotinamide, picolinamide, isonicotinamide, isonicotinic acid, and nicotinic acid.

[0043] The present invention also relates to co-crystals comprising (i) a component capable of binding to APP and / or inhibiting the transcriptional activity of AICD and / or modulating microglia, and (ii) a co-crystal former. The co-crystal former itself may or may not be biologically active. The component and the co-crystal former are not covalently and ionically bound in the co-crystal. Instead, the component and the co-crystal former are bound by non-ionic and non-covalent bonds, such as hydrogen bonds, van der Waals forces, and π interactions. The co-crystal has physical and chemical properties that are different from those of the component, the co-crystal former, their polymorphs, salts, hydrates, and solvates. For example, the co-crystal may exhibit improved water solubility and / or stability compared to the component and the co-crystal former, their polymorphs, salts, hydrates, and solvates. The co-crystal may also exhibit improved bioavailability and / or improved dissolution rate and / or faster time to Cmax compared to the bioavailability, dissolution rate, and time to Cmax of the component. Cocrystals can also be, for example, less hygroscopic than the components and more suitable for incorporation into solid dosage forms. Cocrystals can be used, for example, as active pharmaceutical ingredients (APIs) in pharmaceutical formulations, including, for example, solid dosage forms (e.g., tablets and capsules). Cocrystals and pharmaceutical formulations can be used in the prevention and treatment of neurodegenerative disorders, including, for example, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), juvenile neuronal ceroid lipofuscinosis (JNCL) (Batten disease type 3), age-related macular degeneration (AMD); dementia (e.g., MCI), neuroinfections, neuroinjuries (traumatic brain injury (TBI)), and neuroinflammation.

[0044] More specifically, the present invention relates, in part, to a co-crystal comprising itanapraced and a co-crystal former. Itanapraced and the co-crystal former are not covalently and ionically bound in the co-crystal. Instead, itanapraced and the co-crystal former are bound by non-ionic and non-covalent bonds. The co-crystal former in the co-crystal may or may not be biologically active and may be selected, for example, from the group consisting of nicotinamide, picolinamide, isonicotinamide, isonicotinic acid, and nicotinic acid. The co-crystal has physical and chemical properties that are different from those of itanapraced, the co-crystal former, their polymorphs, salts, hydrates, and solvates. For example, the co-crystal may exhibit improved water solubility and / or stability and may be more suitable for incorporation into solid dosage forms compared to itanapraced and the co-crystal former, their polymorphs, salts, hydrates, and solvates. The cocrystals may be less hygroscopic than itanapraced and / or more water soluble than itanapraced. The cocrystals may also be non-hygroscopic. The cocrystals may also improve the bioavailability, dissolution rate, and C max Increased bioavailability and / or increased dissolution rate and / or C max This may demonstrate a reduction in the time to

[0045] In a particular embodiment, the present invention relates to a co-crystal comprising a crystal lattice comprising molecules of itanapraced and a co-crystal former, wherein the AICD inhibitor interacts non-ionically with the co-crystal former in the crystal lattice, and the co-crystal former is a non-volatile heterocyclic organic compound having a pyridinyl moiety, and wherein the AICD inhibitor and the co-crystal former are bound only by non-ionic and non-covalent bonds.

[0046] The present invention further relates to a cocrystal comprising itanapraced and nicotinamide. The stoichiometric ratio of itanapraced to nicotinamide in the cocrystal can be about 0:8:1.2 to about 1.2:0.8 (e.g., about 1:1). Itanapraced and nicotinamide are not covalently and ionically bonded in the cocrystal. Rather, itanapraced and nicotinamide are bonded by nonionic and noncovalent bonds. In certain embodiments, itanapraced and nicotinamide can be bonded at the pyridinyl moiety of nicotinamide and the carboxylic acid moiety of itanapraced. The co-crystal may comprise an X-ray powder diffraction pattern (XRPD) having specific peaks at about 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (all ±0.2 degrees 2θ) generated from a Cu source (λ=1.54 Å after Ni filtering). The X-ray powder diffraction pattern (XRPD) may be substantially identical to the X-ray powder diffraction pattern (XRPD) shown in FIG. 3A. For example, the cocrystal may have an X-ray powder diffraction pattern (XRPD) with specific peaks at about 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° in 2θ generated from a Cu source (λ=1.54 Å after Ni filtering). The co-crystal may exhibit a first endothermic event with an onset of 114.0° C., a peak maximum of 116.7° C., and a ΔH of 60.5 J / g as measured by differential scanning calorimetry (DSC analysis). The co-crystal may further exhibit a second endothermic event with a peak maximum of 159.1° C. and an end of 183.2° C. as measured by differential scanning calorimetry (DSC analysis).Cocrystals have physical and chemical properties that are different from those of itanapraced, nicotinamide, their polymorphs, salts, hydrates, and solvates. Cocrystals exhibit improved water solubility and / or reduced hygroscopicity relative to itanapraced compared to itanapraced and nicotinamide, their polymorphs, salts, hydrates, and solvates. Cocrystals may exhibit improved stability compared to itanapraced. Cocrystals may be non-hygroscopic. Thus, cocrystals may be more suitable for incorporation into solid dosage forms (e.g., tablets or capsules). Cocrystals may also exhibit improved bioavailability and / or improved dissolution rate and / or reduced time to Cmax compared to the bioavailability, dissolution rate, and time to Cmax of itanapraced.

[0047] The invention relates, in part, to a co-crystal comprising itanapraced and nicotinamide, wherein the co-crystal comprises nicotinamide and has a) an X-ray powder diffraction pattern (XRPD) with specific peaks at 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (all ±0.2 degrees 2θ) generated from a Cu source (λ=1.54 Å after Ni filtering); and / or b) the X-ray powder diffraction pattern as depicted in FIG. 3A.

[0048] The invention relates, in part, to a cocrystal comprising itanapraced and nicotinamide, wherein the cocrystal comprises nicotinamide and has an X-ray powder diffraction pattern (XRPD) with specific peaks expressed in 2θ at 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (all ±0.2 degrees 2θ) generated from a Cu source (λ=1.54 Å after Ni filtering); and the cocrystal is less hygroscopic than itanapraced.

[0049] The present invention relates, in part, to a co-crystal comprising itanapraced and nicotinamide, said co-crystal comprising nicotinamide and having the X-ray powder diffraction pattern shown in FIG. 3A; and wherein the co-crystal is less hygroscopic than itanapraced.

[0050] The present invention relates, in part, to a co-crystal comprising itanapraced and nicotinamide, the co-crystal comprising nicotinamide and having a wavelength of 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.1°, expressed as 2θ, generated from a Cu source (λ=1.54 Å after Ni filtering): and 39.14° (all ±0.2 degrees 2θ); and relates to a cocrystal in which itanapraced and nicotinamide are linked at the pyridinyl moiety of nicotinamide and the carboxylic acid moiety of itanapraced.

[0051] The present invention relates, in part, to a co-crystal comprising itanapraced and nicotinamide, said co-crystal comprising nicotinamide and having the X-ray powder diffraction pattern shown in FIG. 3A; wherein itanapraced and nicotinamide are bonded at the pyridinyl moiety of nicotinamide and the carboxylic acid moiety of itanapraced.

[0052] The present invention relates, in part, to a co-crystal comprising itanapraced and nicotinamide, the co-crystal comprising nicotinamide and having a wavelength of 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.4°, expressed as 2θ, generated from a Cu source (λ=1.54 Å after Ni filtering): 7°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (all ±0.2 degrees 2θ), wherein the cocrystal exhibits a first endothermic event with an onset of 114.0° C., a peak maximum of 116.7° C., and a ΔH of 60.5 J / g, as measured by differential scanning calorimetry (DSC analysis).

[0053] The present invention relates, in part, to a co-crystal comprising itanapraced and nicotinamide, the co-crystal comprising nicotinamide and having a wavelength of 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.4°, expressed as 2θ, generated from a Cu source (λ=1.54 Å after Ni filtering): and 39.14° (all ±0.2 degrees 2θ), wherein the co-crystal exhibits a first endothermic event with an onset of 114.0° C., a peak maximum of 116.7° C., and a ΔH of 60.5 J / g as measured by differential scanning calorimetry (DSC analysis), and a second endothermic event with a peak maximum of 159.1° C. and an end of 183.2° C. as measured by differential scanning calorimetry (DSC analysis).

[0054] The present invention further provides a method for preparing a co-crystal comprising a component that binds to APP and / or inhibits the transcriptional activity of AICD and / or is capable of regulating microglia, the method comprising dissolving the component and a co-crystal former in a solvent and isolating the co-crystal comprising the component and the co-crystal former.

[0055] In yet a further aspect, the present invention provides a method for the production of a co-crystal comprising a component that binds to APP and / or inhibits the transcriptional activity of AICD and / or is capable of modulating microglia, the method comprising the steps of: (i) grinding, heating, or contacting in solution the component and a co-crystal former under crystallization conditions to form a solid phase; and (ii) isolating a co-crystal comprising the component and the co-crystal former.

[0056] In a further aspect, the present invention provides a method for the production of co-crystals comprising the steps of: (i) obtaining a component that binds to APP and / or inhibits the transcriptional activity of AICD and / or is capable of modulating microglia; (ii) obtaining a co-crystal former; (iii) grinding, heating or contacting in solution the component and the co-crystal former under crystallization conditions; and (iv) isolating the co-crystal thereby formed.

[0057] The present invention also provides a method for preparing a co-crystal comprising dissolving itanapraced and a co-crystal former in a solvent and isolating the co-crystal comprising itanapraced and the co-crystal former.

[0058] In yet a further aspect, the present invention provides a method for the preparation of a co-crystal comprising the steps of: (i) grinding, heating or contacting in solution itanapraced with a co-crystal former under crystallization conditions to form a solid phase; and (ii) isolating the co-crystal comprising itanapraced and the co-crystal former.

[0059] In a further aspect, the present invention provides a method for the preparation of a co-crystal comprising the steps of: (i) obtaining itanapraced; (ii) obtaining nicotinamide; (iii) grinding, heating or contacting in solution itanapraced and nicotinamide under crystallization conditions; and (iv) isolating the co-crystal thereby formed.

[0060] The present invention also provides a method for preparing a co-crystal comprising dissolving itanapraced and nicotinamide in a solvent and isolating the co-crystal comprising itanapraced and nicotinamide.

[0061] In yet a further aspect, the present invention provides a method for the preparation of a co-crystal comprising the steps of: (i) grinding, heating or contacting in solution itanapraced and nicotinamide under crystallization conditions to form a solid phase; and (ii) isolating the co-crystal comprising itanapraced and nicotinamide.

[0062] In a further aspect, the present invention provides a method for the preparation of a co-crystal comprising the steps of: (i) obtaining itanapraced; (ii) obtaining nicotinamide; (iii) grinding, heating or contacting in solution itanapraced and nicotinamide under crystallization conditions; and (iv) isolating the co-crystal thereby formed.

[0063] Any of the cocrystals described herein can be used, for example, as an active pharmaceutical ingredient (API) in pharmaceutical formulations, including, for example, solid dosage forms (e.g., tablets and capsules).

[0064] The invention further relates, in part, to a pharmaceutical formulation comprising an effective amount of a cocrystal according to any of the above paragraphs, and a pharma- ceutically acceptable excipient. The cocrystal may, for example, comprise about 2% to about 98% by weight of the formulation. The pharma- ceutically acceptable excipient may comprise about 0.1% to about 99.9% by weight of the formulation. A unit dose of the pharmaceutical formulation may comprise about 3 mg to about 3500 mg of the cocrystal, the cocrystal comprising itanapraced and nicotinamide, the stoichiometric ratio of itanapraced to nicotinamide in the cocrystal being 0:8:1.2 to about 1.2:0.8 (e.g., about 1:1). The pharmaceutical formulation may, for example, be a solid dosage form. The solid dosage form may, for example, be an oral solid dosage form, such as a tablet or capsule. These oral solid dosage forms may be formulated as immediate release, controlled release, sustained (extended) release, or modified release formulations.

[0065] The present invention further provides a method for the treatment of rheumatoid arthritis by administering itanapraced to a patient having rheumatoid arthritis, comprising administering to said patient a therapeutically effective amount of itanapraced, the method ...max and / or a decrease in the time to reach peak serum levels, and / or C max and / or relates to a pharmaceutical formulation of itanapraced that exhibits increased maximum serum concentrations.The pharmaceutical formulation comprises a cocrystal of itanapraced rather than a neutral form, polymorph, solvate, hydrate, or salt of itanapraced.

[0066] In a further aspect, the present invention provides a method for modulating the bioavailability of itanapraced such that AUC is increased and / or time to Tmax is decreased and / or Cmax is increased when administered in the normal and effective dose range, comprising: (1) grinding, heating, or contacting in solution, under crystallization conditions, itanapraced and a co-crystal former to form a co-crystal of itanapraced and the co-crystal former; (2) isolating a co-crystal comprising itanapraced and a co-crystal former. The present invention provides a method comprising:

[0067] As an example of the above embodiment, max Co-crystal compositions having a time to T that is reduced by at least 10% compared to the free crystalline form. max Co-crystal compositions in which the time to T is reduced by at least 20% compared to the free crystalline form. max Co-crystal compositions in which the time to T is reduced by at least 40% compared to the free crystalline form. max Co-crystal compositions in which the time to T is reduced by at least 50% compared to the free crystalline form. max Co-crystal compositions having a Tmax reduced by at least 60% compared to the free crystalline form, co-crystal compositions having a Tmax reduced by at least 70% compared to the free crystalline form, max A co-crystal composition having at least 80% reduction in C compared to the free crystalline form. max Co-crystal compositions having at least 20% increased relative to the free crystalline form, C max Co-crystal compositions, C max Co-crystal compositions, C maxCo-crystal compositions, C max Co-crystal compositions, C max cocrystal compositions having an AUC increased by at least 70% relative to the free crystalline form, a cocrystal composition having an AUC increased by at least 80% relative to the free crystalline form, a cocrystal composition having an AUC increased by at least 10% relative to the free crystalline form, a cocrystal composition having an AUC increased by at least 20% relative to the free crystalline form, a cocrystal composition having an AUC increased by at least 30% relative to the free crystalline form, a cocrystal composition having an AUC increased by at least 40% relative to the free crystalline form, a cocrystal composition having an AUC increased by at least 50% relative to the free crystalline form, a cocrystal composition having an AUC increased by at least 60% relative to the free crystalline form, a cocrystal composition having an AUC increased by at least 70% relative to the free crystalline form, or a cocrystal composition having an AUC increased by at least 80% relative to the free crystalline form.

[0068] In a further aspect, the present invention provides a method for improving the dose response of itanapraced, comprising: (i) contacting itanapraced with a co-crystal former in solution under crystallization conditions so as to form a co-crystal of itanapraced and the co-crystal; (ii) isolating the co-crystals comprising itanapraced and a co-crystal former. The present invention provides a method comprising:

[0069] In yet a further aspect, the present invention provides a method for improving the stability of itanapraced in free form or as a salt thereof, comprising the steps of: (i) grinding, heating, or contacting in solution, under crystallization conditions, itanapraced and a co-crystal former to form a co-crystal of itanapraced and the co-crystal former; (ii) isolating the co-crystals comprising itanapraced and a co-crystal former. The present invention provides a method comprising:

[0070] In any of the methods described herein, the co-crystal former may be selected from the group consisting of nicotinamide, picolinamide, isonicotinamide, isonicotinic acid, and nicotinic acid. Other co-crystal formers are also encompassed by the present invention.

[0071] In any of the above methods, the co-crystal former can be nicotinamide.

[0072] The cocrystals and pharmaceutical formulations described herein can be used in the prevention and treatment of neurodegenerative disorders including, for example, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), juvenile neuronal ceroid lipofuscinosis (JNCL) (Batten disease type 3), age-related macular degeneration (AMD); dementia (e.g., MCI), neuroinfection, neuroinjury (traumatic brain injury (TBI)), and neuroinflammation. The cocrystals and pharmaceutical formulations can also be used in the treatment of tauopathies, particularly amyotrophic lateral sclerosis (ALS), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), as well as hypoxic encephalopathy.

[0073] The invention further relates to a method of preventing, inhibiting, and / or treating a neurodegenerative condition in a human comprising administering a therapeutically effective dosing regimen of a cocrystal that includes a moiety that binds to APP.

[0074] The present invention further relates to a method of preventing, inhibiting, and / or treating a neurodegenerative condition in a human comprising administering a therapeutically effective dosing regimen of a cocrystal that includes a component that inhibits the transcriptional activity of AICD.

[0075] The present invention further relates to a method of preventing, inhibiting, and / or treating a neurodegenerative condition in a human, comprising administering a cocrystal in a therapeutically effective dosing regimen that includes a component capable of modulating microglia.

[0076] The present invention further relates to a method of preventing, inhibiting and / or treating a neurodegenerative condition in a human comprising administering a cocrystal comprising itanapraced in a therapeutically effective dosing regimen. In certain embodiments, the cocrystal comprises itanapraced and a cocrystal former, the cocrystal former being nicotinamide, the stoichiometric ratio of itanapraced to nicotinamide being about 0:8:1.2 to about 1.2:0.8, the cocrystal being approximately 14.63°; 14.90°; 15.56°; 16.71°; expressed in 2θ generated from a Cu source (λ=1.54 Å after Ni filtering). and 39.14° (all ±0.2 degrees 2θ).

[0077] The present invention further relates to a method of preventing, inhibiting, and / or treating inflammation in a human comprising administering a therapeutically effective dosing regimen of a cocrystal that includes a component that inhibits the transcriptional activity of AICD.

[0078] The present invention further relates to a method of preventing, inhibiting, and / or treating inflammation in a human, comprising administering a cocrystal comprising a component capable of modulating microglia in a therapeutically effective dosing regimen.

[0079] The invention further relates to a method of preventing, inhibiting, and / or treating inflammation in a human comprising administering a therapeutically effective dosing regimen of a cocrystal that includes a moiety that binds to APP.

[0080] The present invention further relates to a method of preventing, inhibiting and / or treating inflammation in a human comprising administering a cocrystal comprising itanapraced in a therapeutically effective dosing regimen. In certain embodiments, the cocrystal comprises itanapraced and a cocrystal former, the cocrystal former being nicotinamide, the stoichiometric ratio of itanapraced to nicotinamide being about 0:8:1.2 to about 1.2:0.8, and the cocrystal is expressed in terms of 2θ of about 14.63°; 14.90°; 15.56°; 16.71°; generated from a Cu source (λ=1.54 Å after Ni filtering). and 39.14° (all ±0.2 degrees 2θ).

[0081] The present invention further relates to a method of preventing, inhibiting, and / or treating dementia in a human comprising administering a therapeutically effective dosing regimen of a cocrystal that includes a component that inhibits the transcriptional activity of AICD.

[0082] The present invention further relates to a method of preventing, inhibiting, and / or treating dementia in a human, comprising administering a cocrystal in a therapeutically effective dosing regimen that includes a component capable of modulating microglia.

[0083] The present invention further relates to a method of preventing, inhibiting, and / or treating dementia in a human comprising administering a cocrystal comprising a moiety that binds to APP in a therapeutically effective dosing regimen.

[0084] The present invention further relates to a method of preventing, inhibiting and / or treating dementia in a human comprising administering a co-crystal comprising itanapraced in a therapeutically effective dosing regimen. In certain embodiments, the co-crystal comprises itanapraced and a co-crystal former, the co-crystal former being nicotinamide, the stoichiometric ratio of itanapraced to nicotinamide being about 0:8:1.2 to about 1.2:0.8, the co-crystal exhibiting a 2θ of about 14.63°; 14.90°; 15.56°; 16.71°; generated from a Cu source (λ=1.54 Å after Ni filtering). and 39.14° (all ±0.2 degrees 2θ).

[0085] The present invention further relates to a method of preventing, inhibiting, and / or treating neurological injury (e.g., TBI) in a human, comprising administering a therapeutically effective dosing regimen of a cocrystal that includes a component that inhibits the transcriptional activity of AICD.

[0086] The present invention further relates to a method of preventing, inhibiting, and / or treating neuronal damage in a human, comprising administering a cocrystal comprising a component capable of modulating microglia in a therapeutically effective dosing regimen.

[0087] The invention further relates to a method of preventing, inhibiting, and / or treating neuronal damage in a human comprising administering a therapeutically effective dosing regimen of a cocrystal that includes a moiety that binds to APP.

[0088] The present invention further relates to a method of preventing, inhibiting and / or treating neuronal damage in a human comprising administering a cocrystal comprising itanapraced in a therapeutically effective dosing regimen. In certain embodiments, the cocrystal comprises itanapraced and a cocrystal former, the cocrystal former being nicotinamide, the stoichiometric ratio of itanapraced to nicotinamide being about 0:8:1.2 to about 1.2:0.8, and the cocrystal is expressed in terms of 2θ of about 14.63°; 14.90°; 15.56°; 16.71°; generated from a Cu source (λ=1.54 Å after Ni filtering). and 39.14° (all ±0.2 degrees 2θ).

[0089] The present invention is particularly directed to a method of treating a neurodegenerative condition in a human comprising administering a therapeutically effective dosing regimen of a co-crystal, the co-crystal comprising itanapraced and a co-crystal former, the co-crystal former being nicotinamide, the stoichiometric ratio of itanapraced to nicotinamide being about 0:8:1.2 to about 1.2:0.8, the co-crystal being generated from a Cu source (λ=1.54 Å after Ni filtering) at a 2θ of about 14.63°; and 39.14° (all ±0.2 degrees 2θ), comprising an X-ray powder diffraction pattern (XRPD) having specific peaks at: .90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (all ±0.2 degrees 2θ). The neurodegenerative condition may be selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, juvenile neuronal ceroid lipofuscinosis, age-related macular degeneration, dementia, neuroinfection, neuronal injury, tauopathy, Pick's disease, progressive supranuclear palsy, hypoxic encephalopathy, and neuroinflammation.

[0090] Thus, in certain embodiments, the present invention provides a method of treating Parkinson's disease comprising administering a therapeutically effective dosing regimen of a co-crystal, wherein the co-crystal comprises itanapraced and a co-crystal former, the co-crystal former being nicotinamide, the stoichiometric ratio of itanapraced to nicotinamide being about 0:8:1.2 to about 1.2:0.8, and the co-crystal is at a stoichiometric angle of about 14.6 expressed as 2θ generated from a Cu source (λ=1.54 Å after Ni filtering). 3°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (all ±0.2 degrees 2θ).

[0091] The present invention further relates to a method for preventing, inhibiting, and / or treating Acute Respiratory Distress Syndrome (ARDS) induced by the release of cytokines and other toxic molecules from the brain into the bloodstream in humans infected with COVID-19, comprising administering a therapeutically effective dosing regimen of a cocrystal comprising a component that inhibits the transcriptional activity of AICD.

[0092] The present invention further relates to a method for preventing, inhibiting, and / or treating Acute Respiratory Distress Syndrome (ARDS) induced by the release of cytokines and other toxic molecules from the brain into the bloodstream in humans infected with COVID-19, comprising administering a therapeutically effective dosing regimen of a cocrystal comprising a moiety that binds to APP.

[0093] The present invention further relates to a method for preventing, inhibiting, and / or treating Acute Respiratory Distress Syndrome (ARDS) induced by the release of cytokines and other toxic molecules from the brain into the bloodstream in humans infected with COVID-19, comprising administering a cocrystal in a therapeutically effective dosing regimen comprising a component capable of modulating microglia.

[0094] The present invention further relates to a method for preventing, inhibiting, and / or treating Acute Respiratory Distress Syndrome (ARDS) induced by the release of cytokines and other toxic molecules from the brain into the bloodstream in humans infected with COVID-19, comprising administering a cocrystal comprising itanapraced in a therapeutically effective dosing regimen. In certain embodiments, the cocrystal comprises itanapraced and a cocrystal former, the cocrystal former being nicotinamide, the stoichiometric ratio of itanapraced to nicotinamide being about 0:8:1.2 to about 1.2:0.8, the cocrystal exhibiting a 2θ of about 14.63°; 14.90°; 15.56°; 16.71°; generated from a Cu source (λ=1.54 Å after Ni filtering). and 39.14° (all ±0.2 degrees 2θ).

[0095] The present invention further relates to a method of prophylactic treatment for preventing or reducing the risk of neuronal infection with COVID-19 in humans exposed to COVID-19 and / or reducing the severity of COVID-19 disease, comprising administering a therapeutically effective dosing regimen of the cocrystals of the present invention. The method may further comprise co-administering another drug that prevents, inhibits, or treats neuroinfection in human patients with coronaviruses such as COVID-19 by the same or a different mechanism of action.

[0096] The present invention also relates to a method of preventing, inhibiting, and / or treating a neuroinfection caused by a virus in a human, comprising administering a therapeutically effective dosing regimen of a cocrystal comprising a drug that binds to amyloid precursor protein (APP) and inhibits the transcriptional activity of its intracellular domain (AICD) in a human, or modulates microglial function by inhibiting inflammatory cytokine production and promoting phagocytosis, thereby enhancing pathogen clearance, thereby preventing, inhibiting, and / or treating acute respiratory distress syndrome (ARDS) in a human.

[0097] The present invention further relates to the use of a pharmaceutical composition comprising a therapeutically effective amount of a cocrystal of the present invention for preventing, inhibiting, and / or treating neuroinfection in humans with COVID-19.

[0098] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a cocrystal of the present invention for inhibiting neuroinfection in humans with COVID-19.

[0099] The pharmaceutical composition or pharmaceutical formulation used in the method of the present invention can be an oral solid dosage form, such as a tablet or capsule. The pharmaceutical composition can be administered prophylactically to a human, for example, to prevent or inhibit neuroinfection caused by a coronavirus, such as COVID-19.

[0100] The present invention also relates to a method of preventing, inhibiting, and / or treating neurological disorders in a human, comprising administering a therapeutically effective dosing regimen of a cocrystal with a drug that binds to amyloid precursor protein (APP) and / or inhibits the transcriptional activity of its intracellular domain (AICD) in a human.

[0101] In other embodiments, the invention relates to a method of preventing, inhibiting, and / or treating COVID-19 neuroinfection in humans, comprising administering a cocrystal in a therapeutically effective dosing regimen that includes drugs that enhance pathogen clearance by modulating microglial function through inhibition of inflammatory cytokine production and promotion of phagocytosis.

[0102] The present invention also relates to a method of preventing, inhibiting, and / or treating a neuroinfectious disease caused by a virus in a human, comprising administering a therapeutically effective dosing regimen of a cocrystal comprising a drug that binds to the amyloid precursor protein (APP) and inhibits the transcriptional activity of its intracellular domain (AICD) or modulates microglial function by inhibiting inflammatory cytokine production and promoting phagocytosis, thereby enhancing viral (pathogen) clearance, thereby preventing, inhibiting, and / or treating the neuroinfectious disease acute respiratory distress syndrome (ARDS) in a human.

[0103] The present invention further relates to a method of preventing, inhibiting, and / or treating Acute Respiratory Distress Syndrome (ARDS), from which COVID-19 patients often die, comprising administering a therapeutically effective dosing regimen of cocrystals comprising a drug that binds to the amyloid precursor protein (APP) and inhibits the transcriptional activity of its intracellular domain (AICD) or modulates microglial function by inhibiting inflammatory cytokine production and promoting phagocytosis in humans, thereby enhancing pathogen clearance.

[0104] The present invention relates, in part, to a pharmaceutical composition comprising a therapeutically effective amount of a cocrystal with Praced for inhibiting neuroinfection in humans caused by a coronavirus. In certain embodiments, the coronavirus is COVID-19.

[0105] In certain preferred embodiments of the invention, the formulations of the invention are administered prophylactically to a human to prevent or inhibit neuroinfection by a coronavirus, such as COVID-19.

[0106] The invention further relates, in part, to a method of prophylactic treatment for preventing or reducing the risk of a human being infected with COVID-19 and / or reducing the severity of disease due to COVID-19 in a human being exposed to COVID-19, comprising administering a therapeutically effective amount of a cocrystal comprising itanapraced. In certain embodiments, the method further comprises co-administering another drug that prevents, inhibits, or treats infection of a human patient with a coronavirus, such as COVID-19, by the same or a different mechanism of action.

[0107] definition As used herein, each of the following terms has the meaning associated with it in this section.

[0108] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one or more elements.

[0109] The term "about" as used herein means a value within 20% (±20%) of the value immediately following the term "about", including the upper limit (i.e., +20%) and the lower limit (i.e., -20%) of the range. For example, the phrase "about 100" encompasses any number between 80 and 120, inclusive.

[0110] The term "co-crystal" refers to a crystalline material composed of molecules of two or more different compounds, one or more of which is an API, in the same crystal lattice, in a defined stoichiometric ratio, bound by non-ionic and non-covalent bonds.

[0111] The term "co-crystal former" refers to a component that is preferably not a solvent, is usually non-volatile, and includes heterocyclic organic compounds that interact non-ionically with the API in the crystal lattice.

[0112] "Effective amount" or "therapeutically effective amount," used interchangeably herein, means an amount of a compound, formulation, material, or composition described herein effective to achieve a particular biological result, which may include, but is not limited to, the treatment of a disease or condition, as determined by any means suitable in the art.

[0113] The term "polymorphs" refers to different crystalline forms of the same API, as well as amorphous forms of the same API.

[0114] The term "pharmaceutical composition" as used herein refers to a mixture of at least one compound of the present invention with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. Pharmaceutical compositions facilitate the administration of a compound to an organism. There are multiple techniques of administering a compound in the art, including but not limited to oral administration and parenteral (e.g., intravenous) administration.

[0115] "Pharmaceutically acceptable" means properties and / or substances that are acceptable to a patient from a pharmacological / toxicological standpoint and acceptable to a manufacturing pharmaceutical chemist from a physical / chemical standpoint with respect to composition, formulation, stability, patient acceptability, and bioavailability.

[0116] As used herein, the term "treat" or "treatment" includes, but is not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable; reduction in the severity of a disease, disorder, or condition; a stable (i.e., not worsening) status of a disease, disorder, or condition; prevention of the spread of a disease, disorder, or condition (e.g., delaying or slowing the progression of a disease, disorder, or condition); improvement or palliation of a disease, disorder, or condition; and remission (whether partial or complete).

[0117] By "alleviating" a disease, disorder, or condition, it is meant that the severity and / or undesirable clinical symptoms of the disease, disorder, or condition are reduced and / or the time course of progression is slowed or prolonged compared to the severity and time course in the absence of treatment.

[0118] As used herein, "preventing" includes preventing the onset of a disease and / or reducing the severity or intensity of a disease.

[0119] As used herein, "alleviate" is used interchangeably with the term "treat." Treating a disease, disorder, or condition may or may not include the complete eradication or elimination of symptoms.

[0120] The term "salt" refers to compounds obtained by replacing some or all of the acidic hydrogens of an acid by a metal or by a radical which acts like a metal, i.e. ionic or ionically bonded crystalline compounds.

[0121] The term "therapeutic" as used herein means treatment and / or prophylaxis. Throughout this disclosure, various aspects of this invention can be presented in a range format.

[0122] It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, etc., as well as individual numerical values ​​within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0123] The term "substantially identical to the X-ray powder diffraction pattern shown in FIG. 3A" is intended to indicate that the 2-theta angle values ​​of an X-ray powder diffraction pattern may vary slightly (±0.2°) from sample preparation to sample preparation, from machine to machine, from sample to sample, or as a result of slight variations in the sample preparation and measurement conditions utilized, and therefore the peak positions shown in FIG. 3A and listed in the peak list should not be construed as absolute values.

[0124] The abbreviation "CSP-1103" stands for Itanapraced.

[0125] The abbreviation "CHF5074" stands for Itana Praced.

[0126] The abbreviation "NCT" stands for nicotinamide.

[0127] The abbreviation "CSPNCT" means cocrystal of itanapraced and nicotinamide.

[0128] For the purposes of the present invention, the term "non-hygroscopic" means that the weight of a molecule increases or decreases by less than 0.20% w / w at 25° C. and between 5-95% RH (relative humidity).

[0129] For the purposes of the present invention, the term "slightly hygroscopic" means that the weight of a molecule increases or decreases by more than 0.20% w / w but less than 2% w / w at 25°C and between 5 and 95% RH (relative humidity).

[0130] For purposes of the present invention, "neurodegenerative conditions" include Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), juvenile neuronal ceroid lipofuscinosis (JNCL) (Batten disease type 3), age-related macular degeneration (AMD); dementia (e.g., MCI), neuroinfection, neuroinjury (traumatic brain injury (TBI)), and neuroinflammation. "Neurodegenerative conditions" also include tauopathies, particularly amyotrophic lateral sclerosis (ALS), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), as well as hypoxic encephalopathy.

[0131] For purposes of the present invention, "AUC" refers to the area under a plot of plasma concentration of itanapraced (not the logarithm of the concentration) versus time after administration of itanapraced. This area is conveniently determined by the "trapezoidal rule": data points are connected by straight line segments, perpendicular lines are erected from the horizontal axis to each data point, and the sum of the areas of the triangles and trapezoids thus constructed is calculated. The final measured concentration (t n C at the time n ) is not zero, t n The AUC from time to infinity is C n / k el It is estimated by

[0132] AUC is particularly used in estimating the bioavailability of itanapraced and in estimating the total clearance (ClT) of itanapraced. After a single intravenous dose, for a single compartment system following first-order elimination kinetics, AUC=D / ClT; alternatively, AUC=C0 / k el For routes other than intravenous, AUC = F D / ClT for these systems, where F is the availability of itanapraced.

[0133] For the purposes of the present invention, "dose response" refers to the quantitative relationship between the magnitude of response and the dose that induces the response, which can be measured by conventional means known in the art. The curve relating the effect (as the dependent variable) vs. dose (as the independent variable) in the itanapraced-cell system is the "dose response curve". Usually, the dose response curve is a measurement of the response to itanapraced plotted against the dose (mg / kg) of itanapraced administered. The dose response curve can also be a curve of AUC vs. the dose of itanapraced administered. [Brief description of the drawings]

[0134] [Figure 1-1] 1 is a graph showing the XRPD of CSP-1103. [Figure 1-2] 1 shows micrographs of CSP-1103 at various magnifications. [Figure 1-3] 1 shows micrographs of CSP-1103 at various magnifications. [Diagram 2] 1 is a micrograph of CSPNCT needle-like crystals along the NCT. [Figure 3-1] 1 is a graph showing the XRPD of CSPNCT. [Figure 3-2] 1 is a graph showing a comparison of XRPD of CSPNCT (top), CSP-1103 (bottom), and NCT (middle). [Figure 4] FIG. 1 shows a unit cell of CSPNCT with four NCT and four CSP molecules. [Diagram 5] FIG. 1 is a graph showing DVS kinetic plot of CSPNCT (5-95% RH, 25° C.). [Figure 6] 1 is a graph showing a DVS isothermal plot of CSPNCT (5-95% RH, 25° C.). [Figure 7] FIG. 13 shows XRPD (5-95% RH, 25° C.) of DVS samples before (second from top) and after (top) exposure to CSPNCT. [Figure 8-1]1 shows the water vapor sorption and desorption isotherms for CSP, CSPNCT, and NCT, respectively. All isotherms are on the same scale for percent weight change (y-axis) and percent relative humidity (x-axis) for comparison purposes. [Figure 8-2] 1 shows the water vapor sorption and desorption isotherms for CSP, CSPNCT, and NCT, respectively. All isotherms are on the same scale for percent weight change (y-axis) and percent relative humidity (x-axis) for comparison purposes. [Figure 8-3] 1 shows the water vapor sorption and desorption isotherms for CSP, CSPNCT, and NCT, respectively. All isotherms are on the same scale for percent weight change (y-axis) and percent relative humidity (x-axis) for comparison purposes. [Figure 9-1] 13A-13C are micrographs of CSPNCT at various magnifications. [Figure 9-2] 13A-13C are micrographs of CSPNCT at various magnifications. [Figure 9-3] 13A-13C are micrographs of CSPNCT at various magnifications. [Figure 9-4] 13A-13C are micrographs of CSPNCT at various magnifications. [Figure 10] 1 shows a model for dysregulated response to oxidative stress. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0135] A component in the cocrystal of the present invention can be itanapraced, a first-in-class, orally active small molecule compound being developed by applicant CereSpir under a license agreement with Chiesi for the treatment of mild cognitive impairment, i.e., prevention of disease progression in patients at risk of developing Alzheimer's Disease (AD).

[0136] Itanapraced Itanapraced, 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (also known as CSP-1103, formerly CHF 5074), belongs to a novel class of drug compounds ("praceds") that bind to the amyloid precursor protein (APP) and inhibit the transcriptional activity of its intracellular domain (AICD). Itanapraced can also modulate microglia.

[0137] The chemical structure of itanapraced is:

[0138] [ka]

[0139] Itanapraced is an orally available, brain-penetrant small molecule that has been tested in over 200 subjects in several Phase 1 and one Phase 2 trial for mild cognitive impairment (MCI) with favorable results ( Ross, 2013 ).

[0140] In addition to a good safety and tolerability profile, itanapraced produced dose-correlated beneficial differences in CSF levels of two key neuroinflammatory mediators, TNF-α and soluble CD40L, and total tau levels, a recognized marker of neurodegeneration, and patients showed cognitive stability throughout the study period.

[0141] Itanapraced has also been reported to exhibit numerous beneficial effects in transgenic mouse models of Alzheimer's disease (Imbimbo, 2007, 2009; Lanzillotta 2011), a rat model of traumatic brain injury (Lin et al., 2017), as well as mouse models of Parkinson's disease (manuscript submitted) and juvenile Batten disease (unpublished).

[0142] Itanapraced therefore appears to be effective in a wide range of disease indications that point to a common mechanism linked by oxidative stress and neuroinflammation. Potential mechanisms are shown in FIG.

[0143] Of particular importance is the finding that itanapraced prevented the accumulation of hypertrophic microglia in the injured brain and attenuated both neuronal injury and acute lung injury in rats following TBI (Li 2017).

[0144] Itanapraced may potentially be used to prevent, inhibit, or treat CNS infection and neuronal damage in humans following peripheral COVID-19 infection, which may also mitigate lung injury and loss of function.

[0145] Itanapraced is being investigated by the applicant for several disease indications including Parkinson's disease, early-onset Batten disease, and mild cognitive impairment. It is a small molecule that exhibits good oral bioavailability, a long plasma half-life, and substantial brain penetration.

[0146] In a Phase 2 study (double-blind for 3 months; open-label thereafter) in patients with mild cognitive impairment (MCI) treated for up to 2 years, itanapraced was found to be well tolerated and to produce dose-related and statistically significant reductions in the brain of two key neuroinflammatory mediators, soluble CD40 ligand and TNF-α, as well as total tau, a recognized marker of neurodegeneration. Furthermore, patients showed stabilization of cognitive function throughout the long duration of the study.

[0147] With itanapraced, Applicants have the most advanced compound targeting LRRK-mediated neurotoxicity with significant clinical trial experience involving over 200 human subjects.

[0148] Nicotinamide Nicotinamide (NCT) is a form of vitamin B3. It is a water-soluble vitamin. Nicotinamide has the following structure:

[0149] [ka]

[0150] Nicotinamide is a precursor to (NAD)(+), which means that cells can use chemical reactions to convert nicotinamide into (NAD)(+), a critical component of the chemical reactions mitochondria use to generate energy.

[0151] Nicotinamide is found in foods and is used as a dietary supplement and drug. As a supplement, it can be used orally to prevent and treat pellagra (niacin deficiency). Nicotinic acid (niacin) may also be used for this purpose, but nicotinamide has the advantage of not causing skin flushing. As a cream, nicotinamide can be used to treat acne.

[0152] Nicotinamide can be used as a co-crystal former to form the co-crystals of the present invention. Depending on the embodiment and dosage, it may or may not exhibit biological activity in the co-crystals of the present invention.

[0153] In the cytoplasm of mammalian cells, AICD physically interacts with the transcription factor forkhead box O (FoxO), a critical downstream mediator of APP-induced cell death and impaired locomotion; it also translocates into the nucleus together with FoxO upon oxidative stress.

[0154] Under conditions of acute oxidative stress, the transcriptional activity of AICD can cause cellular damage by interacting with FOXO3a, a critical component of the mechanism of the physiological response to oxidative stress.

[0155] Thus, APP may regulate FoxO-mediated cell death through AICD, which acts as a transcriptional coactivator of FoxO.

[0156] Furthermore, in neurons, astrocytes, and microglia, APP can exhibit proinflammatory functions.

[0157] Itanapraced can bind to amyloid precursor protein (APP) and inhibit the transcriptional activity of its intracellular domain (AICD). Itanapraced can also regulate microglia. Itanapraced can also inhibit inflammation. In some of these embodiments, nicotinamide can enhance the therapeutic activity of itanapraced.

[0158] The cocrystals of the present invention can include itanapraced and nicotinamide and can therefore be used in the treatment of neurodegenerative disorders, infections, dementia, inflammation, and injury.

[0159] Dosage Cocrystals of the present disclosure can be administered to a human subject at a dose of about 3 mg / day to about 3000 mg / day, about 4 mg / day to about 2500 mg / day, about 5 mg / day to about 2000 mg / day, about 10 mg / day to about 1500 mg / day, 10 mg / day to about 1000 mg / day, about 50 mg / day to about 600 mg / day, about 50 mg / day to about 500 mg / day, about 50 mg / day to about 400 mg / day, 50 mg / day to about 300 mg / day, or about 100 mg / day to about 30 mg / day.

[0160] The formulations of the invention may contain from about 3 mg to about 3500 mg of a cocrystal (e.g., a cocrystal containing itanapraced and nicotinamide), which corresponds to more than one daily administration. Thus, the formulations of the invention can be administered anywhere from 1 to 4 times daily to provide a total daily dose.

[0161] Administration The formulations of the present invention can be administered by any pharma- ceutically effective route. For example, cocrystals can be formulated to be administered orally, intranasally, rectally, vaginally, sublingually, buccally, parenterally, or transdermally, and can be formulated accordingly. Cocrystals can be administered in liquid, tablet, parenteral, rectal, transdermal, or any other dosage form suitable for achieving a therapeutic effect. These formulations can contain additional fillers, carriers, excipients, or excipients, inert or not, known to those skilled in the art of pharmaceutical preparations, to achieve the appropriate volume and / or to facilitate absorption of the active drug.

[0162] Various embodiments of the present invention include, but are not limited to, the following examples: all possible combinations and permutations of cocrystals. In certain embodiments, the cocrystals are administered together or separately but simultaneously with additional drugs that may act by the same or different mechanisms to prevent, inhibit, or treat infections caused by neurodegenerative disorders. Another embodiment of the present invention includes multiple different forms of combinations of pharmaceutical dosage forms of each drug in one dosage form, as further outlined below. Another embodiment of the present invention includes various preparation forms, including the use of solid, liquid, immediate release, delayed release, or extended release forms. As known to those skilled in the art, there can be many types of different forms. Another embodiment of the present invention includes multiple routes of administration (intravenous, oral, transdermal, etc.), which may vary from patient to patient depending on preferences, comorbidities, side effect profiles, and other factors. Another embodiment of the invention includes the presence in the formulation of other materials known to one of skill in the art, such as fillers, carriers, gels, skin patches, lozenges, or other modifiers, with the cocrystal containing the active drug to facilitate absorption through various routes (e.g., gastrointestinal, transdermal, etc.) and / or to prolong the effect of the drug and / or to increase or further stabilize the serum levels of the active drug in the combination or to enhance the therapeutic effect of the active drug.

[0163] Dosage form In certain embodiments, the cocrystals of the present invention may be formulated as pharma- ceutically acceptable oral dosage forms. Oral dosage forms may include, but are not limited to, oral solid dosage forms and oral liquid dosage forms. Oral solid dosage forms may include, but are not limited to, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combination thereof. These oral solid dosage forms may be formulated as immediate release, controlled release, sustained (extended) release, or modified release formulations.

[0164] The oral solid dosage forms of the present invention may also include pharma- ceutically acceptable excipients, such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersants, suspending agents, disintegrants, viscosity enhancers, film-forming agents, granulation enhancers, flavorings, sweeteners, coating agents, solubilizers, and combinations thereof. Each of these excipients may comprise, for example, about 0.1% to about 99.9%, about 0.5% to about 95%, about 1% to about 95%, about 2% to about 95%, about 3% to about 95%, or about 5% to about 95% by weight of the formulation.

[0165] The solid dosage form comprises itanapraced and a co-crystal former, where the co-crystal former is nicotinamide and the co-crystals are generated from a Cu source (λ=1.54 Å after Ni filtering) with 2θ values ​​of approximately 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24. The cocrystal may comprise an X-ray powder diffraction pattern (XRPD) having specific peaks at: 17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (all ±0.2 degrees 2θ); and (ii) a pharma- ceutical composition comprising a pharma- ceutical acceptable excipient.

[0166] In some embodiments, the solid dosage forms of the present invention can be in the form of a tablet (including suspension tablets, fast dissolving tablets, chewable disintegrating tablets, fast disintegrating tablets, effervescent tablets, or caplets), a pill, a powder (including sterile packaged powders, dispersible powders, or effervescent powders), a capsule (including both soft or hard capsules, such as capsules made of animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), a solid dispersion, a solid solution, a bioerodible dosage form, a controlled release formulation, a pulsed release dosage form, a multiparticulate dosage form, a pellet, a granule, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet, including, but not limited to, a fast dissolving tablet. Furthermore, the pharmaceutical formulation of the present invention can be administered as a capsule or in the form of multiple capsules. In some embodiments, the pharmaceutical formulation is administered as two, or three, or four capsules or tablets.

[0167] The solid pharmaceutical dosage forms described herein may include the cocrystals of the present invention as API and one or more pharma- ceutically acceptable excipients, such as compatible carriers, binders, complexing agents, ionic dispersion modifiers, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or a combination of one or more thereof. In yet another aspect, a film coating is applied around the active agent formulation of the present invention using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, some or all of the particles of the active agent of the present invention are coated. In another embodiment, some or all of the particles of the active agent of the present invention are microencapsulated. In yet another embodiment, some or all of the active agent of the present invention is an amorphous material that is coated and / or microencapsulated with inert excipients, hi yet another embodiment, the particles of the active agent of the present invention are not microencapsulated and are uncoated.

[0168] Carriers suitable for use in the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0169] Fillers suitable for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose (e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, etc.), cellulose powder, glucose, dextrates, glucose, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0170] Where necessary, suitable disintegrants for use in the solid dosage forms described herein include natural starches, such as corn starch or potato starch, pregelatinized starches, such as National 1551 or Amijel®, or sodium starch glycolate, such as Promogel® or Explotab®, cellulose, such as wood products, microcrystalline cellulose, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable surfactants include, but are not limited to, Tia®, and Solka-Floc®, Ac-Di-Sol, methylcellulose, croscarmellose, or crosslinked celluloses such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or alginates such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, carob, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combined starches, and the like.

[0171] Binders impart cohesiveness to the solid oral dosage formulation. In powder-filled capsule formulations, binders facilitate the formation of a plug that can be filled into soft or hard shell capsules, and in tablet formulations, binders help ensure that the tablet remains intact after compression and ensure blend uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603, Hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g. Klucel®), ethylcellulose (e.g. Ethocel®), and microcrystalline cellulose (e.g. Avicel®), crystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymers, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars such as sucrose (e.g. Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g. Xylitab®), lactose, natural or synthetic gums such as arabic. Examples of binders that may be used include, but are not limited to, gum tragacanth, gum ghatti, mucilage of isagol husk, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabinogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like. Generally, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. The level of binder use in tablet formulations is a function of whether it is direct compression, wet granulation, roller compaction, or the use of other excipients such as fillers that may themselves act as moderate binders.A formulator skilled in the art can determine the binder level for a formulation, however binder usage levels up to 70% are common in tablet formulations.

[0172] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal salts and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.

[0173] Diluents suitable for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and glucose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0174] Non-water soluble diluents such as calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline and microcellulose (e.g., those having a density of about 0.45 g / cm3, e.g., Avicel, powdered cellulose), and talc are compounds commonly used in pharmaceutical formulations.

[0175] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, etc. Wetting agents include surfactants.

[0176] Suitable surfactants for use in the solid dosage forms described herein include, for example, docusate and its pharma- ceutically acceptable salts, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and the like.

[0177] Suspending agents suitable for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., polyethylene glycol which may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 18000, vinylpyrrolidone / vinyl acetate copolymer (S630), sodium alginate, gums such as gum tragacanth and gum arabic, guar gum, xanthan including xanthan gum, sugars, cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate 80, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0178] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium ascorbate, vitamin E TPGS, ascorbic acid, sorbic acid, and tocopherol.

[0179] Immediate release formulations can be prepared by combining superdisintegrants such as croscarmellose sodium with various grades of microcrystalline cellulose in various ratios. Sodium starch glycolate is added to facilitate disintegration.

[0180] If two (or more) drugs included in the fixed dose combinations of the present invention are incompatible, cross-contamination can be avoided, for example, by incorporating the drugs into different drug layers in the oral dosage form, such that a barrier layer comprising one or more inactive / non-functional materials is included between the different drug layers.

[0181] The additives listed above should be considered merely as examples, not limitations, of the types of additives that may be included in the solid dosage forms of the present invention, the amounts of which can be readily determined by one of skill in the art depending on the particular properties desired.

[0182] Oral liquid dosage forms include, but are not limited to, solutions, emulsions, suspensions, and syrups.These oral liquid dosage forms can be formulated with any pharma- ceutically acceptable excipients known to those skilled in the art for the preparation of liquid dosage forms.For example, water, glycerin, simple syrup, alcohol, and combinations thereof.

[0183] Liquid dosage forms for oral administration may be in the form of pharma- ceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain inert diluents such as water. Pharmaceutical preparations and medicaments may be prepared as liquid suspensions or solutions using sterile liquids, such as, but not limited to, oil, water, alcohol, and the like, and combinations of these pharma- ceutically suitable surfactants, suspending agents, and emulsifying agents may be added for oral or parenteral administration. Suspensions may contain oils. These oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suspensions may contain fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension preparations may contain alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol. Ethers, such as, but not limited to, poly(ethylene glycol); petroleum hydrocarbons, such as mineral oil and petrolatum; and water may be used in suspension preparations.

[0184] In some embodiments, a formulation for oral administration to a subject is provided, comprising particles of the cocrystal of the present invention as described herein and at least one dispersing or suspending agent. The formulation can be a powder and / or granules for suspension, which when mixed with water, results in a substantially uniform suspension. As described herein, the aqueous dispersion can comprise amorphous and non-amorphous particles of the active agent of the present invention of multiple effective particle sizes, such that particles of the active agent of the present invention having a relatively small effective particle size are absorbed relatively quickly, and particles of the active agent of the present invention having a relatively large effective particle size are absorbed relatively slowly. In certain embodiments, the aqueous dispersion or suspension is an immediate release formulation. In another embodiment, the aqueous dispersion comprising amorphous particles of the active agent of the present invention is formulated such that a portion of the particles of the active agent of the present invention are absorbed, for example, within about 3 hours after administration, and about 90% of the particles of the active agent of the present invention are absorbed, for example, within about 10 hours after administration. In other embodiments, the addition of a complexing agent to the aqueous dispersion extends the drug absorption phase of the particles, such that 50-80% of the particles containing the active agent of the present invention are absorbed within the first 3 hours, and about 90% are absorbed by about 10 hours. The dosage form for oral administration can be an aqueous suspension selected from the group including, but not limited to, pharma-ceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). The liquid dosage form can include, in addition to particles of the active agent of the present invention, additives such as (a) a disintegrant; (b) a dispersant; (c) a wetting agent; (d) at least one preservative; (e) a viscosity enhancer; (f) at least one sweetener; and (g) at least one flavoring agent.

[0185] Examples of disintegrants for use in aqueous suspensions and dispersions include starches, such as natural starches, for example corn starch or potato starch, pregelatinized starches, for example National 1551 or Amijel®, or sodium starch glycolate, for example Promogel® or Explotab®; cellulose, for example wood products, microcrystalline cellulose, for example Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable surfactants include, but are not limited to, Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose; crosslinked starches, such as sodium starch glycolate; crosslinked polymers, such as crospovidone; crosslinked polyvinylpyrrolidone; alginates, such as alginic acid, or alginates such as sodium alginate; clays, such as Veegum® HV (magnesium aluminum silicate); gums, such as agar, guar, carob, karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; natural sponges; surfactants; resins, such as cation exchange resins; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combined starches; and the like.

[0186] In some embodiments, dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersing agents, such as hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K200). K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymers (Plasdone®, e.g., S-630), polymers of 4-(1,1,3,3-tetramethylbutyl)-phenol with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, (BASF Corporation, Parsippany, NJ), which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine).In other embodiments, the dispersing agent is selected from the group that does not include one of the following agents: hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); sodium carboxymethylcellulose; methylcellulose; hydroxyethylcellulose; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate stearate; amorphous cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); polymers of 4-(1,1,3,3-tetramethylbutyl)-phenol with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics, which are block copolymers of ethylene oxide and propylene oxide). F68®, F88®, and F108®); or poloxamine (e.g. Tetronic 908®, also known as Poloxamine 908®).

[0187] Wetting agents (including surfactants) suitable for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, acetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Tweens, such as Tween 20 and Tween 80 (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowax 3350 and 1450, and Carpool 934 (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphatidylcholine, and the like.

[0188] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben) and their salts, benzoic acid and its salts, other para-hydroxybenzoic acid esters, such as butylparaben, alcohols, such as ethyl alcohol or benzyl alcohol, phenolic compounds, such as phenol, or quaternary compounds, such as benzalkonium chloride. The preservatives used herein are incorporated into the dosage form in a concentration sufficient to inhibit microbial growth.

[0189] In one embodiment, the aqueous liquid dispersion may contain methylparaben and propylparaben at concentrations ranging from about 0.01% to about 0.3% by weight of methylparaben relative to the weight of the aqueous dispersion, and from about 0.005% to about 0.03% by weight of propylparaben relative to the total weight of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion may contain from about 0.05 to about 0.1% by weight of methylparaben and from about 0.01 to about 0.02% by weight of propylparaben relative to the total weight of the aqueous dispersion.

[0190] Suitable viscosity enhancers for the aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Plasdone® S-630, carbomer, polyvinyl alcohol, alginates, gum arabic, chitosan, and combinations thereof. The concentration of the viscosity enhancer depends on the agent selected and the viscosity desired.

[0191] Liquid formulations of the active agents of the present invention may contain, in addition to the additives listed above, inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, emulsifying agents, and / or sweeteners.

[0192] Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders that are reconstituted into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, Cremophor, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters, such as ethyl oleate. In addition, the active agent of the present invention can be dissolved at a concentration of more than 1 mg / ml using water-soluble beta-cyclodextrins (e.g., beta-sulfobutyl-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin). Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations of the active agent of the present invention suitable for subcutaneous injection may also include additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, such as parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, sorbic acid, and the like. It may be desirable to include isotonicity agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the drug from injectable pharmaceutical forms can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin. Suspension formulations of the active agent of the present invention designed for extended release by subcutaneous or intramuscular injection can avoid first-pass metabolism and can reduce the dosage of the active agent of the present invention required to maintain a plasma level of about 50 ng / ml. In these formulations, the particle size of the active agent of the present invention and the range of particle sizes of the active agent of the present invention can be used to control the release of the drug by controlling the dissolution rate in fat or muscle.

[0193] In yet another embodiment, effervescent powders can be prepared that contain at least one cocrystal of the present invention. Effervescent salts have been used to disperse pharmaceuticals in water for oral administration. Effervescent salts are granules or coarse powders that contain pharmaceutical agents in a dry mixture that is usually composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salts of the present invention are added to water, the acid and base react to liberate carbon dioxide gas, thereby causing "effervescence." Examples of effervescent salts include, for example, sodium bicarbonate, or a mixture of sodium bicarbonate with sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate with citric and tartaric acids, as long as these components are suitable for pharmaceutical use and produce a pH of about 6.0 or higher.

[0194] In other embodiments, a powder containing the formulation of the cocrystal of the present invention described herein can be formulated to include one or more pharmaceutical excipients and flavorings. The powder can be prepared, for example, by mixing the formulation of the active agent of the present invention with optional pharmaceutical excipients to form a bulk blend composition. Further embodiments also include a suspending agent and / or a wetting agent. The bulk blend is uniformly subdivided into unit dose packages or multi-dose package units. The term "uniform" means that the homogeneity of the bulk blend is substantially maintained during the packaging process.

[0195] In certain embodiments of the invention, the pharmaceutical composition can be formulated into a dosage form suitable for parenteral use, for example, the dosage form can be a lyophilized powder, a solution, a suspension (e.g., a depot suspension).

[0196] In other embodiments, the pharmaceutical compositions may be formulated into topical dosage forms such as, but not limited to, patches, gels, pastes, creams, emulsions, liniments, balms, lotions, and ointments.

[0197] The tablet of the present invention described herein can be prepared by methods well known in the art.Various methods for preparing immediate release dosage forms, modified release dosage forms, controlled release dosage forms, and extended release dosage forms (such as matrix tablets, tablets with one or more modified release layers, controlled release layers, or extended release layers, etc.) and the media contained therein are well known in the art.Generally recognized overviews of methods include Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro, Editor, 20th Edition, Lippincott Williams & Wilkins, Philadelphia, PA; Sheth et al. (1980) Compressed tablets, in Pharmaceutical dosage forms, Vol 1, edited by Lieberman and Lachtman, Dekker, NY.

[0198] In certain embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of the active agent of the present invention with one or more pharmaceutical excipients to form a bulk blend composition.When these bulk blend compositions are called homogeneous, it means that particles of the active agent of the present invention are uniformly distributed throughout the composition, and therefore the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.In addition, each unit dosage form can include a film coating that disintegrates when taken orally or when contacted with a diluent.These formulations of the active agent of the present invention can be manufactured by conventional pharmaceutical techniques.

[0199] Conventional pharmaceutical techniques for preparing solid dosage forms include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) melting. See, for example, Lachman et al., Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tabletting, extrusion, and the like.

[0200] Compressed tablets are solid dosage forms prepared by compressing a bulk blend of the active agent formulation of the present invention described above. In various embodiments, compressed tablets designed to dissolve in the mouth include one or more flavorings. In other embodiments, compressed tablets include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of the active agent formulation of the present invention. In other embodiments, the film coating promotes patient compliance (e.g., Opadry® coating or sugar coating). Typically, film coatings including Opadry® range from about 1% to about 3% of the tablet weight. Typically, film coatings for delayed release comprise 2-6% of the tablet weight, or 7-15% of the weight of spray-layered beads. In other embodiments, compressed tablets include one or more excipients.

[0201] Capsules can be prepared, for example, by placing a bulk blend of the formulation of the cocrystal of the present invention described above into a capsule. In some embodiments, the cocrystal is placed in a soft gelatin capsule. In other embodiments, the cocrystal is placed in a standard gelatin capsule or a non-gelatin capsule, such as a capsule containing HPMC. In other embodiments, the formulation of the cocrystal of the present invention is placed in a sprinkle capsule, which may be swallowed whole or opened and the contents sprinkled on food before a meal. In some embodiments of the present invention, the therapeutic dose is divided into multiple (e.g., 2, 3, or 4) capsules. In some embodiments, the entire dose of the formulation of the active agent of the present invention is delivered in the form of a single capsule. For example, the capsule may contain between about 100 mg and about 1000 mg of the active agent of the present invention.

[0202] In a particular preferred embodiment, the formulation of the present invention is a fixed dose combination of cocrystals containing itanapraced and at least one drug capable of preventing, inhibiting or treating coronavirus infection in humans by a similar or different mechanism to the praced drug.The fixed dose combination formulation may include, but is not limited to, the following combinations in the form of a monolithic or multi-layered monolithic tablet, or in the form of a tablet in a core tablet or a multi-layered multi-disc tablet, or in the form of a capsule in a bead or a capsule in a tablet:(a) a therapeutically effective fixed dose combination of an immediate release formulation;(b) a therapeutically effective fixed dose combination of an immediate release drug and an extended release drug in one dosage form;(c) a therapeutically effective fixed dose combination of an extended release formulation of a drug.

[0203] The pharmaceutical compositions described herein can be formulated into any suitable dosage form, including, but not limited to, aqueous oral dispersions, aqueous oral suspensions, solid dosage forms including oral solid dosage forms, aerosols, controlled release formulations, fast dissolving formulations, effervescent formulations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized formulations, tablets, capsules, pills, powders, delayed release formulations, immediate release formulations, modified release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and combined immediate and controlled release formulations. In some embodiments, formulations of the cocrystals of the invention deliver a therapeutically effective amount of an active agent of the invention over an interval of about 30 minutes to about 24 hours after administration, allowing for administration, for example, four times a day (QID), three times a day (tid), twice a day (bid), or once a day (qd). The dosage form comprises a cocrystal and a controlled release agent mixed with and / or coating the cocrystal in an amount sufficient to achieve the desired in vitro release profile and to render the dosage form suitable for administration, for example, four times a day, three times a day, twice a day, or once a day. In one embodiment, the cocrystal is formulated into a controlled release or pulsatile solid dosage form for twice daily administration. In another embodiment, the cocrystal of the invention is dispersed in an aqueous dispersion for twice daily administration. Generally speaking, one will desire to administer the cocrystal of the invention in an amount effective to achieve plasma levels commensurate with concentrations found to be effective in vivo for a period of time effective to elicit the desired therapeutic effect.

[0204] Depending on the desired release profile, the oral solid dosage form of the present invention may include a suitable amount of a controlled release agent, an extended release agent, and / or a modified release agent (e.g., a delayed release agent). Furthermore, the pharmaceutical solid oral dosage form comprising the active agent of the present invention described herein may be formulated to achieve a modified or controlled release of the active agent of the present invention. In some embodiments, the solid dosage form described herein may be formulated as a delayed release dosage form, for example as an enteric-coated delayed release oral dosage form, i.e., as an oral dosage form of the pharmaceutical composition described herein that utilizes an enteric coating to affect release in the small intestine of the gastrointestinal tract. The enteric-coated dosage form may be a compressed or molded or extruded tablet / form (coated or uncoated) that includes granules, powders, pellets, beads, or particles of the active ingredient and / or other composition ingredients, which may themselves be coated or uncoated. The enteric-coated oral dosage form may also be a capsule (coated or uncoated) that includes pellets, beads, or granules of the solid carrier or composition, which may itself be coated or uncoated. Enteric coatings may also be used to prepare other controlled release dosage forms, including extended release and pulsatile release dosage forms.

[0205] In other embodiments, the active agent of the formulation described herein is delivered using a pulsatile dosage form.The pulsatile dosage form comprising the formulation of the active agent of the present invention described herein can be administered using various formulations known in the art.For example, these formulations include, but are not limited to, those described in U.S. Patent Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329, all of which are specifically incorporated by reference.Other dosage forms suitable for use in the formulation of the active agent of the present invention are described, for example, in U.S. Patent Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441, and 5,837,284, all of which are specifically incorporated by reference. In one embodiment, the controlled release dosage form is a pulsatile release solid oral dosage form comprising at least two particle populations, both of which comprise an active agent of the present invention as described herein. The first particle population provides a substantially immediate administration of the active agent of the present invention upon ingestion by a subject. The first particle population may be uncoated or may comprise a coating and / or sealant. The second particle population comprises a mixture of coated particles, which may comprise about 2% to about 75% by weight, preferably about 2.5% to about 70% by weight, or about 40% to about 70% by weight of the total amount of the active agent of the present invention in the formulation, and one or more binders.

[0206] A coating to provide controlled, delayed, or extended release can be applied to the drug or to a core containing the drug. The coating can include a pharma- ceutically acceptable component in an amount sufficient to provide a delay, for example, from about 2 hours to about 7 hours after ingestion, before the release of the second dose. Suitable coatings include one or more differentially degradable coatings, such as, by way of example only, pH-sensitive coatings (enteric coatings), such as acrylic resins (e.g. Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, and Eudragit® NE30D, Eudragit® NE 40D®), used alone or blended with cellulose derivatives, such as ethylcellulose, or non-enteric coatings having a variable thickness to achieve differential release of the active agent formulation of the present invention.

[0207] Many other types of controlled release / delayed release / extended release systems known to those skilled in the art are suitable for use in the formulation of the active agent of the present invention described herein.Examples of these delivery systems include, for example, polymer-based systems, such as polylactic acid and polyglycolic acid, polyanhydrides, and polycaprolactone, cellulose derivatives (e.g. ethylcellulose), porous matrices; non-polymer-based systems, such as lipids, including sterols such as cholesterol, cholesterol esters, and fatty acids, or neutral fats such as monoglycerides, diglycerides, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders, etc. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, all of which are specifically incorporated by reference. In certain embodiments, the controlled release system may include controlled / delayed / extended release materials incorporated into the matrix along with the drug, while in other formulations, the controlled release materials may be applied to the core containing the drug. In certain embodiments, one drug may be incorporated into the core while the other drug is incorporated into the coating. In some embodiments, materials include shellac, acrylic polymers, cellulose derivatives, polyvinyl acetate phthalate, and mixtures thereof.In other embodiments, the materials include Eudragit® series E, L, RL, RS, NE, L, L300, S, 100-55, cellulose acetate phthalate, Aquateric, cellulose acetate trimellitate, ethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, and Cotteric. Controlled / delayed / extended release systems may utilize hydrophilic polymers, including but not limited to water-swellable polymers (e.g., natural or synthetic rubbers). The hydrophilic polymer may be any pharma- ceutically acceptable polymer that swells and expands in the presence of water to slowly release the active agent of the present invention. These polymers include polyethylene oxide, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like.

[0208] The performance of acrylic polymers (mainly solubility in biological fluids) may vary depending on the degree and type of substitution. Examples of suitable acrylic polymers that can be used in matrix formulations or coatings include methacrylic acid copolymers and ammonia methacrylate copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available as solutions in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable and are primarily used for colon targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach and dissolve in the intestine. Opadry Enteric is also insoluble in the stomach and dissolves in the intestine.

[0209] Examples of cellulose derivatives suitable for use in matrix formulations or coatings include ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. Performance may vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH above 6. Aquateric (FMC) is a water-based system and is a spray-dried CAP pseudolatex with particles above 1 μm. Other components in Aquateric may include Pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g. AQOAT (Shin Etsu)). Performance may vary depending on the degree and type of substitution. For example, HPMCP, such as HP-50, HP-55, HP-55S, HP-55F grades, are suitable. Performance may vary depending on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are provided as granules or as fine powders for aqueous dispersion. Other suitable cellulose derivatives include hydroxypropyl methylcellulose.

[0210] In some embodiments, the coating may include a plasticizer, and optionally other coating excipients known in the art, such as colorants, talc, and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers typically contain 10-25% by weight of a plasticizer, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques, such as spray coating or pan coating, are used to apply the coating. The thickness of the coating must be sufficient to ensure that the oral dosage form remains intact until the desired local delivery site in the intestinal tract is reached.

[0211] Extended release multi-layer matrix tablets can be prepared using a fixed dose combination of a drug from group 1 and a drug from group 2. These formulations can contain one or more drugs in a hydrophilic or hydrophobic polymer matrix. For example, the hydrophilic polymer can include guar gum, hydroxypropyl methylcellulose, and xanthan gum as matrix formers. Lubricated formulations can be compressed by wet granulation.

[0212] Multi-layer tablet delivery (such as that used in GeoMatrix™ technology) includes a hydrophilic matrix core containing the active ingredient and one or two impermeable or semi-permeable polymer coatings. In this technology, a film or compressed polymer barrier coating is used on one or both sides of the core. The presence of a polymer coating (such as that used in GeoMatrix™ technology) modulates the hydration / swelling rate of the core and reduces the surface area available for drug release. These partial coatings modulate the drug dissolution profile, i.e., reduce the release rate from the device and shift the typical time-dependent release rate to a steady release. This technology allows customization of the level of controlled release of a particular drug and / or simultaneous release of two different drugs at different rates that can be achieved by one tablet. A combination of multiple layers, each exhibiting different swelling, gelling, and leaching rates, is used for drug release rate in the body. Exposure of the multi-layer tablet as a result of partial coating may affect release and leaching rates, therefore consideration may be given to reformulating the multi-layer tablet so that all sides are exposed to gastrointestinal fluids upon peeling of the barrier layer.

[0213] Multi-layer tablets containing a combination of immediate and modified / extended release of two different drugs, or two release rates of the same drug in one dosage form, can be prepared using hydrophilic and hydrophobic polymer matrices.

[0214] Dual release, repeated action, multi-layer tablets can be prepared having a compressed outer layer that provides an initial dose of a rapidly disintegrating matrix in the stomach and a core inner layer tablet formulated with ingredients that are insoluble in gastric media but are efficiently released in the intestinal environment.

[0215] In one embodiment, the dosage form is a solid oral dosage form that is an immediate release dosage form in which more than 80% of the particles of the active agent of the invention are released several hours after administration. In another embodiment, the invention provides a (e.g., solid oral) dosage form that is a controlled release dosage form or a pulsatile release dosage form. In this case, the release can be, for example, such that 30-60% by weight of the particles of the active agent of the invention are released from the dosage form within about 2 hours after administration, and about 90% by weight of the active agent of the invention is released from the dosage form within, for example, about 7 hours after administration. In yet another embodiment, the dosage form comprises at least one active agent in immediate release form and at least one active agent in delayed or sustained release form. In yet another embodiment, the dosage form comprises at least two active agents that are released at different rates as determined by in vitro dissolution testing or oral administration.

[0216] The various release dosage formulations described above, and other formulations known to those skilled in the art, can be characterized by a disintegration profile. The profile is characterized by the test conditions selected. Thus, a disintegration profile can be generated at a preselected type of device, shaft speed, temperature, volume, and pH of the dispersion medium. Several disintegration profiles can be obtained. For example, a first disintegration profile can be measured at a pH level that approximates that of the stomach (pH about 1.2), and a second disintegration profile can be measured at a pH level that approximates that of one point in the intestine, or at several pH levels that approximate several points in the intestine (about 6.0 to about 7.5, more specifically about 6.5 to 7.0). Another disintegration profile can be measured using distilled water. The release of the formulation can also be characterized by the pharmacokinetic parameters of the formulation, such as Cmax, Tmax, and AUC(0-τ).

[0217] In certain embodiments, the controlled, delayed or extended release of one or more drugs of the fixed dose combination of the present invention can be in the form of a capsule with a shell comprising a material of a rate-limiting membrane, including any of the coating materials already described, and filled with particles of the active agent of the present invention. A particular advantage of this configuration is that the capsule can be prepared independently of the particles of the active agent of the present invention, and therefore process conditions that would be detrimental to the drug may be used to prepare the capsule. Alternatively, the formulation can include a capsule with a shell made of a porous or pH-sensitive polymer made by a thermoforming process. Another alternative is a capsule shell in the form of an asymmetric membrane, i.e., a membrane with a thin skin on one surface and the majority of the thickness of the membrane being composed of a highly permeable porous material. Asymmetric membrane capsules can be prepared by solvent exchange phase inversion, where a polymer solution coated on a capsule-shaped form is induced to phase separate by exchanging the solvent for a miscible non-solvent. In another embodiment, spray-layered particles of the active agent of the present invention are filled into the capsule. An exemplary process for producing the spray-layered active agent of the present invention is a fluidized bed spray process. The suspension of the active agent of the invention, or of the complex of the active agent of the invention, described above, can be sprayed onto sugar or microcrystalline cellulose (MCC) beads (20-35 mesh) by means of a Wurster column insert at an inlet temperature of 50° C.-60° C. and an air temperature of 30° C.-50° C. A suspension with a total solids content of 15-20% by weight, containing 45-80% by weight of the active agent of the invention, 10-25% by weight of hydroxymethylpropylcellulose, 0.25-2% by weight of SLS, 10-18% by weight of sucrose, 0.01-0.3% by weight of simethicone emulsion (30% emulsion), and 0.3-10% by weight of NaCl, based on the total solids content of the suspension, is sprayed onto the beads (bottom spray) at 10 mL / min and a pressure of 1.5 bar through a 1.2 mm nozzle until a stratification of 400-700% by weight is achieved compared to the initial bead weight. The resulting spray-layered particles of an active agent of the invention, or of a complex of an active agent of the invention, contain about 30-70% by weight of the active agent of the invention, based on the total weight of the particle. In one embodiment, the capsule is a size 0 soft gelatin capsule.In one embodiment, the capsule is a swelling plug device. In another embodiment, the swelling plug device is further coated with cellulose acetate phthalate or a copolymer of methacrylic acid and methyl methacrylate. In some embodiments, the capsule comprises at least 100 mg (or at least 300 mg or at least 400 mg) of the active agent of the present invention and has a total weight of less than 800 mg (or less than 700 mg). The capsule may comprise a plurality of beads, e.g., spray-layered beads, comprising the active agent of the present invention. In some embodiments, the beads are 12-25% by weight of the active agent of the present invention. In some embodiments, some or all of the beads comprising the active agent of the present invention are coated with a coating that comprises 6-15% (or 8-12%) of the total weight of the beads. Typically, optimization work involves reducing loading levels, with the beads comprising 30-60% of the final bead weight. The capsule may comprise a granulated composition comprising the active agent of the present invention.

[0218] The capsules can provide a pulsatile release oral dosage form of the active agent of the present invention. These formulations can include (a) a first dosage unit containing a first dose of the active agent of the present invention that is released substantially immediately after oral administration of the dosage form to a patient; (b) a second dosage unit containing a second dose of the active agent of the present invention that is released about 3-7 hours after administration of the dosage form to a patient. In pulsatile release capsules containing beads, the beads can be coated with a coating that comprises 6-15% (or 8-12%) of the total weight of the beads. In some embodiments, the coating is a coating that is insoluble at pH 1-2 and soluble above pH 5.5. In certain embodiments, the formulation can include a pulsatile release capsule that includes at least two active agents (e.g., one drug from a first group and one drug from a second group). The pulsatile release capsule can include a plurality of beads, where some beads are immediate release beads and other beads are formulated for modified release, typically from about 3 hours to about 10 hours after administration, e.g., by use of a coating. In other embodiments, the pulsatile release capsule contains a plurality of beads formulated for modified release and a powder of the active agent of the invention for immediate release, such as aerosol granules of the active agent of the invention.

[0219] In some embodiments, the release of the particles of the active agent of the present invention can be modified by a modified release coating, for example, an enteric coating using cellulose acetate phthalate, or a sustained release coating comprising a copolymer of methacrylic acid and methyl methacrylate. In one embodiment, the enteric coating can be present, for example, in an amount of about 0.5 to about 15% by weight, more specifically about 8 to about 12% by weight, based on the weight of the spray-layered particles. In one embodiment, the spray-layered particles coated with a delayed release coating and / or a sustained release coating can be loaded into a modified release capsule, where both the enteric coated beads of the active agent of the present invention and the immediate release beads are loaded into a soft gelatin capsule. Additional suitable excipients may be loaded into the capsule along with the coated particles. Uncoated particles release the active agent of the present invention immediately after administration, whereas coated particles do not release the active agent of the present invention until the particles reach the intestine. The ratio of coated to uncoated particles can be controlled to obtain a desired pulsatile release profile. In some embodiments, the ratio between uncoated and coated particles to obtain the desired release is, for example, 20 / 80, or 30 / 70, or 40 / 60, or 50 / 50 (w / w).

[0220] In certain embodiments, the drugs included in the fixed dose combinations of the present invention may be in the form of beads contained within a capsule. In certain embodiments, some beads may release one or both drugs immediately, while other beads will release one or both drugs over an extended period of time or after a delay (delayed release).

[0221] In certain embodiments, the spray-layered particles of the active agent of the present invention can be compressed into a tablet with commonly used pharmaceutical excipients. Any suitable device for forming a coating can be used to make the enteric coated tablet, such as fluidized bed coating using a Wurster column; powder layering in a coating pan or rotary coater; dry coating by double compression technique; tablet coating by film coating technique; etc. See, for example, U.S. Patent No. 5,322,655; Remington's Pharmaceutical Sciences Handbook: Chapter 90 "Coating of Pharmaceutical Dosage Forms", 1990. In certain embodiments, the spray-layered active agent of the present invention described above and one or more excipients are dry blended and compressed into a mass, such as a tablet, having sufficient hardness to achieve a pharmaceutical composition that substantially disintegrates within about 30 minutes, within about 35 minutes, within about 40 minutes, within about 45 minutes, within about 50 minutes, within about 55 minutes, or within about 60 minutes after oral administration, thereby releasing the formulation of the active agent of the present invention into gastrointestinal fluids. In other embodiments, spray-layered particles of an active agent of the invention, or a complex of an active agent of the invention, are dry blended with the enteric coating described above, and one or more excipients, and compressed into a mass, such as a tablet. In one embodiment, the enteric coated particles in the tablet substantially prevent release of the active agent of the invention in the stomach (e.g., less than 15% by weight), but release substantially all, e.g., greater than 80% by weight, of the active agent of the invention (enteric coated or sustained release coated) in the intestine.

[0222] In a particular embodiment, the pulsatile release formulation of the active agent of the present invention comprises a first dosage unit comprising a formulation made of granules comprising the active agent of the present invention produced by a spray drying or spray granulation procedure without an enteric or sustained release coating, or a formulation made of granules comprising the active agent complex of the present invention produced by a spray drying or spray granulation procedure, and a second dosage unit comprising spray layered particles of the active agent of the present invention or spray layered particles of the active agent complex of the present invention with an enteric or sustained release coating. In one embodiment, the first dosage unit and the second dosage unit are wet or dry blended and compressed into a mass to produce a pulsatile release tablet.

[0223] In certain embodiments, binders, lubricants, and disintegrants are blended (wet or dry) with the spray-layered active agent of the present invention to create a compressible blend. The first dosage unit and the second dosage unit are compressed separately and then compressed together to form a bilayer tablet. In yet another embodiment, the first dosage unit is in the form of an overcoat and completely covers the second dosage unit.

[0224] In certain embodiments, the components of the present invention (with or without active agents) are wet granulated. The individual steps in the wet granulation process of tablet preparation include milling and sieving of the components, dry powder blending, wet massing, granulation, drying, and final grinding. In various embodiments, the other excipients of the pharmaceutical formulation are wet granulated before the composition of the active agent of the present invention is added thereto. Alternatively, the components can be subjected to dry granulation, for example, by compressing the powder mixture into rough tablets or "slugs" on a heavy duty rotary tablet press. The slugs are then broken down into granular particles by a milling operation, usually by passing through a tumbling granulator. The individual steps include powder blending, compression (slugging), and milling (slug reduction or granulation). None of the steps involve wet binders or moisture. In some embodiments, the formulation of the active agent of the present invention is dry granulated with the other excipients in the pharmaceutical formulation. In other embodiments, other excipients of the pharmaceutical formulation are dry granulated before the active agent formulation of the present invention is added thereto.

[0225] In other embodiments, the formulations of the present invention described herein are solid dispersions. Methods for producing these solid dispersions are known in the art, including, but not limited to, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Patent Publication No. 2004 / 0013734, all of which are specifically incorporated by reference. In some embodiments, the solid dispersions of the present invention contain both amorphous and non-amorphous active agents of the present invention, and may exhibit improved bioavailability compared to previous formulations of the active agents of the present invention. In yet other embodiments, the formulations of the active agents of the present invention described herein are solid solutions. Solid solutions encompass combinations of one substance with an active agent and other excipients, where the mixture is heated to dissolve the drug, and the resulting composition is then cooled to obtain a solid blend that can be further formulated or added directly to capsules or compressed into tablets.

[0226] The pharmaceutical agents that make up the combination therapeutic agent disclosed herein may be in a combined dosage form, or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapeutic agent may also be administered sequentially, in which case either therapeutic compound is administered by a regimen calling for two-step administration.

[0227] Covid-19 Various reports indicate that a significant proportion of COVID-19 patients exhibit neurological symptoms such as headache, nausea, vomiting, as well as loss of taste and smell, and in rare cases even encephalitis (Li, 2020; Yeager 2020; Filatov, 2020). These neurological symptoms would indicate that the virus can also invade the central nervous system, as previously reported for SARS-CoV or MERS. Although the route by which the virus invades the CNS is still unclear, increasing evidence indicates that the virus may reach the CNS via transsynaptic movement after first invading peripheral nerve endings (Li 2012, 2013).

[0228] The resulting neurological damage caused by coronaviruses such as COVID-19 may exacerbate lung injury in two ways: First, it has been demonstrated that some coronaviruses can spread to the medullary cardiopulmonary center in the brainstem, causing damage that can interfere with the control of respiratory function. Second, the inventors believe that cytokines and other toxins released into the bloodstream may lodge in the lungs and contribute to the acute respiratory distress syndrome (ARDS) from which COVID-19 patients often die.

[0229] It has been suggested that a similar mechanism may account for the large proportion (20-30%) of ARDS in patients with traumatic brain injury (TBI), where subsequent damage to the blood-brain barrier (BBB) ​​results in the acute release of various factors, including inflammatory immune cells, cytokines, and toxins, from overactivated or damaged microglia, astrocytes, and neurons (Hu, 2017; Puntambekar, 2018). Similarly, the brain orchestrates a complex immune system response to coronavirus infection (Bergman, 2006). Recent reports have shown that microglia, in particular, are essential for protection against coronavirus-induced encephalitis (Wheeler, 2018).

[0230] [Example 1] Equipment and experimental details X-ray powder diffraction (XRPD) X-ray powder diffraction analyses are obtained by using a BRUKER D8 ADVANCE with a Cu source (λ=1.54 Å after Ni filtering) operated at 40 kV and 40 mA, configured in a Bragg-Brentano configuration, equipped with a 90-position AUTO-CHANGER and a silicon strip detector (SSD160-2). θ-2θ coupled PSD (optical position sensor) continuous fast scans from 4 to 40 degrees are collected over approximately 32 min (0.5 s / 0.01° steps). Samples are mounted on polished zero-background silicon wafers by gently dispensing onto the flat surface and analyzed as flat specimens.

[0231] Differential Scanning Calorimetry (DSC) DSC runs are generated on a TA Instruments DSC 2500 equipped with an autosampler and RCS90. Typically, when using T4P mode, 1-3 mg of sample is heated in a Tzero hermetic aluminum pan from -80°C or near ambient temperature to near the onset of decomposition temperature as determined by TGA at a heating rate of 10°C per minute. A purge of dry nitrogen at 50 mL / min is maintained over the sample during the experiment. Instrument control and data analysis are operated under TRIOS software.

[0232] Thermogravimetric analyzer (TGA) TGA data are collected using a TA Instruments Discovery TGA equipped with an autosampler. Typically, 2-5 mg of sample is placed into a tared Tzero aluminum pan, either as a closed pan in which a hole will be automatically punched prior to sample addition for analysis, or as an open pan. A heating rate of 10°C per minute from ambient to 375°C is used with a nitrogen purge of 25mL / min. Instrument control and data analysis are operated under TRIOS software.

[0233] Dynamic Vapor Sorption (DVS) Samples are analyzed using a TA Instruments Q5000SA Gravimetric Moisture Sorption Analyzer. Relative humidity (RH) is adjusted in 10% RH increments ranging between 5-95% (±1% RH) at 25 °C (±0.5% °C). Sample mass is continuously monitored and recorded versus RH and time, with a criterion for mass balance set at less than 0.0100 percent mass change in 5 min and a time limit of 720 min per step. Humidity is controlled by mixing dry and humid nitrogen streams at a total flow rate of 200 mL / min. Instrument control and data analysis are operated under Advantage for Q Series and Universal Analysis software, respectively.

[0234] Polarized Light Microscope (PLM) Samples are analyzed using a Nikon Eclipse LV100N POL polarized optical microscope equipped with a FLIR Grasshopper3, 3.2 MP, 121 FPS color digital camera.

[0235] Nuclear magnetic resonance spectroscopy (NMR) 1 1 H-NMR data was acquired on a Bruker 400 MHz spectrometer at ambient temperature and chemical shifts are reported in ppm.

[0236] pKa values pKa values ​​are calculated using ACD / pKa (Classic, GALAS), version 2019.2.1, Advanced Chemistry Development, Inc., Toronto, Ontario, Canada, www.acdlabs.com.

[0237] [Example 2] CSP-1103 The XRPD of CSP-1103 showed a typical crystalline pattern, which is reproduced in Figure 1A.

[0238] The DSC of CSP-1103 showed one endothermic event with an onset of 200.2° C. and a peak maximum of 201.0° C. and a ΔH of 123.1 J / g, followed by decomposition. By TGA, decomposition appears to begin to occur after 200° C. Mass loss from ambient temperature was 0.6% up to 195.0° C. and 0.9% (total loss) up to 208.0° C.

[0239] The adsorption and desorption results of CSP-1103 (5–95% RH, 25 °C) on DVS are shown in Table 1 .

[0240] [Table 1]

[0241] The average moisture sorption or desorption of this material is 1.1±0.0% between 5-95% RH. This material should be considered slightly hygroscopic at 95% RH (<2% and ≥0.2%, European Pharmacopoeia 9.0). XRPD results of the pre-exposed and post-exposed material are comparable to each other, i.e. there is no change in the solid form.

[0242] Micrographs were obtained by PLM for CSP-1103 and then calibrated according to the objective lens magnification. The particles show birefringence indicating that the material is crystalline. At relatively low magnification the particles appear as agglomerates (loosely bound particles) consisting of irregularly shaped primary particles in the range of <2-25 μm to <2-25 μm. See Figure 1B-E.

[0243] The calculated pKa of the carboxylic acid moiety of CSP-1103 is 4.1±0.4.

[0244] 1H-NMR of CSP-1103 in DMSO-d6 showed three distinct chemical shift regions: (1) an acidic proton at δ 12.5 ppm; (2) an aromatic proton at δ 7.2-7.8 ppm; and (3) a cyclopropyl proton with a set of two protons at δ 1.2 ppm and another set of two protons between 1.4-1.5 ppm, all integrals to the two protons for each set.

[0245] Integrating the CSP using the acidic protons, the aromatic proton at δ 7.8 (singlet), the aromatic proton at δ 7.7 (doublet), or either set of cyclopropyl protons to determine the ratio between it and the co-crystal former;

[0246] [Table 2]

[0247] The stoichiometric ratios in the cocrystal can be confirmed.

[0248] [Example 3] Co-crystallization screening using solvent-assisted grinding (SAG) and slurry / solubilization (S / S) techniques was investigated with CSP-1103 and various co-crystal formers.

[0249] Co-crystal formers that are considered generally regarded as safe (GRAS) and / or have been confirmed as approved inactive excipients for drug products were investigated. Information related to co-crystal formers is shown in Table 2.

[0250] Table 2 1) The numbers in parentheses are conclusions from the Special Committee on Substances Generally Recognized as Safe (SCOGS US FDA) and can be found at https: / / www.fda.gov / food / generally-recognized-safe-gras / gras-substances-scogs-database. 2) An inactive excipient search for approved drug products can be found at https: / / www.accessdata.fda.gov / scripts / cder / iig / index.cfm.

[0251] The XRPDs of all the co-crystal formers showed typical crystalline patterns and were used as reference points during the co-crystallization screening. Further characterization of the co-crystal formers was performed as necessary.

[0252] The solubility of the co-crystal formers was then evaluated. The following solvents were selected based on these solvent classes, as they represent typical manufacturing solvents and demonstrate good solvent-solvent miscibility: 1. Aprotic polar: acetone, ethyl acetate, acetonitrile; 2. Hydrogen bond donors: ethanol, methanol; and 3. Electron pair donor: MTBE instead of diethyl ether.

[0253] Approximately 0.1 mmol of co-crystal former was weighed into a 1 dram vial, sufficient solvent was added to achieve a 0.2 M concentration, and gentle heat was applied, if necessary, at about 45° C. for about 1 minute. If the co-crystal former did not dissolve, additional solvent was added to achieve a 0.1 M or 0.05 M concentration, and gentle heat was applied, if necessary. After 65 hours, observations were made to determine if the co-crystal former remained in solution. Qualitative results regarding the solubility of the co-crystal former in various solvents are shown in Tables 3(A)-3(F).

[0254] [Table 3]

[0255] [Table 4]

[0256] [Table 5]

[0257] [Table 6]

[0258] [Table 7]

[0259] [Table 8]

[0260] [Table 9]

[0261] The solubility of CSP-1103 was then evaluated. Approximately 0.05 mmol of CSP-1103 was weighed into a 1-dram vial, sufficient solvent was added to achieve a 0.2M concentration, and gentle heat was applied, if necessary, at 45° C. for 1 minute. If the API did not dissolve, additional solvent was added to achieve a 0.1M or 0.05M concentration, and gentle heat was applied, if necessary. After 12 hours, observations were made to determine if the API remained in solution. Qualitative results for the solubility of CSP-1103 in various solvents are shown in Table 4.

[0262] [Table 10]

[0263] The water solubility of the co-crystal formers and CSP-1103 was then evaluated. In a 1 dram vial, sufficient solvent was added to achieve a concentration of 0.05 M in water with some gentle heating at 45° C. for 1 minute to determine if the material was completely dissolved. After 24 hours, observations were made to determine if any material remained in solution. Qualitative results for the water solubility of the co-crystal formers and CSP-1103 in various solvents are shown in Table 5.

[0264] [Table 11]

[0265] Solvent-assisted grinding and slurry co-crystallization were then investigated. The solubility results were compiled to identify suitable co-crystal formers and solvents to be investigated for the potential formation of co-crystals between the co-crystal formers and CSP-1103 by both solvent-assisted grinding (SAG) and slurrying / solubilization (S / S) techniques. All organic solvents are miscible with each other. Water is not miscible with ethyl acetate and MTBE. The compiled results for the solubility of the co-crystal formers and CSP-1103 in various solvents are shown in Table 6.

[0266] [Table 12]

[0267] 0.08-0.11 mmol of CSP-1103 was weighed into a 1-dram vial. Approximately 0.09-0.13 mmol of co-crystal former was then weighed into the vial. In each case, the co-crystal former was at or above the millimolar concentration of CSP-1103, but not to exceed 0.2 mmol. The grinding media was then added to the vial containing 50 μL of solvent and milled in a mixer.

[0268] After mixing, a portion of the material was removed and placed on an XRPD plate for analysis. Where permitted, the dried material from the XRPD plate was used to run TGA and DSC. If not, the dried material was placed back into the vial for the slurry / solubilization cocrystallization experiments. 2 mL of the same solvent used in the SAG experiments was added to the vial and heated between 45-75 °C for up to 15 min to dissolve the components. In both cases, the solvent was evaporated to dryness prior to XRPD analysis. The aggregated XRPD results for the SAG and S / S cocrystallization studies are shown in Table 7.

[0269] [Table 13-1]

[0270] [Table 13-2]

[0271] [Table 13-3]

[0272] Based on the experimental results from the co-crystallization screen, it was concluded that co-crystals between CSP-1103 and the following co-crystal formers could potentially be formed: 1. Citric acid from methanol or acetonitrile, 2. Nicotinamide from ethyl acetate, 3. Saccharin from ethyl acetate, and 4. Vanillin from ethyl acetate.

[0273] There is some evidence that co-crystals may exist between CSP-1103 and ascorbic acid formed from ethyl acetate, and between CSP-1103 and caffeine formed from acetonitrile.

[0274] The qualitative solvent solubilities of CSP-1103 and co-crystal formers overlaid with the results of the co-crystallization screen are shown in Table 8. Table 8 shows the molar concentrations of components that have not yet been investigated for their potential for co-crystal formation with that component and solvent combination.

[0275] [Table 14]

[0276] Based on a qualitative assessment of solubility, in most cases the co-crystal former is more soluble than CSP-1103, and if the solubilities of the two are sufficiently different, the co-crystal may be randomly saturated in the solvent system.

[0277] [Example 4] Next, the API to co-crystal former ratio was investigated. Approximately 0.5 mmol of CSP-1103 was weighed into a 1 dram vial. Depending on the ratio of co-crystal former to CSP, the appropriate mmol of co-crystal former was then weighed and transferred into the vial. Solvent was then added to the vial and heated with stirring between 45-75°C for up to 60 minutes. The slurry was then allowed to cool overnight with continued stirring.

[0278] After stirring overnight, a minimum of a portion of the slurry was removed and placed on an XRPD plate for analysis. If permitted, the dried material from the XRPD plate was used to run the TGA and DSC. If not, the dried material was placed back into the vial.

[0279] Additional solvent was then added to the vial and heated with stirring between 45-75 °C for up to 60 minutes. The slurry was then allowed to cool overnight with continued stirring. After XRPD analysis, the solvent addition was repeated again for all studies except VN (first study).

[0280] The results of the survey are shown in Table 9.

[0281] [Table 15-1]

[0282] [Table 15-2]

[0283] XRPD results showed that no co-crystals occurred in the slurry studies, but only mixtures of CSP-1103 and the co-crystal former. The greater than symbol (">") implies that the amount of CSP-1103 was qualitatively greater than the co-crystal former. The less than symbol ("<") implies that the amount of CSP-1103 was qualitatively less than the co-crystal former. In some cases, both components appear to be in equal concentrations ("≒").

[0284] [Example 5] Co-crystal formation from saturated co-crystal former solutions After various solvents were saturated with the co-crystal formers, known volumes were transferred into 1-dram vials. Approximately 0.01 mmol of CSP-1103 was weighed into the 1-dram vial containing the saturated solution and heated between 45-75 °C with gentle stirring for up to 60 minutes. The vial was then left to evaporate slowly at ambient temperature. Crystalline material was obtained after the solution had sufficiently evaporated.

[0285] The crystalline material was loaded onto an XRPD plate for analysis. When permitted, the crystalline material from the XRPD plate was used to run the TGA and DSC, and to perform other physicochemical techniques. Otherwise, the material was placed back into the vial.

[0286] Experimental details for investigating saturated co-crystal former solutions are shown in Table 10.

[0287] [Table 16]

[0288] Based on the XRPD results, experiments R23809-012-005 (CA), R23809-012-001 (NCT), and R23809-013-002 (NCT) likely indicated the formation of cocrystals, permitting further thermal and NMR characterization of these samples. Based on the experimental results, R23809-012-005 was found to be a mixture of single components, CSP and CA, R23809-012-001 was found to be a nearly pure cocrystal of CSP and NCT-CSPNCT, and R23809-013-002 was found to be a mixture of two components, NCT and a lesser amount of CSPNCT. The ratio between CSP and NCT was 1.1 to 1.0 for R23809-012-001 and 1 to 4 for R23809-013-002.

[0289] [Example 6] Co-crystallization of itanapraced (CSP-1103) with nicotinamide (NCT) was attempted. By attempting to generate co-crystals from a solvent saturated with the co-crystal former, a co-crystal of CSP-1103 with nicotinamide (CSPNCT) was obtained.

[0290] The crystal habit of NCT is that of colorless plate-like crystals, the crystal habit of CSP is that of colorless needle-like crystals, and the crystal habit of CSPNCT is that of colorless needle-like crystals. See Figure 2.

[0291] Preliminary single crystal X-ray diffraction results indicate that supramolecular structural interactions occur between the pyridinyl moiety of NCT and the carboxylic acid moiety of CSP.

[0292] The unit cells and symmetries of the two components of the cocrystal were characterized by single crystal diffraction to be as follows: CSP-1103 (300°K): P2(1) / c (monoclinic), with a = 23.9851(4) Å, b = 7.36928(15) Å, c = 8.22003(15) Å, and β = 95.0080(17)°, and · NCT(150°K): P2(1) / c(monoclinic), with a = 3.877(4) Å, b = 15.60(1) Å, c = 9.375(6) Å, and β = 98.45(7)°.

[0293] The XRPD of CSPNCT showed a typical crystalline pattern and has a unique diffraction pattern in comparison with CSP and NCT. The XRPD of CSPNCT is shown in Figure 3A. The peak list expressed in 2θ generated from a Cu source (λ = 1.54 Å after Ni filtering) is as follows: Cu Kα λ=1.54060

[0294] [Table 17]

[0295] A comparison between CSPNCT, CSP, and NCT is shown in Figure 3B.

[0296] Micrographs were obtained by PLM for CSPNCT and then calibrated according to the objective magnification. The micrographs are shown in Figures 9A-9D. The particles show birefringence indicating that the material is crystalline. The particles appear as aggregates of needle-like fibers (4-8 μm up to 40 μm) and larger crystals above 40 μm.

[0297] [Example 7] The crystals of CSPNCT were characterized by single crystal diffraction analysis.

[0298] A suitable single crystal of CSPNCT was isolated and mounted on glass fiber with paratone oil on an XtaLAB Synergy diffractometer equipped with a microfocus rotating anode X-ray tube (Rigaku (Cu|Mo) X-ray source) and a Hybrid Pixel Array Detector (HyPix) detector. The temperature of the crystal was controlled by an Oxford Cryosystems cryodevice. Data reduction was performed with CrysAlisPro software using multiscan absorption correction. The structure was solved by the ShelXT1 structure solution program using the intrinsic phasing method and using Olex22 as the graphical interface. The model was refined with ShelXL3 using least-squares minimization.

[0299] CSPNCT is formed by the cocrystallization of four NCTs and four CSPs in a unit cell. See Figure 4. A positional order for the orientation of the F-substituted phenyl rings of CSPs was found crystallographically, with the F atoms oriented along two different separate directions. After careful examination of the reflections of low intensity, the formation of a two-fold supercell was observed for CSPNCT. The average image of the CSPNCT structure, in which four NCT molecules cocrystallize with four CSP molecules, is the same with or without the supercell. Crystal refinement of the supercell at 100°K showed that the distribution of the two orientations of the F-substituted phenyl rings is about 80:20%, unlike the 50:50% observed for the subcell (without consideration of the supercell), which was incorrect in the initial case at 250°K.

[0300] The apparent unit cell dimensions of CSPNCT are 5.1288(2) Å x 12.1484(7) Å x 32.2055(16) Å, 90.618(4)°, 91.393(4)°, and 90.394(4)° at 250°K. Careful examination of the reciprocal lattice reveals weak intensity reflections due to the formation of a supercell with a two-fold superlattice. C 88 H 68 Cl8F4N8O 12Summary of crystal data for (CSPNCT) (M = 1789.10 g / mol)*: triclinic, space group P-1 (no. 2), a = 10.2281(4) Å, b = 13.0200(7) Å, c = 32.0677(18) Å, α = 89.774(4)°, β = 88.722(4)°, γ = 67.267(4)°, V = 3937.7(4) Å 3 , Z=2, T=100.00(10)°K, μ(Cu Kα)=3.296mm -1 , D calc =1.509g / mm 3 , number of measured reflections 17101 (5.514°≦2θ≦103.858°), number of independent reflections 7845 (R int =0.0553, R sigma =0.1061). These were used in all calculations. The final R1 was 0.0714 (I>2σ(I)) and wR2 was 0.1842 (I>2σ(I)). *: The bulk properties are not significantly affected by this supercell, and for practical purposes the CSPNCT can be described by its apparent MW (447.02 g / mol).

[0301] Detailed crystallographic information on the refinement and structure of CSPNCT can be found in the accompanying tables, which were generated by Olex2 and compiled for OlexSys as svn.r5f609507 on 12 November 2020.

[0302] [Table 18-1]

[0303] [Table 18-2]

[0304] [Table 19-1]

[0305] [Table 19-2]

[0306]

Table 19-3

[0307]

Table 19-4

[0308]

Table 19-5

[0309]

Table 19-6

[0310]

Table 19-7

[0311]

Table 19-8

[0312]

Table 19-9

[0313]

Table 19-10

[0314]

Table 20-1

[0315]

Table 20-2

[0316]

Table 20-3

[0317]

Table 20-4

[0318]

Table 20-5

[0319]

Table 20-6

[0320]

Table 20-7

[0321]

Table 20-8

[0322]

Table 20-9

[0323]

Table 20-10

[0324]

Table 21-1

[0325]

Table 21-2

[0326]

Table 21-3

[0327]

Table 21-4

[0328]

Table 21-5

[0329]

Table 22-1

[0330]

Table 22-2

[0331]

Table 22-3

[0332]

Table 22-4

[0333]

Table 22-5

[0334]

Table 22-6

[0335]

Table 22-7

[0336]

Table 22-8

[0337]

Table 23-1

[0338]

Table 23-2

[0339]

Table 23-3

[0340]

Table 23-4

[0341]

Table 23-5

[0342]

Table 23-6

[0343]

Table 23-7

[0344]

Table 23-8

[0345]

Table 23-9

[0346] [Table 23-10]

[0347] [Table 24-1]

[0348] [Table 24-2]

[0349] [Table 24-3]

[0350] [Table 24-4]

[0351] [Table 24-5]

[0352] [Table 25-1]

[0353] [Table 25-2]

[0354] [Example 8] The DSC of CSPNCT showed an endothermic event with an onset of 114.0° C., a peak maximum of 116.7° C., and a ΔH of 60.5 J / g, and an end of 121.1° C. This event was followed by a broader endothermic event with a peak maximum of 159.1° C. and an end of 183.2° C. By TGA, decomposition appears to begin to occur at approximately 135° C. Mass loss from ambient was 0.3% to 105.0° C., 0.6% to 122.0° C., and 7.2% (total mass loss) to 183.2° C.

[0355] Results from completed DVS experiments on CSPNCT (R23809-012-001) at 5-95% RH are shown as DVS kinetic and isothermal curves in Figures 5 and 6, respectively, and in Table 11.

[0356] [Table 26]

[0357] The average moisture sorption or desorption of this material is 0.17 ± 0.00% between 5 and 95% RH. This material should be considered non-hygroscopic at 95% RH (<0.2%, European Pharmacopoeia 9.0).

[0358] The XRPD results of the pre-exposed and post-exposed materials are shown in Figure 7 and are comparable to each other. There was no change in the solid forms of CSP, CSPNCT, and NCT after exposure to two DVS sorption / desorption cycles. These conclusions were based on the fact that the XRPD patterns of the pre-exposed materials were comparable to the XRPD patterns of the post-exposed materials.

[0359] Tables 12A, 12B, and 12C tabulate the water vapor sorption and desorption results for CSP, CSPNCT, and NCT, respectively.

[0360] [Table 27]

[0361] [Table 28]

[0362] [Table 29]

[0363] 8A, 8B, and 8C show the water vapor sorption and desorption isotherms for CSP, CSPNCT, and NCT, respectively.

[0364] Based on the DVS results, the non-hygroscopicity of CSPNCT is a clear advantage over CSP-1103 alone.

[0365] [Example 9] An HPLC assay for CSP-1103 and the co-crystal formers was developed.

[0366] Method requirements: Column: Agilent Poroshell 120 EC-C18, 4.6x50mm, 2.7μm Mobile phase A: 0.05% TFA in water Mobile phase B: 0.05% TFA in ACN Flow rate: 1.0mL / min Profile: Gradient (see Table 13A below) Column temperature: 40℃ UV detection: 262 nm (bandwidth = 4 nm; reference = OFF) 220 nm (bandwidth = 4 nm; reference = OFF) Concentration: 0.03mg / L Sample diluent: 0.05% TFA in 50 / 50 (v / v) water / ACN Injection volume: 2.0μL Needle crystal cleaning mode: Vial rinse Needle crystal washing solvent: Diluent Driving time: 15 minutes.

[0367] [Table 30]

[0368] The predicted retention times are shown in Table 13B.

[0369] [Table 31]

[0370] Glutamic acid was not detected. Citric acid elutes with very low response in the injection cavity. All other components were detected with appreciable response levels at 262 nm. There were two pairs of co-crystal formers below resolution: nicotinamide with ascorbic acid, and phenylalanine with saccharin.

[0371] The linearity of the method was demonstrated for CSP-1103 from 3 to 300 μg / mL. Mixtures of co-crystal formers were prepared and stored at 4°C for use in future RT marking of the components.

[0372] [Example 10] A second set of co-crystal formers was investigated with an emphasis on acid-acid homosynthon supramolecular interactions. Two screens were attempted: (1) saturated solution co-crystallization and (2) solvent-assisted grinding co-crystallization. The results are shown in Table 14.

[0373] [Table 32]

[0374] [Table 33]

[0375] No new cocrystals were discovered through any of these screens.

[0376] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed disclosure. In case of conflict, the present specification, including definitions, will control.

Claims

1. 1. A pharmaceutical formulation comprising a therapeutically effective amount of an AICD inhibitor, wherein the AICD inhibitor is in the form of a co-crystal, the co-crystal comprising a crystal lattice comprising molecules of the AICD inhibitor and a co-crystal former, the AICD inhibitor interacting non-ionically with the co-crystal former in the crystal lattice, the AICD inhibitor comprising a carboxylic acid moiety, the co-crystal former being a non-volatile heterocyclic organic compound having a pyridinyl moiety, the AICD inhibitor and the co-crystal former being bound only by non-ionic and non-covalent bonds, and the co-crystal former is not a solvent.

2. 2. The pharmaceutical formulation of claim 1, wherein the AICD inhibitor is praced and the co-crystal former is selected from the group consisting of nicotinamide, picolinamide, isonicotinamide, isonicotinic acid, and nicotinic acid.

3. wherein the praced is itanapraced, the co-crystal former is nicotinamide, the stoichiometric ratio of itanapraced to nicotinamide is from about 0:8:1.2 to about 1.2:0.8, and the co-crystals are generated from a Cu source (λ=1.54 Å after Ni filtering) at 2θ angles of about 14.63°; 14.90°; 15.56°; 16.71°; 18.24°.

3. The pharmaceutical formulation of claim 2, comprising an X-ray powder diffraction pattern (XRPD) having particular peaks at: 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (all ±0.2 degrees 2θ).

4. 4. The pharmaceutical formulation of claim 3, wherein the X-ray powder diffraction pattern (XRPD) is substantially identical to the X-ray powder diffraction pattern (XRPD) shown in Figure 3A.

5. 1. A co-crystal comprising itanapraced and a co-crystal former, wherein the co-crystal former is nicotinamide, wherein the co-crystal comprises an X-ray powder diffraction pattern (XRPD) with specific peaks in terms of 2-theta at about 14.63°; 14.90°; 15.56°; 16.71°; 18.24°; 18.46°; 20.03°; 20.27°; 22.01°; 22.27°; 24.17°; 24.47°; 26.14°; 26.47°; 27.83°; 28.85°; 29.97°; 30.64°; 32.42°; 34.07°; and 39.14° (each ±0.2 degrees 2-theta) generated from a Cu source (λ=1.54 Å after Ni filtering).

6. 6. The co-crystal of claim 5, wherein the X-ray powder diffraction pattern (XRPD) is substantially identical to the X-ray powder diffraction pattern (XRPD) shown in Figure 3A.

7. 6. The co-crystal of claim 5, wherein the itanapraced and nicotinamide are not covalently and ionically bound in the co-crystal.

8. 6. The co-crystal of claim 5, which is less hygroscopic than itanapraced.

9. 6. The co-crystal of claim 5, which is more water soluble than itanapraced.

10. 6. The co-crystal of claim 5, wherein itanapraced and nicotinamide are linked at the pyridinyl moiety of nicotinamide and the carboxylic acid moiety of said itanapraced.

11. 6. The co-crystal of claim 5, which exhibits a first endothermic event with an onset of 114.0°C, a peak maximum of 116.7°C, and a ΔH of 60.5 J / g as measured by differential scanning calorimetry (DSC analysis).

12. 12. The co-crystal of claim 11, further exhibiting a second endothermic event with a peak maximum of 159.1°C and an end of 183.2°C as measured by differential scanning calorimetry (DSC analysis).

13. 6. A solid dosage form comprising the cocrystal of claim 5 and a pharmaceutically acceptable excipient.

14. 14. The solid formulation of claim 13 for treating a neurodegenerative condition in a human, wherein the neurodegenerative condition is selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, juvenile neuronal ceroid lipofuscinosis, age-related macular degeneration, dementia, neuroinfections, neuronal injury, tauopathy, Pick's disease, progressive supranuclear palsy, hypoxic encephalopathy, and neuroinflammation.

15. 15. The solid formulation of claim 14, wherein the neurodegenerative condition is neuroinflammation.

Images