Taste-masked oral formulation of fasudil

Abstract

A taste-masking composition for pharmaceutical use is provided, comprising a rho kinase inhibitor, a pharma- ceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, wherein the rho kinase inhibitor has a bitter taste and is present at a concentration above a taste threshold concentration. The rho kinase inhibitor can include fasudil. The composition further includes a taste-masking agent that masks the bitter taste. The taste-masking agent can partially or completely mask the bitter taste of the rho kinase inhibitor. The taste-masking agent can include one or more drugs. The composition can be formulated to treat a neurodegenerative disease, such as one or more symptoms of such a disease, such as wandering. A method of treating a neurodegenerative disease using such a composition is also provided. A method of making the composition of the present disclosure is further provided.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This international application claims the benefit of U.S. Provisional Patent Application No. 63 / 311,269, filed February 17, 2022, and U.S. Provisional Patent Application No. 63 / 387,994, filed December 19, 2022, each of which is incorporated by reference in its entirety. [Background technology]

[0002] Elderly people, especially those suffering from neurodegenerative diseases, may have difficulty in adhering to a consistent drug regimen. Adherence may be even more complicated for patients on multiple drug regimens and those who experience dysphagia, which may have many different causes. Increased aversion to certain tastes and mouthfeels, as well as organoleptic perceptions, may pose significant obstacles for such patients. New problems may arise when attempting to address other issues related to compliance and dysphagia by using liquid dosage forms. Active pharmaceutical ingredients (APIs) with unpleasant tastes may be particularly unpleasant when consumed in liquid. Reducing or even eliminating such tastes may present significant obstacles to formulators, given the significant number of variables related to both the contents of the API formulation and the patient. Summary of the Invention

[0003] A taste-masking composition is provided that includes a rho kinase inhibitor, a pharma- ceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof, where the rho kinase inhibitor has a very high bitter taste and is present at a concentration significantly above the taste threshold concentration. The bitter taste may be accompanied by a numbing taste, or the numbing taste may be present in the absence of the bitter taste. The rho kinase inhibitor may include fasudil, e.g., hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine monohydrochloride hemihydrate, or a metabolite thereof, or both. For example, the metabolite may be hydroxyfasudil. The composition further includes a taste-masking agent that masks the bitter taste. The taste-masking agent may partially or completely mask the bitter taste of the rho kinase inhibitor. The taste-masking agent may include one or more agents. The taste-masking agent may include a bitter taste-masking agent.

[0004] The taste masking composition comprising a rho kinase inhibitor is particularly suitable for patients suffering from neurodegenerative diseases. The taste masking composition can be any oral dosage form, including liquids as solutions or suspensions, or solids, including tablets, capsules, powders, films, or granules. Taste masking techniques / methods include organoleptic methods (sweeteners / flavors), polymer coating, hot melt extrusion, microencapsulation, complexation with ion exchange resins, and spray drying. Solutions can include complexing the active ingredient with, for example, cyclodextrins or ion exchange resins. Suspensions can include microspheres and liposomes. Tablets can be orally disintegrating tablets (ODT), fast dissolving tablets (FDT), or chewable tablets. Powder formulations can be sprinkles or ready-to-suspend powders.

[0005] The taste-masking composition as a liquid dosage form may be aqueous and may include one or more suspending agents. Examples of suspending agents may include non-cellulose polysaccharides such as cellulose ethers, gums, or pyrrolidinone-containing polymers, carbomers, or any combination thereof. The aqueous composition may include a solution, a suspension, an emulsion, a gel, or a colloid, or any combination thereof. The liquid dosage form may be, for example, a thickened solution. For example, a pharmaceutically acceptable taste-masking composition is disclosed that includes a rho kinase inhibitor, such as fasudil (including salts and hydrates), at least one taste-masking agent, and at least one pharmaceutically acceptable additive.

[0006] The taste-masking composition may be a liquid formulation containing a taste-masking agent capable of ionically interacting with a rho kinase inhibitor. The concentration of the rho kinase inhibitor in the composition is above the taste threshold concentration of the rho kinase inhibitor, while the concentration of the unbound rho kinase inhibitor is about 3 times or less than the threshold concentration. The active ingredient may be fasudil (including its salts and / or hydrates), and the taste-masking agent may be a weak ion-exchange resin, and the concentration of fasudil in the composition is greater than 0.3 mg / ml, and the concentration of free fasudil is about 1 mg / ml or less. In general, fasudil may be present in a concentration of 1 mg / ml to 30 mg / ml. The taste-masking composition may, for example, include fasudil hydrochloride, an ion-exchange resin, and a suspending agent, and the ratio of resin to fasudil (w / w) is about 2.5:1 to about 4.5:1.

[0007] The taste masking composition of the present disclosure can be formulated such that the rho kinase inhibitor is present in an amount sufficient to treat a neurodegenerative disease. Neurodegenerative diseases include, for example, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis (ALS), motor neuron disease (including amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), pseudobulbar palsy, progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), spinal muscular atrophy (SMA) and monomuscular muscular atrophy (MMA), as well as some rarer variants that resemble ALS), Parkinson's disease, Huntington's disease, multiple sclerosis, progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS), or any combination thereof. A method of treating a neurodegenerative disease is provided by the present disclosure. The method can include administering to a patient a composition of the present disclosure in an amount sufficient to treat the neurodegenerative disease in one or more doses. Also provided are methods of administering the compositions of the present disclosure to a patient in an amount sufficient to alleviate symptoms of a neurodegenerative disease in one or more doses, which may include, for example, wandering, agitation, cognitive impairment, anxiety, muscle weakness and / or degeneration, sleep disorders, dyspnea, sleep apnea, depression, psychiatric disorders, and the like, or any combination thereof.

[0008] The present disclosure also includes a method for producing the taste masking composition of the present disclosure.The present disclosure also provides the use of a rho kinase inhibitor for producing the composition of the present disclosure, for example, for treating one or more neurodegenerative diseases.The present disclosure also provides the use of a rho kinase inhibitor in the taste masking composition for treating one or more neurodegenerative diseases of the present disclosure. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows a graph of the binding rate of fasudil to the sulfonate resin as a function of pH.

[0010] [Diagram 2] FIG. 2 shows a graph of the binding rate of fasudil to polacrilin IRP 64 resin as a function of pH.

[0011] [Diagram 3] FIG. 3 shows a graph of the dissolution profile of fasudil-containing sprinkles over time under two different conditions.

[0012] [Figure 4] FIG. 4 shows the dissolution of Fasudil and IRP 64 resin complex USP II, 900 mL, 50 rpm. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present disclosure is not limited to the specific embodiments of the present disclosure described herein, since variations of the specific embodiments may be made and still fall within the scope of the present disclosure and claims. The terms are used in a non-limiting manner and are intended to describe the specific embodiments. The singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.

[0014] As used herein, when a particular compound name is used, it should be read as including all forms of the compound, including free base (or acid), any salt, any hydrate, any hydrophobic ion pair, any polymorph, and any combination thereof, unless otherwise expressly stated.Thus, when fasudil or hydroxyfasudil (M3) is used, for example, it is understood that these terms include free base, any salt, any hydrate, any hydrophobic ion pair, any polymorph, and any combination thereof, unless otherwise expressly stated.

[0015] The present disclosure is based in part on the unexpected discovery that certain rho kinase inhibitors, including fasudil hydrochloride and the main metabolite hydroxyfasudil (M3), have a highly adverse numbing and bitter taste. This presents a need for a pharmaceutical composition containing an agent that masks this taste, which is expected to increase patient compliance. Thus, a taste masking composition is provided that can include at least a rho kinase inhibitor having a bitter taste and a taste masking agent. The taste masking composition can be any oral dosage form, including liquids (e.g., thickened solutions or suspensions) or solids (tablets, mini-tablets, capsules, powders, or granules). Exemplary forms of the taste masking composition include solutions, suspensions, gels, jellies, films, tablets (coated and uncoated), mini-tablets (coated and uncoated, containing 5 mg or less of active ingredient), bilayer tablets (coated and uncoated), slurries, capsules, granules (coated and uncoated), dissolving tablets, multiparticulates, granules, powders, and sprays. As used herein, the formulation suitable for dysphagia is the formulation suitable for administration to the patient with dysphagia.The tablets and capsules of conventional size (e.g., containing at least 10mg of active ingredient) would not be considered suitable for dysphagia, because the patient with dysphagia would have difficulty in swallowing them.Examples of the formulation suitable for dysphagia include thickened liquid and solid formulations, which can be combined with food such as granules or sprinkles.

[0016] In certain instances, conventional film coatings (typically containing wax, cellulose, polyvinyl alcohol, or similar bases applied in a thin layer) that are not sufficiently viscous and / or durable to mask the taste in the absence of additional taste masking agents are not considered taste masking formulations. These films primarily serve to improve appearance and fragility, but when administered to patients with dysphagia, they are released in the mouth due to swallowing problems and delays. In addition, when patients have dysphagia, it is often necessary to add medication to soft foods (e.g., yogurt, applesauce, etc.), which also provides an opportunity for such coatings to release active ingredients. Thus, such films are inappropriate for treating patients with dysphagia, as the patient is exposed to any aversive taste. Thus, formulations with such simple film coatings (e.g., coated tablets, beads, or granules) and capsules containing ingredients that are not otherwise taste masked are excluded. In other words, film-coated formulations and capsules (soft or hard) that do not have sufficient viscosity and / or durability for taste masking and do not contain additional taste masking agents or mechanisms are excluded from the present compositions unless further taste masked in accordance with the present disclosure.

[0017] The composition may be, for example, an aqueous composition. Any rho kinase inhibitor or combination of rho kinase inhibitors may be used. Reference to a rho kinase inhibitor includes compounds in the composition that can directly inhibit rho kinase, as well as compounds that become rho kinase inhibitors upon one or more modifications after administration, such as metabolic modification by one or more enzymes or other processes. Rho kinase inhibitors may inhibit rho kinase using any relevant mechanism. For example, inhibition may be competitive, noncompetitive, reversible, or reversible, or any combination thereof. The rho kinase inhibitor may be the only active pharmaceutical ingredient (API) in the composition, or one or more additional APIs may be present in the composition.

[0018] Rho kinase inhibitors can inhibit one or more types of rho kinase. Rho kinases are generally serine / threonine kinases. Examples of rho kinases include rho kinase 1 (rho-associated coiled-coil-containing protein kinase 1, ROCK1, p160-ROCK) and rho kinase 2 (rho-associated coiled-coil-containing protein kinase 2, ROCK2). Rho kinase inhibitors can inhibit ROCK1, or ROCK2, or both. The inhibited rho kinase can be human rho kinase, mammalian rho kinase, or vertebrate rho kinase, or any combination thereof. Rho kinase inhibitors can exclusively inhibit human rho kinase, or also inhibit one or more rho kinase homologs in other species.

[0019] The rho kinase inhibitor can include a rho kinase inhibitor having a bitter taste, a pharma- ceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof. The rho kinase inhibitor can include one or more of an isoquinoline ring, a sulfonyl group, and a homopiperazine ring, or one or more equivalent structural moieties. For example, the rho kinase inhibitor can include fasudil, a pharma- ceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof. The rho kinase inhibitor can be in crystalline form, or in amorphous form, or both. Any polymorph or combination of polymorphs of the rho kinase inhibitor can be used. Pseudopolymorphs can be used.

[0020] Fasudil contains an isoquinoline ring linked to a homopiperazine ring via a sulfonyl group. Isoquinoline derivatives such as fasudil, its active metabolite hydroxyfasudil (M3), dimethylfasudil, and ripasudil are classes of ROCK inhibitors that can be used. Other ROCK inhibitors are based on 4-aminopyridine structures, such as Y-27632 (Yoshitomi Pharmaceuticals). Other ROCK inhibitors that can be used include, for example, indazole, pyrimidine, pyrrolopyridine, pyrazole, benzimidazole, benzothiazole, benzathiophene, benzamide, aminofurazan, quinazoline, or boron derivatives, or any combination thereof. Some exemplary ROCK inhibitors are shown below. [ka]

[0021] Other examples of isoquinoline-derived ROCK inhibitors include, for example, dimethylfasudil and ripasudil.Fasudil can be present as free base or salt, and can be in the form of hydrate, such as hemihydrate.Unless otherwise specified, reference to rho kinase inhibitor applies equally to free acid or its free base, salt, hydrate, polymorph, and prodrug derivative.Fasudil can be in the form of, for example, hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine monohydrochloride hemihydrate. [ka]

[0022] In vivo, fasudil undergoes hepatic metabolism to its active metabolite hydroxyfasudil (also known as M3). Fasudil is substantially converted in vivo to its 1-hydroxy (M3) metabolite. M3 exists as two tautomers, as shown below: [ka]

[0023] Rho kinase inhibitors, such as fasudil, include pharmaceutically acceptable salts and hydrates.Salts can be formed through reaction with inorganic acid and organic acid, or both.Suitable examples of acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, maleic acid, maleic acid, oxalic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid, or para-toluenesulfonic acid, or combinations thereof.

[0024] As used herein, a "taste masking agent" is a pharma- ceutically acceptable agent capable of masking the bitter taste of a rho kinase inhibitor, other unpleasant tastes present in the liquid composition, or any combination thereof. One or more taste masking agents can be present in the liquid composition. When two or more taste masking agents are present, the taste masking agents can act by the same or different mechanisms to mask the bitter taste of a rho kinase inhibitor. Multiple taste masking agents can act synergistically. A taste masking agent can directly target the bitter taste of a rho kinase inhibitor, for example, by binding to the rho kinase inhibitor or by blocking bitter taste receptors in the patient. A taste masking agent can indirectly target the bitter taste of a rho kinase inhibitor, for example, by using a sweetener, or a flavoring agent, or both, to deflect the patient's taste sensation to the bitter taste. Taste masking can be partial or complete. A taste masking agent can be present in the composition in an amount sufficient to substantially neutralize the bitter taste. Substantial neutralization can essentially completely neutralize the bitter taste, or the bitter taste is still perceptible but the composition is palatable, either alone or in combination with other ingredients.

[0025] The taste masking agent can include a bitter taste masking agent. As used herein, "bitter taste masking agent" refers to a taste masking agent configured to directly target or otherwise block the bitter taste of the rho kinase inhibitor, for example, by binding to the rho kinase inhibitor and preventing it from interacting with taste receptors or by preventing it from binding to bitter taste receptors in the mouth. The bitter taste masking agent can include a single type of molecule or a combination of different molecules that collectively mask the bitter taste of the rho kinase inhibitor. Different bitter taste masking agents can utilize the same, similar, or different mechanisms of action. The bitter taste masking agent can mask the bitter taste using any suitable mechanism. For example, the bitter taste masking agent can bind to or otherwise modify the rho kinase inhibitor. The bitter taste masking agent can be, for example, an ion exchange resin, such as a cation exchange resin, and can be bound to the rho kinase inhibitor. Cyclodextrins, particularly β-cyclodextrins such as hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin, represent another class of such bitterness masking agents that can form complexes with rho kinase inhibitors, thereby preventing their interaction with taste receptors. Ionic polymers, such as alginic acid, which is a linear ionic polymer, are another example of such bitterness masking agents. Carbomer is another example of such bitterness masking agents. The bitterness masking agent can be bound to less than 50% of the rho kinase inhibitor. The bitterness masking agent can be bound to at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or about 100% of the rho kinase inhibitor, or any intervening percentage or percentage therebetween. The more rho kinase inhibitor that is bound to the bitterness masking agent, the more effective the taste masking can be. Sufficient bitterness-masking agent can be added to reduce the concentration of the unbound rho kinase inhibitor to a level near or below the taste threshold.

[0026] Certain bitterness masking agents can block or otherwise directly inhibit bitterness receptors, and such bitterness masking agents are referred to as "bitterness inhibitors." Examples of bitterness inhibitors include sodium acetate, sodium gluconate, adenosine 5'-monophosphate, and combinations thereof. A single type of bitterness masking agent may be present in the composition. The composition may include a combination of two or more different types of bitterness masking agents. Multiple types of bitterness masking agents may act additively or synergistically in their ability to mask the bitterness of the rho kinase inhibitor. Synergy may exist between the bitterness masking agent and one or more other taste masking agents.

[0027] An example of a bitterness masking agent that can be bound to a rho kinase inhibitor is an ion exchange resin. Thus, a rho kinase inhibitor can be bound to an ion exchange resin. The ion exchange resin can include a cation exchange resin, an anion exchange resin, or an amphoteric ion exchange resin, or any combination thereof. A single type of ion exchange resin can be used, or a combination of different ion exchange resins can be used. The different ion exchange resins can act synergistically. The ion exchange resin can include a single type of functional group. The ion exchange resin can include multiple different functional groups that differ, for example, in terms of pKa. The bitterness masking agent can include a cation exchange resin. A single type of cation exchange resin can be used, or a combination of different cation exchange resins can be used. The different cation exchange resins can act synergistically. The cation exchange resin can include a salt of a polymer with a carboxylic acid functional group. The cation exchange resin can include a weak acid or a salt thereof. The cation exchange resin can include a strong acid or a salt thereof. The cation exchange resin can include a copolymer of methacrylic acid or styrene and divinylbenzene. The cation can include a crosslinked polymer. Examples of cation exchange resins include AMBERLITE IRP 64 (polacrylin, also known as polacrilex, DuPont) [2-methyl-2-propenoic acid polymer with diethenylbenzene], AMBERLITE IRP 69 (DuPont) (sulfonated copolymer of styrene and divinylbenzene), AMBERLITE IRP 88 (polacrylin potassium, DuPont) [2-methyl-2-propenoic acid potassium salt polymer with diethenylbenzene], INDION 204 (Ion Exchange, Mumbai, India), and INDION 234 (Ion Exchange, Mumbai, India). Polacrilin resin (AMBERLITE IRP-64 or polacrilex) can be prepared by copolymerization of methacrylic acid and divinylbenzene (DVB).The resin can then be neutralized with potassium hydroxide to produce polacrilin potassium (AMBERLITE IRP-88). Other salts of polacrilin can be produced and employed, for example, polacrilin sodium can be produced using sodium hydroxide. Examples of some ion exchange resins are shown in Table A. [Table 1]

[0028] A combination of two or more ion exchange resins can be used, for example, two, three, four, five, six, seven, eight, nine, ten or more different ion exchange resins can be used. When different ion exchange resins are employed, they can be all cation exchange resins, or all anion exchange resins, or all amphoteric ion exchange resins, or any combination of different categories of ion exchange resins. When two or more different ion exchange resins are employed, the weight ratio between any two different ion exchange resins, for example, the weight ratio between a first ion exchange resin and a second ion exchange resin, can be from about 1:100 to about 1:1, from about 1:50 to about 1:25, from about 1:25 to about 1:10, from about 1:10 to about 1:5, from about 1:5 to about 1:2.5, from about 100:1 to about 1:1, from about 50:1 to about 25:1, from about 25:1 to about 10:1, from about 5:1 to about 2.5:1, from about 1.5:1 to about 3:1, from about 2.0:1 to about 2.7:1, or about 2.5:1, or any intermediate ratio, or any intermediate range.

[0029] Thus, a composition is provided that may include at least a rho kinase inhibitor and an ion exchange resin with a bitter taste. Once bound to an ion exchange resin, the complex can be used directly as a pharmaceutical product or as a building block to be included in other formulations. It can be, for example, pressed into tablets, encapsulated, and used to make powders for suspensions, among other approaches. The present invention relates to pharmaceutical formulations, and therefore does not relate to fasudil or any other rho kinase inhibitor bound to an ion exchange resin on a chromatography column. The resins of such columns are not suitable for good manufacturing process standards, are not suitable for human consumption, and have much less pharmaceutical use. Thus, the formulation according to the present invention does not explicitly include a chromatography column. Advantageously, the formulations, such as dry power, granules, beads, etc., can be divided into unit doses. Such unit doses typically contain 20-180 mg of fasudil hydrochloride hemihydrate together with a cation exchange resin in a ratio (drug:resin) of about 1:2 to about 1:5, about 1:2.75 to about 1:3.3, about 1:2.5 to about 1:4.5, or about 1:3. Other unit doses contain an appropriate amount of fasudil for the desired dose, as well as a corresponding amount of resin. Exemplary unit doses may contain 20, 30, 40, 60, 80, 120, or 180 mg of fasudil hydrochloride hemihydrate.

[0030] The taste masking composition can comprise any suitable amount of rho kinase inhibitor and taste masking agent.The taste masking agent can be present in a sufficient amount relative to the rho kinase inhibitor to make the composition more palatable, but not enough to prevent patients from consuming the composition, although some of the aversive taste remains.However, the aversive taste can be reduced to a level that the composition can be deployed in a placebo-controlled study, so that patients cannot distinguish the difference between the same composition with or without the rho kinase inhibitor. Thus, the composition can include any suitable weight ratio of taste masking agent to rho kinase inhibitor, for example, the weight ratio of taste masking agent to rho kinase inhibitor can be about 1:100 to about 1:1, about 1:50 to about 1:25, about 1:25 to about 1:10, about 1:10 to about 1:5, about 10:1 to about 1:10, about 1:5 to about 1:2.5, about 100:1 to about 1:1, about 50:1 to about 25:1, about 25:1 to about 10:1, about 5:1 to about 2.5:1, about 1.5:1 to about 3:1, about 2.0:1 to about 2.7:1, or about 2.5:1, or any intermediate ratio or range. For example, the weight ratio of the rho kinase inhibitor to the taste masking agent can be about 1:1 to about 1:10, about 1:2 to about 1:9, about 1:3 to about 1.6.5, about 1:3.5 to about 1:4, about 1:3.5 to about 1:4.5, about 1:3.3 to about 1:3.6, about 1:3.6 to about 1:3.9, about 1:4 to about 1:6, about 1:4 to about 1:4.5, about 1:4.2 to about 1:4.7, about 1:4.5 to about 1.5.5, about 1:4.5 to about 1:5, about 10:1 to about 1:10, or any intermediate ratio or range. For example, the rho kinase inhibitor can include fasudil, and the taste masking agent can include a resin to which fasudil can be bound.

[0031] The taste masking composition in liquid form may be aqueous and may include one or more suspending agents. A suspending agent is an agent that aids in the suspension of one or more components of a composition when the composition is formulated as an aqueous composition. A suspending agent may also have one or more other functions. A suspending agent may include, for example, a viscosity modifier or a dispersing agent. A viscosity modifier may include, for example, a thickener, or a viscosity reducing agent, or both. One or more wetting agents may be used. A suspending agent may include cellulose or a derivative thereof, such as a cellulose ether, or a cellulose ester, or both. A cellulose ether may include one or more cellulose ethers. A cellulose ether may include, for example, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose (HEMC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), or sodium carboxymethylcellulose (NaCMC), or any combination thereof. A cellulose ester may include one or more cellulose esters. A cellulose ester may include, for example, an ester of one or more acids containing from about 1 to about 6 carbons. The cellulose esters can include, for example, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose nitrate, cellulose phosphate, or cellulose sulfate, or any combination thereof.

[0032] The suspending agent may include one or more non-cellulosic polysaccharides. For example, the non-cellulosic polysaccharides may include one or more gums. The non-cellulosic polysaccharides may include pentosans, hexoses, or both. The non-cellulosic polysaccharides may include one or more types of monosaccharides. The non-cellulosic polysaccharides may include two or more of glucose, mannose, and glucuronic acid. The non-cellulosic polysaccharides may include a repeating subunit that includes two glucose residues, two mannose residues, and a glucuronic acid residue. The non-cellulosic polysaccharides may include one or more gums. The gums may include synthetic gums, or natural gums, or both. The gum may include guar gum, ghatti gum, karaya gum, kaya gum, tragacanth gum, carrageenan, acacia gum, albidi gum, mond gum, bara gum, carob gum, cashew gum, benjamin gum, olibanum gum, gellan gum, locust bean gum, pullulan gum, phosphomannan gum, scleroglucan gum, tabland gum, xanthan gum, alginate, starch, dextrin, or pectin, or any combination thereof. The suspending agent may include one or more pyrrolidinone-containing polymers. The pyrrolidinone-containing polymer may include a crosslinked pyrrolidinone-containing polymer. The pyrrolidinone-containing polymer may include povidone, copovidone, or crospovidone, or any combination thereof. The suspending agent may include one or more of bentonite, calcium stearate, carbomer, colloidal silicon dioxide, gelatin, kaolin, magnesium aluminum silicate, monoglycerides, diglycerides, triglycerides, polycarbophil, polyethylene glycol, or oils, or any combination thereof.

[0033] The taste masking composition in liquid form can be aqueous and can include any number of different suspending agents. For example, the composition can include one, two, three, four, five, six, or more different suspending agents. The composition can include a first suspending agent and a second suspending agent. The first suspending agent can include, for example, a cellulose ether, and the second suspending agent can include, for example, a non-cellulose polysaccharide. The composition can include any suitable amount of the first suspending agent and the second suspending agent. The composition can include any suitable weight ratio of the first suspending agent to the second suspending agent, for example, the weight ratio of the first suspending agent to the second suspending agent can be about 1:100 to about 1:1, about 1:50 to about 1:25, about 1:25 to about 1:10, about 1:10 to about 1:5, about 1:5 to about 1:2.5, about 100:1 to about 1:1, about 50:1 to about 25:1, about 25:1 to about 10:1, about 5:1 to about 2.5:1, about 1.5:1 to about 3:1, about 2.0:1 to about 2.7:1, or about 2.5:1, or any intermediate ratio or range.

[0034] The taste masking agent may include one or both of a sweetener and a flavoring agent. Any number and type of sweetener may be used. The sweetener may include one or more syrups. The sweetener may include one or both of a sugar and an artificial sweetener. The sugar may include, for example, a sugar alcohol. The sugar may include glucose, fructose, galactose, erythritol, sucrose, lactose, mannose, raffinose, or dextrose, or any combination thereof. The sweetener may include a natural sweetener, or an artificial sweetener, or both. The natural sweetener may include, for example, stevia or another steviol glycoside. The artificial sweetener may include aspartame, sucralose, acesulfame potassium, saccharin, or xylitol, or any salt thereof, or any combination thereof. The sweetener may include a low-calorie sweetener or a zero-calorie sweetener, the low calorie being compared to the calorie content of sucrose. The flavoring agent may include natural flavoring agents, or artificial flavoring agents, or both. The flavoring agent may be, for example, a fruit or fruit-like flavoring agent, such as cherry, strawberry, blueberry, banana, orange, lemon, lime, citrus, or mango, or any combination thereof. The flavoring agent may also be a spice or a compound having a spice-like flavor. Other examples of flavoring agents include vanilla, chocolate, cinnamon, menthol, mint, spearmint, or peppermint, or any combination thereof. The composition may include a coloring agent or a combination of coloring agents. One or more coloring agents may be selected to complement one or more flavoring agents of the composition and aid in compliance.

[0035] The taste-masking composition may include a humectant, such as ammonium alginate, cyclomethicone, glycerin, polydextrose, propylene glycol, sodium hyaluronate, sodium lactate, sorbitol, trehalose, triacetin, triethanolamine, or xylitol, or any combination thereof. The composition may include a chelating agent, an antioxidant, or a preservative, or any combination thereof. The pharmaceutical composition of the present disclosure may include a preservative. Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, antiprotozoal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. The preservative may be an antioxidant. The preservative may be a chelating agent. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, parabens (e.g., methyl-, ethyl-, and propyl-paraben and mixtures thereof), sorbic acid, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0036] The taste masking composition may be buffered to resist or minimize changes in pH. For example, the composition may contain a buffering agent, whether aqueous or otherwise. Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and combinations thereof. The aqueous composition can have a pH of less than about 4.0, greater than about 10.0, about 4.0 to about 10.0, about 5.0 to about 8.0, about 5.5 to about 7.5, about 6.0 to about 7.0, about 6.2 to about 6.8, or about 6.3 to about 6.5, or any value or range therebetween. The pH of the aqueous composition can affect the bitterness, and in turn the taste threshold concentration, of the rho kinase inhibitor. The pH can be slightly acidic to aid palatability.

[0037] The aqueous taste-masking composition may comprise a solution, a suspension, an emulsion, a gel, or a colloid, or any combination thereof. The aqueous composition may comprise a single phase or multiple phases. The aqueous composition may be an elixir. The aqueous composition may be a syrup. Water may be the only solvent present in the aqueous composition. One or more additional solvents may be present in the aqueous composition. The additional solvents may include, for example, ethanol, glycerin, propylene glycol, or polyethylene glycol, or any combination thereof. One or more components of the aqueous composition may be in solution. One or more components of the same aqueous solution may be in suspension. After mixing, shaking, vortexing, sonication, or other agitation, the components in the suspension can remain in suspension for less than about 10 seconds, about 10 seconds to about 10 years, about 30 seconds to about 5 years, about 1.0 minutes to about 2.5 years, about 2.0 minutes to about 1.5 years, about 5.0 minutes to about 1.0 years, about 10 minutes to about 8 months, about 20 minutes to about 6 months, about 30 minutes to about 3 months, about 1.0 hours to about 1.0 month, about 3.0 hours to about 30 days, about 6.0 hours to about 3 weeks, about 12 hours to about 2.0 weeks, about 1.0 day to about 1.0 week, about 3 days, or 10.0 years or more, any period in between, or any range in between. Components of the suspension or solution, or both, can include, for example, a rho kinase inhibitor, or a taste masking agent, or both. Powder, granule, or sprinkle, or any combination thereof, can be a solution or suspension, or both.When added to aqueous carrier, the solid dosage form can be considered as an aqueous composition according to the present disclosure.For example, powder, granule, sprinkle, effervescent tablet, or dissolving tablet, or any combination thereof, can be added to liquid and can be the aqueous composition of the present disclosure.

[0038] The composition, aqueous or otherwise, can be prepared, stored, or administered at any suitable temperature. For example, the temperature can be less than about -20°C, about -20°C to about 100°C, about -10°C to about 75°C, about 0°C to about 60°C, about 5°C to about 50°C, about 10°C to about 40°C, about 15°C to about 30°C, about 20°C to about 25°C, or about ambient temperature, or any temperature therebetween, or any range therebetween. The composition can be stored at a controlled room temperature, for example, in the range of 20°C to 30°C. Aqueous compositions can be lyophilized and then reconstituted. Aqueous compositions can be concentrated or otherwise prepared in a more concentrated form and then diluted.

[0039] Aqueous compositions can be formulated as oil-in-water emulsions, water-in-oil emulsions, or both. One or more components of the aqueous composition can be in the aqueous phase of the emulsion. One or more components of the same aqueous solution can be in the oil phase of the emulsion. Aqueous compositions can include an emulsifier. The emulsifier can include one or more suspending agents. Emulsifiers include, for example, anionic emulsifying wax, calcium stearate, carbomer, cetosteryl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glyceryl monostearate, glyceryl monooleate, hectite, lanolin, lauric acid, lecithin, linoleic acid, triglycerides, mineral oil, monobasic sodium phosphate, monoethanolamine, myristic acid, nonionic emulsifying wax, octyldodecanol, oleic acid, oleyl alcohol, palmitic acid, polycarbophil, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, saponite, self-emulsifying glyceryl monostearate, sodium borate, sodium citrate dihydrate, sodium lauryl sulfate, sorbitan esters, stearic acid, or triethanolamine, or any combination thereof.

[0040] Aqueous compositions can be formulated as gels.One or more gelling agents can be used, including, for example, aluminum stearate, calcium silicate, carbomer, sodium carboxymethylcellulose, carrageenan, chitosan, colloidal silicon dioxide, gelatin, glyceryl monooleate, glyceryl palmitostearate, guar gum, hydroxyethylcellulose, microcrystalline cellulose, pectin, polyethylene alkyl ether, polyethylene glycol, polyethylene oxide, polymethacrylate, propylene carbonate, sodium ascorbate, sodium alginate, sorbitol, urethane, or zinc acetate, or any combination thereof.Gels can have any desired viscosity.Gels or other compositions described herein can be thixotropic.

[0041] The taste threshold concentration is the concentration at which the bitter taste of the rho kinase inhibitor can be perceived by the patient on average. The taste threshold concentration can be significant for at least two reasons. First, it can establish the concentration above which taste masking is desirable. Hence, liquid formulations requiring taste masking will contain the active ingredient at a concentration above the taste threshold. Second, if the formulation contains a taste masking agent that binds to or forms a complex with the active ingredient, the taste threshold becomes a target for assessing the amount of "free" active ingredient. Taste masking can be most effective when the supernatant / unbound fraction contains a concentration of the active ingredient near or below the taste threshold.

[0042] The amount of free unbound rho kinase inhibitor in the formulation can be below the taste threshold. The unbound rho kinase inhibitor can be present at less than twice the taste threshold. For example, fasudil hydrochloride has a taste threshold concentration for most people in the range of 0.3-0.4 mg / ml. Thus, a liquid formulation taste-masked formulation containing fasudil can have an overall minimum (bound and unbound) concentration of greater than 0.3-0.4 mg / ml, and an effectively taste-masked formulation can have unbound fasudil of about 1 mg / ml or less.

[0043] The threshold concentration can be less than about 0.01 mg / mL, about 0.01 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 5.0 mg / mL, about 1.0 mg / mL to about 3.0 mg / mL, greater than about 10 mg / mL, about 0.01 mg / mL to about 100 mg / mL, about 0.1 mg / mL to about 75 mg / mL, about 0.2 mg / mL to about 0.5 mg / mL, about 0.3 mg / mL to about 0.4 mg / mL, about 0.25 mg / mL to about 0.35 mg / mL, about 0.5 mg / mL to about 50 mg / mL, about 1.0 mg / mL to about 25 mg / mL, about 2.0 mg / mL to about 20 mg / mL, about 2.5 mg / mL to about 15 mg / mL, or about 100 mg / mL or greater, or any concentration therein, or any intervening range. The rho kinase inhibitor can be present in any corresponding concentration or range. The taste threshold concentration can be influenced and adjusted based on one or more parameters of the aqueous composition. For example, the taste threshold concentration can be influenced or adjusted based on pH, the taste of one or more other compounds present in the aqueous composition, temperature, or viscosity, or any combination thereof. The one or more taste masking agents present in the aqueous composition, or the taste threshold concentration, or both, can be less than about 0.01 mg / mL, about 0.01 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 5.0 mg / mL, about 1.0 mg / mL to about 3.0 mg / mL, greater than about 10 mg / mL, about 0.01 mg / mL to about 100 mg / mL, about 0.1 mg / mL to about 75 mg / mL, about 0.5 mg / mL to about 50 mg / mL, about 1.0 mg / mL to about 25 mg / mL, about 2.0 mg / mL to about 20 mg / mL, about 2.5 mg / mL to about 15 mg / mL, or about 100 mg / mL or greater, or any concentration therein, or any intervening range.

[0044] The taste threshold concentration may be based on, for example, the average of a taster population. The taster population may include one or more of average tasters, supertasters, and non-tasters. The taster population may include essentially all or exclusively supertasters, for example, to provide an aqueous composition of acceptable palatability independent of the patient to whom the composition is administered. Tasters may be characterized based on their ability to detect qualitatively, quantitatively, or both of one or more compounds. The rho kinase inhibitor of the composition may be used alone, or alternatively substituted with one or more other compounds, or used in combination with one or more other compounds for taste testing.

[0045] Tasters may be characterized based on, for example, perception of phenylthiocarbamide (PTC), or 6-n-propylthiouracil, or both. Tasters may be characterized based on a genetic profile defined by one or more taste receptors. The genetic profile may be based on one or more alleles of one or more taste receptor genes. The one or more taste receptors may include one or more type 2 family taste receptors (T2Rs). The one or more taste receptors may include, for example, the TAS2R38 gene. An allele may include one or more polymorphisms associated with a taste receptor gene, for example, one or more polymorphisms in the TAS2R38 gene. An allele may include one or more haplotypes associated with a taste receptor gene, for example, one or more polymorphisms in the TAS2R38 gene. A polymorphism may include a single nucleotide polymorphism (SNP). Three examples of SNPs include 145 C>G (Pro49Ala), 785 C>T (Ala262Val), and 886 G>A (Val296Iso). SNP-based TAS2R38 alleles can help determine tasters' sensitivity to bitterness. The PAV (proline, alanine, valine) TAS2R38 haplotype can be associated with bitterness sensitivity as a supertaster. The AVI (alanine, valine, isoleucine) TAS2R38 haplotype can be associated with bitterness insensitivity as a non-taster variation. Tasters homozygous for PAV (PAV / PAV) can be classified as supertasters with respect to bitterness. Tasters heterozygous for PAV (PAV / AVI) can be classified as (normal) tasters with respect to bitterness. Tasters homozygous for AVI (AVI / AVI) can be classified as non-tasters with respect to bitterness.

[0046] The amount of free, unbound rho kinase inhibitor in the formulation can be below the taste threshold. In the presence of an agent that binds to the rho kinase inhibitor, the unbound rho kinase inhibitor is generally present at about 3 times or less the taste threshold. Up to about 1 times above the taste threshold, the taste is generally palatable, but can be tasted even without additional taste masking. Up to about 2 times above the taste threshold, the taste is tolerable and less palatable. Above 3 times the taste threshold, the taste begins to become aversive without some taste masking. For example, fasudil hydrochloride has a taste threshold concentration for most people in the range of 0.1-0.4 mg / mL (a range that accounts for "super" and "ordinary" tasters). Thus, liquid formulations containing fasudil generally do not require taste masking at concentrations below this threshold. Exemplary minimum fasudil concentrations of taste-masking liquid formulations include 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, and 0.4 mg / mL. Similarly, the taste threshold of hydroxyfasudil (M3) is within the range of about 0.3 mg / mL to about 0.75 mg / mL, so exemplary minimum hydroxyfasudil concentrations of taste-masking liquid hydroxyfasudil formulations are 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, and 0.75 mg / mL. The taste threshold of hydroxyfasudil can be, for example, about 0.7 mg / mL to about 0.9 mg / mL. The amount of hydroxyfasudil in the supernatant can be, for example, less than about 3 mg / mL for palatability. When assessing the potential palatability of formulations containing drugs that bind to rho kinase inhibitors, the unbound amount (indicating palatability) should generally be less than 3x the taste threshold, approximately 1 mg / ml for fasudil and 2.25 mg / ml for hydroxyfasudil.

[0047] The rho kinase inhibitor may be present in a concentration that allows for a reasonable volume of aqueous composition per dose administered. For example, the rho kinase inhibitor may be present in about 0.1% w / v to about 10% w / v, about 0.25% w / v to about 4.0% w / v, about 0.33% w / v to about 3.0% w / v, about 0.5% w / v to about 5.0% w / v, about 1.0% w / v to about 2.5% w / v, about 1.0% w / v to about 4.9% w / v, about 1.0% w / v to about 3.0% w / v, about 1.2% w / v to about 1.8% w / v, about 1.5% w / v to about 2.0% w / v of the aqueous composition, or any intervening percentage, or any intervening range. The taste threshold concentration may also correspond to one or more of these percentages or ranges. Reasonable volumes for a single dose can be less than about 1.0 mL, about 1.0 mL to about 1.0 L, about 2.5 mL to about 500 mL, about 4.0 mL to about 8 mL, about 4.5 mL to about 6 mL, about 5.0 mL to about 250 mL, about 7.5 mL to about 100 mL, about 10 mL to about 50 mL, about 15 mL to about 30 mL, or more than about 1.0 L, or any intervening volume, or any intervening volume range. Dosage volume ranges can be, for example, 0.5 mL to 20 mL, or 1 mL to 10 mL, or 3 mL to 6 mL. The compositions can be provided in concentrates and then diluted prior to administration.

[0048] Each of the one or more suspending agents may be present in the composition in any suitable amount. The suspending agents may be present, for example, in less than about 0.1% w / v, about 0.1% w / v to about 50% w / v, about 0.25% w / v to about 25% w / v, about 1.0% w / v to about 20% w / v, about 1.5% w / v to about 15% w / v, about 2.0% w / v to about 10% w / v, about 2.5% w / v to about 7.5% w / v, about 3.5% w / v to about 6.0% w / v, about 4.0% w / v to about 5.0% w / v, or about 25% w / v or more of the aqueous composition, or any intervening percentage, or any intervening percentage range. For example, the first suspending agent may be present at about 0.5% w / v to about 2.0% w / v of the aqueous composition and the second suspending agent may be present at about 0.1% w / v to about 1.0% w / v of the aqueous composition, or vice versa.

[0049] The aqueous taste-masking composition can have any desired viscosity. For example, the viscosity of the aqueous composition can be less than about 1.0 cSt, about 1.0 cSt to about 1,000 cSt, about 5.0 cSt to about 500 cSt, about 10 cSt to about 400 cSt, about 25 cSt to about 300 cSt, about 40 cSt to about 250 cSt, about 50 cSt to about 200 cSt, about 50 cSt to about 2,500 cSt, about 60 cSt to about 180 cSt, about 75 cSt to about 150 cSt, about 100 cSt, about 500 cSt to about 5,000 cSt, about 1,000 cSt to about 3,500 cSt, greater than about 1,000 cSt, greater than about 5,000 cSt, or any intervening viscosity, or any intervening range. The selected viscosity value or range can be achieved, optionally, by the presence of a viscosity modifier. A particular viscosity may be selected to aid in compliance. Aqueous compositions may be formulated according to the International Dysphagia Diet Standardization Initiative (IDDSI) for beverage thickness on a scale of "0" for thin, "1" for slightly thick, "2" for mildly thick, "3" for moderately thick, or "4" for extremely thick, as confirmed by IDDSI flow tests, all such tests being incorporated herein in their entirety. The IDDSI Framework and Level of Detail Definitions (July 2019) are incorporated herein by reference in their entirety. Suspensions for use with dysphagia populations may range, for example, from 2 on the IDDSI scale.

[0050] The aqueous taste masking composition of the present disclosure can be packaged in any suitable form. For example, the composition can be packaged in a bottle or other liquid container in a ready-to-use form. An optional cup or other volumetric dispenser can be provided with the bottle. The cup can have a volume associated with a predetermined volumetric dose of the composition. The cup can optionally be graduated to allow for volumetric measurement. The cup can include one or more graduations or other markings indicating one or more volumetric doses. The composition can be packaged as a dry concentrate, a liquid concentrate, or both. The composition can be packaged in separate mixtures such that one or more components are separated from one or more other components in two or more compartments of the package. For example, a sachet, stick, capsule, or blister pack, or any combination thereof, can be used, where each sachet, stick, capsule, or blister unit of the pack contains, for example, a dose of powder, granule, or sprinkle, or any combination thereof, to be mixed with water alone or one or more additional components to form an aqueous composition.

[0051] The taste masking composition can be formulated so that the composition can be easily administered to subjects with dysphagia.Dysphagia is characterized by difficulty in swallowing.Dysphagia can be associated with difficulty in moving food or liquid from the mouth to the hypopharynx or through the esophagus.Dysphagia can have any number of different causes. For example, dysphagia may be due to a neurodegenerative disease such as Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis (ALS), motor neuron disease (including amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), pseudobulbar palsy, progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), spinal muscular atrophy (SMA) and monomuscular muscular atrophy (MMA), as well as some rarer variants that resemble ALS), Parkinson's disease, Huntington's disease, multiple sclerosis, progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS), or any combination thereof, or a condition affecting the nervous system (such as a stroke or head injury), cancer (such as oral or esophageal cancer), or gastroesophageal reflux disease (GORD) (stomach acid leaking back into the esophagus). Signs and symptoms associated with dysphagia may include, for example, one or more of the following: pain during swallowing, inability to swallow, feeling that food is stuck in the throat or behind the chest (sternum) or breast bone, drooling, hoarseness, reflux (regurgitation) of food, frequent heartburn, reflux of food or stomach acid into the throat, or coughing or choking when swallowing.Dysphagia-prone formulations may be applied to subjects of any age.Such formulations may be used for elderly people, but may also be useful when administered to pediatric or adult patients who do not necessarily suffer from dysphagia based on weight, renal function, body surface area, or any number of potential variables.

[0052] The taste masking composition can be formulated such that the rho kinase inhibitor is present in an amount sufficient to treat a neurodegenerative disease, including, for example, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, multiple sclerosis, progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS), or any combination thereof.

[0053] Methods of treating neurodegenerative diseases are provided, the methods comprising administering to a patient a taste masking composition of the present disclosure in an amount sufficient to treat the neurodegenerative disease. For example, the amount of rho kinase inhibitor per dose can be less than about 0.5 mg, about 0.5 mg to about 250 mg, about 5.0 mg to about 225 mg, about 10 mg to about 200 mg, about 20 mg to about 180 mg, about 25 mg to about 170 mg, about 30 mg to about 160 mg, about 40 mg to about 150 mg, about 50 mg to about 140 mg, about 60 mg to about 120 mg, about 75 mg to about 100 mg, or 250 mg or more, or any amount therebetween, or any range therebetween. These amounts can refer to the rho kinase inhibitor, its pharma- ceutically acceptable salt, its hydrate, its prodrug, its substituted derivative, or its metabolite, or any combination thereof. Some examples of daily doses are listed in Table B for various therapeutic targets. Doses outside these ranges or overlapping these ranges may also be used. Doses can be adjusted based on the weight, health, and other factors of a particular patient or group of patients. A daily dose of fasudil can be 180-360 mg for an immediate release formulation administered two to three times daily. Thus, each individual dose will contain 60-180 mg of fasudil, e.g., 60, 90, 120, or 180 mg.

[0054] Fasudil hydrochloride hemihydrate may be replaced by a molar equivalent of another salt, hydrate, prodrug, or active metabolite of fasudil or other rho kinase inhibitor. Administration may be performed once a day, twice a day, three times a day, four times a day, every other day, every third day, weekly, biweekly, monthly, less frequently, more frequently, or any frequency in between, or any range of frequencies in between. For example, the daily dose of fasudil is at least 70 mg, but generally can be 180 mg to 360 mg, for immediate release formulations administered two to three times a day. Each individual dose may contain 60 to 180 mg of fasudil, e.g., 60, 90, 120, or 180 mg. Extended release formulations generally contain proportionally more active due to inefficiencies in delivery, such as incomplete release. Thus, for example, extended release targeted to deliver the entire daily dose may contain an additional 10 to 20% fasudil. Examples of daily dose ranges are shown in Table B. Daily dose ranges may be broader than those shown in Table B, and the ranges may shift to lower or higher doses. 180 mg / day is not an upper limit, for example, doses may range to 240 mg / day or more. [Table 2-1] [Table 2-2]

[0055] Dosing can be modified and customized depending on the specific patient situation. For example, doses can be modified for patients with renal impairment. Fasudil dosing for patients with mild to moderate renal impairment can be reduced to about 5.0 to about 25 mg per day to about 2.5 mg to about 15 mg per day. Individual doses of fasudil can be used. For patients with serum creatinine (SCr) >2, and / or an increase in Scr >1.5-fold from baseline, and / or an eGFR decrease of >25% from baseline, doses can be reduced. Liver health and metabolic enzyme alleles can be considered in dosing. For example, dosing can be modified depending on whether the patient is a fast or slow metabolizer of fasudil or other rho kinase inhibitors. Patient size should be considered when using creatinine-based estimates of renal function. The unit of drug clearance can be volume / time (mL / min), while the unit of estimated GFR for chronic kidney disease is volume / time / standard size (mL / min / 1.73 m 2 ) can be used. Doses can be adjusted downwards for smaller patients (e.g., about 2.5 mg to about 15 mg per day) and upwards for obese patients (e.g., up to 30 mg per day). Smaller males can weigh about 160 pounds or less. Smaller female patients can weigh about 130 pounds or less. Patients with a body mass index (BMI) of 30 or greater can be considered obese.

[0056] Older patients may be administered a lower dose at the beginning and gradually increased to the recommended dose after a few days or weeks. Elderly patients may be administered a lower dose during the treatment period. Elderly populations may include "pre-elderly" which may be about 65 to about 74 years old, "elderly" which may be about 75 to about 84 years old, and "frail elderly" which may be 85 years old or older. For example, a starting dose of 10 mg per day may be administered for 2 weeks, followed by 20 mg per day for 4 weeks, followed by 25 mg per day thereafter. Titration may be performed, for example, up to 30 mg per day. The method of administering the composition may continue for any suitable period of time, for example, at least 1 day, up to 30 days, up to 60 days, or up to 90 days, at least 6 months, or more than 90 days. The treatment period depends on the patient's condition and response to treatment. The method may further include diagnosing the neurodegenerative disease in the patient prior to administering the composition to the patient. Treating the neurodegenerative disease may include alleviating symptoms of the neurodegenerative disease. The administering can include self-administration. The method can include tracking compliance with the administration. The method can further include diagnosing the non-neurodegenerative disease in the patient prior to administering the composition to the patient.

[0057] The taste masking compositions, or methods, or both of the present disclosure can combine one or more rho kinase inhibitors, such as fasudil, with other compounds used to treat dementia or other symptoms of dementia. These can be administered in combination, in a single dosage form, in separate dosage forms, through the same route of administration, through different routes of administration, in a common dosing regimen, or in independent dosing regimens, or in any combination thereof. The composition can include, for example, fasudil in combination with one or more active pharmaceutical ingredients (APIs) suitable for treating cortical dementia, such as a cholinesterase inhibitor and an NMDA receptor antagonist. The cholinesterase inhibitor can be selected from one or more of donepezil, rivastigmine, and galantamine. Exemplary doses of the cholinesterase inhibitor can include about 3.0 mg to about 25 mg per day, or about 6.0 mg to about 12 mg per day. The NMDA receptor antagonist can be memantine. For example, memantine can be administered at a dose of about 5.0 to about 28 mg per day, or about 15 mg to about 20 mg per day. The co-administered API can be, for example, a combination of donepezil and memantine at a dose of about 28 mg memantine and about 10 mg donepezil. A combination of fasudil and one or more cholinesterase inhibitors can be administered to patients with proteinosis-associated cortical dementia. A combination of fasudil and a cholinesterase inhibitor is administered to patients with mixed dementia. For patients with only vascular cortical dementia, the coadministration of fasudil and a cholinesterase inhibitor can be excluded. Dextromethorphan hydrobromide is another NMDA receptor antagonist that also has activity as a sigma-1 receptor agonist. The product Nudexta, which is marketed in combination with quinidine sulfate (a CYP450 2D6 inhibitor), is indicated for the treatment of emotional dysregulation that occurs in many forms of dementia. Such APIs and agents can be administered in combination with a rho kinase inhibitor, such as fasudil. Patients treated with the compositions described herein can be treated for depression, for example, patients treated with antidepressants such as citalopram or escitalopram.

[0058] Methods are provided by the present disclosure that include administering to a patient a composition of the present disclosure in an amount sufficient to generally treat a disease or alleviate a symptom of a neurodegenerative disease. Diseases may include, for example, dementia, Huntington's disease, autism spectrum disorder, Down's syndrome, Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, chronic head injury, normal pressure hydrocephalus, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and other motor neuron diseases. Other motor neuron diseases include, for example, X-linked spinal-bulbar muscular atrophy (Kennedy's disease), adult Tay-Sachs disease, spinal muscular atrophy, multifocal motor neuropathy with conduction block, primary lateral sclerosis, and familial spastic paraplegia, or any combination thereof. Dementia associated with cerebrovascular accident (CVA, or stroke) may be referred to as vascular dementia.

[0059] An example of a symptom is wandering. Wandering can include behaviors such as excessive movement and pacing. The patient can be evaluated by assessing physical parameters, psychological parameters, or both. The evaluation can be done, for example, via a verbal neurological examination, such as a written neurological examination, or a verbal neurological examination, or both. The evaluation can be done through observation of the patient's physical behavior, psychological behavior, or both. The evaluation can be done via imaging, for example, brain computer-assisted tomography (CAT), brain magnetic resonance imaging (MRI), brain diffusion tensor imaging (DTI), or brain positron emission tomography (PET), or any combination thereof. The imaging can evaluate any suitable feature, such as, for example, blood flow, brain size, brain morphology, brain tissue, or physical features of the brain, or any combination thereof for the entire brain or a portion thereof. The physical features can include, for example, plaques, tangles, bodies, or inclusions, or any combination thereof. Exemplary relevant brain parts include the ventricles, hippocampus, frontal operculum, precentral gyrus, midbrain, pons and superior cerebellar peduncle, white matter tract integrity, oblique tract, superior longitudinal fasciculus, superior cerebellar peduncle, or substantia nigra, any combination thereof. The evaluation can be performed, for example, by evaluating one or more biomarkers from the patient's urine, the patient's blood, or the patient's cerebellar spinal fluid, or any combination thereof. Biomarkers can include, for example, nucleic acids, proteins, polysaccharides, lipids, metals, salts, neurotransmitters, enzymes, transcription factors, receptors, ligands, vitamins, minerals, or metabolites, or any combination thereof. Biomarkers can be evaluated for levels or changes in concentration, expression, distribution, structure, folding, conformation, molecular interactions, or chemical modifications, or any combination thereof. Examples of neurological biomarkers include amyloid beta protein, alpha-synuclein, tau protein, phosphorylated tau, neurofilament light chain (NfL), total tau fragment levels, fusion in sarcoma (FUS) protein, TAR DNA binding protein 43 (TDP-43), prion, or neurotransmitters such as dopamine, or any combination thereof.Assessment can be through any suitable protocol, such as the Global Inventory of Wandering (GIW), the RAWS-CV (Algase Wandering Scale Revised - Community Version) scale, the Mini-Mental State Examination (MMSE), the Neuropsychiatric Inventory-Questionnaire (NPI-Q), the Cohen-Mansfield Agitation Inventory - Community Version (CMAI-C), the Center for Neurological Study-Labileness Scale (CNS-LS), or the Zarit Caregiver Burden Scale (ZBI), or any combination thereof.

[0060] Patients treatable with the compositions disclosed herein may score poorly on cognitive assessment scales such as the Mini-Mental State Examination (MMSE). A threshold of ≦23 on the MMSE may be set for dementia, with a score of ≦15 representing severe dementia. Patients may be treated if their MMSE score is ≦23, including moderately demented patients with an MMSE score of 16-23, and severely demented patients with an MMSE score of ≦15. When patients have an MMSE score of less than 9, they may have problems walking, and treatment may be omitted for patients with an MMSE score of less than 5. Once the MMSE is less than 15, the Severe Impairment Examination (SIB) may be a useful assessment. Treatment with the compositions disclosed herein may result in improved cognitive function. Patients may show an improvement in MMSE and SIB of at least 3 points during the initial phase of treatment. Cognitive decline may be delayed compared to control patients.

[0061] Wandering and other symptoms can be treated by the compositions and methods of the present disclosure. Wandering can be characterized by two domains. The first domain can be movement, generally in the form of walking, unless the patient becomes disabled and is, for example, limited to a wheelchair. The second domain can be problematic behavior, for example, in the form of boundary deviation or problem with wayfinding ability, or both. Such behavior can be reflected in the movement itself, such as gait or circling behavior. The behavior can include inappropriately following a caregiver. One common problematic behavior is escape or escape attempts. A certain amount of movement can also be considered problematic behavior. A normal person is moving about 10% of the waking time, and movement that exceeds this threshold amount can be considered problematic behavior. A patient can be considered to suffer from wandering when they are moving at least 20% of the waking time, or 30% or more of the waking time. When a patient is moving for a long time, the behavior can be particularly problematic because of the risk of exhaustion and therefore falls and serious injury. Patients are mobile for more than 40% or 50% of their waking hours, or even 60%, 70%, or even 80% or more.

[0062] Wandering and other symptoms may be persistent or sporadic, and the compositions may be used to treat either population. Persistent wandering may present with excessive movement nearly every day, typically at least 4-5 days per week. Sporadic wandering generally does not exhibit excessive movement, but rather is generally sedentary, with occasional movements associated with flight, boundary deviation, escape, or deficits in wayfinding abilities. Sporadic wandering may exhibit the behavior two, three, or four, five, six, or more times per week. Unlike persistent wandering, sporadic wanderers do not spend abnormally long periods of time moving around. Treated patients may wander due to any form of dementia and may not exhibit deficits in wayfinding abilities. Such patients may be persistent or sporadic wanderers.

[0063] The compositions of the present disclosure can be used to treat wandering or other symptoms in patients with vascular dementia (VaD). The compositions can be used to treat mixed dementia that is not exclusively due to VaD and has overlapping pathology with other dementias, such as Alzheimer's disease dementia (AD). For example, any type or subtype of VaD resulting from various etiologies and pathologies related to VaD can be treated. The compositions of the present disclosure can be used to reduce or eliminate various symptoms and mood disorders related to VaD.

[0064] The two main subtypes of vascular dementia are i) cortical large infarct or multi-infarct dementia (MID), and ii) small vessel disease-associated dementia or subcortical vascular dementia. Subcortical vascular dementia can be caused by the disruption of the vasculature in subcortical white matter-rich regions in the brain. The International Classification of Vascular Diseases (10th Revision) (ICD-10) criteria explicitly identify subcortical vascular dementia as a subgroup. Subcortical vascular dementia incorporates the older entities "lacunar conditions" and "Binswanger's disease", which are associated with small vessel disease and hypoperfusion, resulting in focal and diffuse ischemic white matter lesions and incomplete ischemic damage. Most dementia patients (mainly non-VaD patients) are affected by the first type, which affects the cortical regions of the brain and may present with different deficits resulting from very different pathophysiological processes.

[0065] Large vessel cortical stroke and subcortical small vessel disease may tend to produce different types of deficits. Characteristic symptoms of subcortical dementia may include amnesia, slowing of thought processes, mild intellectual disability, apathy, inertia, depression (sometimes with irritability), loss of ability to recall, and inability to manipulate knowledge. Patients with subcortical dementia may have mood disorders. Other behavioral abnormalities, such as repetitive and compulsive behaviors, may occur in some patients suffering from subcortical dementia. The onset of subcortical dementia may be less easily noticed and progressive over time, and is often described as deficits in executive function in subcortical dementia. These may include deficits in speed and "strategic" processing (e.g., attention, planning, and monitoring) in tasks such as memory tests. Cortical vascular dementia may be associated with aphasia, apraxia, and memory loss.

[0066] The American Psychiatric Association distinguishes between minor and major neurocognitive disorders. A minor neurocognitive disorder may be defined as a cognitive decline of 1-2 standard deviations from normal on formal cognitive testing that does not interfere with independence and is not attributable to delirium or other medical or psychiatric disorders. A major neurocognitive disorder may be defined as a cognitive decline of 2 or more standard deviations from normal on formal cognitive testing that interferes with independence but is not attributable to delirium or other medical or psychiatric disorders. VaD patients may have major neurocognitive disorders according to these criteria, such that the impairment interferes with their independence. Impairment of independence may be assessed using scales that measure activities of daily living (ADL), including scales such as the Barthel Index and the Alzheimer's Disease Cooperative Study ADL Questionnaire. Patients treatable with compositions according to the present disclosure may have limited independence in that they reside in assisted living or memory care facilities and do not reside in the community or at home due to their condition.

[0067] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) provides a useful framework for the identification of patients treatable with compositions according to the present disclosure. The DSM-V provides a definition of dementia syndromes. Dementia syndromes include objective cognitive or behavioral impairments in at least two of the following: memory, reasoning and handling of complex tasks, visuospatial abilities, language function, and personality, behavior, or attitude. Dementia syndromes can also include decline from previous levels of function and impairment. VaD dementia can be caused by cardiovascular events, such as ischemic or hemorrhagic stroke, or chronic cardiovascular disease, such as Binswanger's disease or patchy dementia. VaD patients can be readily identified using the criteria of the National Institute of Neurological Disorders and Stroke (NINDS) and the International Association for Research and Education in Neuroscience (AIREN) (NINDS-AIREN criteria). The NINDS-AIREN criteria include confirmation of vascular pathology using imaging. Patients identified according to the NINDS-AIREN criteria can be specifically included.

[0068] The compositions of the present disclosure can be used to treat wandering or other symptoms in diseases with underlying proteinopathies, including Huntington's disease, autism spectrum disorder, Down's syndrome, and dementia. Proteinopathic dementia can result from, for example, Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), head injury, normal pressure hydrocephalus, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, or Parkinson's disease, or any combination thereof. When wandering occurs in a neurological disease associated with a proteinopathies, such disease can be considered to be proteinopathic wandering and treatable with a composition according to the present disclosure.

[0069] A common underlying cause of proteinopathy-associated wandering is dementia in general. Dementia can include a constellation of symptoms associated with severe memory and / or cognitive decline that adversely impacts activities of daily living. Recognizing this, a definitive classification of dementia can be based on the underlying neuropathology. Primary neurodegenerative dementias AD, DLB, Parkinson's disease dementia, FTD, and prion disease-associated dementia (such as CJD) can be characterized by progressive proteinopathy, the accumulation of misfolded proteins that leads to neuronal loss, neuroinflammation, and glial responses. Neurodegenerative dementias can be differentiated by the location and nature of the accumulation of misfolded proteins. Thus, an understanding of the applicable underlying pathology of dementia can be used to inform rational treatment of what are considered different underlying diseases.

[0070] The taste masking compositions of the present disclosure may be used to treat wandering or other symptoms associated with an underlying proteinopathy. Proteinopathy-associated dementia may refer to any form of dementia in which proteinopathy is considered to be part of the pathophysiology of dementia. Proteinopathy is associated with lesions that include protein aggregates or deposits that are not typically present in normal tissue. Alzheimer's disease, for example, is associated with amyloid plaques composed of aggregates of Abeta4, and fibrillary tangles composed of deposits of phosphorylated tau. Frontotemporal dementia is associated with deposits of tau, TDP-43, and / or FUS. Pure vascular dementia may be unrelated to proteinopathy. Both or either Alzheimer's disease and frontotemporal dementia may be included in the treatment regimen. Pure vascular dementia may be excluded from the treatment regimen. The compositions can be used to treat wandering in patients with diseases associated with abnormal deposits of huntingtin protein (HTT), FUS, TDP-43, tau, amyloid-β (e.g., amyloid-β42), optineurin, ubiquitin 2, superoxide dismutase 1, neuropathic locus homolog protein 3 (NOTCH3), or α-synuclein, or any combination thereof. Such deposits and the proteins contained therein can be used as biomarkers.

[0071] The taste masking composition can be used to treat wandering or other symptoms in male or female human patients suspected of having Parkinson's disease using the compositions of the present disclosure. Synucleinopathy, also called α-synucleinopathy, is a degenerative neurological disease characterized by abnormal accumulation of aggregates of α-synuclein protein in nerves, nerve fibers, or glial cells. The three main types of synucleinopathy include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). PD patients can develop motor symptoms, namely tremor, slowing of movement, rigidity, and postural instability, as well as non-motor symptoms, including autonomic dysfunction, neuropsychiatric problems (e.g., mood, cognition, behavior, or thought changes), sensory effects, and sleep difficulties, including wandering.

[0072] The taste masking composition can be used to treat wandering or other symptoms in male or female human patients suspected of having dementia with Lewy bodies (DLB) using compositions according to the present disclosure. Lewy bodies are abnormal clumps of proteins (i.e., alpha-synuclein protein, but may also include tau protein) that occur in neurons affected by PD, dementia with Lewy bodies (DLB), and other disorders. DLB is, in turn, a progressive and degenerative neurological dementia and, like PD, a synucleinopathy. Damage in the brain can be widespread, so many functional domains can be affected. DLB can be distinguished from AD in that short-term memory impairment can be an early and prominent feature of AD, while memory impairment typically occurs later in DLB. Additionally, severe hippocampal atrophy can be more typical in AD than DLB. DLB patients can experience changes in sleep (including wandering), behavior, cognition, movement, and autonomic body functions.

[0073] The taste masking compositions can be used to treat wandering or other symptoms in human patients suspected of having Huntington's disease using the compositions of the present disclosure. Huntington's disease (HD) is associated with aggregates of the Huntington protein (Htt) and is generally hereditary. Individuals have two copies of the Huntington gene (HTT), which contains trinucleotide repeats of cytosine-adenine-guanine (CAG). Individuals with 35 or fewer CAG repeats in the HTT gene are not affected by HD, individuals with 36-39 CAG repeats may or may not be affected by HD, and individuals with 40 or more CAG repeats are usually affected by HD. Htt aggregates accumulate and form inclusions within cells, disrupt neuronal function, and can be cytotoxic.

[0074] The taste masking composition can be used to treat wandering or other symptoms in male or female human patients suspected of having an underlying 4R tauopathy with the compositions according to the present disclosure. Preferred 4R tauopathies include PSP, CBD, AGD, GGT, which are neuropathologically characterized by the accumulation of phosphorylated 4R tau aggregates in neurons and certain glial cells. Depending on the type and location of the specific pathology, 4R tauopathies can manifest as several different clinical syndromes. There can be significant overlap between PSP and CBS (clinical manifestations of CBD), and there can be significant similarities in the neuropathology, suggesting that they are highly related, if not manifestations of the same condition. Definitive diagnosis of 4R tauopathy can be made by examining brain tissue via autopsy. Patients treatable with compositions according to the present disclosure can be considered to have "presumed" or "possible" disease on this basis. These patients can be considered to have 4R tauopathy even if not pathologically confirmed. Treatment of wandering in patients with 4-R tauopathy may be considered as treatment of patients with suspected or possible disease, as well as patients with confirmed pathology, when possible in the future, without autopsy, for example, using imaging or biomarkers.Similarly, in patients treatable with the compositions described herein, co-pathology may also be present.These include Alzheimer's disease-related pathology (including cerebral amyloid angiopathy), Lewy-related and transactivation response DNA binding protein 43, and other proteinopathies.Cerebrovascular disease, including small vessel disease, is a common co-pathology.

[0075] The diagnostic criteria for progressive supranuclear palsy (PSP) can be followed. Probable PSP refers to patients with a definite diagnosis. Depending on the predominant clinical features, various clinical manifestations of probable PSP can be identified. These include, for example, PSP with Richardson syndrome (PSP-RS), PSP with progressive freezing of gait (PSP-PGF), PSP with dominant parkinsonism (PSP-P), PSP with dominant frontal movement disorder (PSP-F), PSP with dominant oculomotor dysfunction (PSP-OM), PSP with dominant speech / language disorder (PSP-SL), PSP with dominant CBS (PSP-CBS), PSP with dominant postural instability (PSP-PI).

[0076] Clinical features of PSP can be divided into functional domains: oculomotor dysfunction, postural instability, akinesia, and cognitive dysfunction. The most highly correlated ("Level 1") clinical features of PSP can be vertical supranuclear gaze palsy, recurrent unprovoked falls within 3 years, progressive freezing of gait within 3 years, and speech / language disorders (primary progressive aphasia or non-fluent / agrammatic variant of progressive apraxia of speech). Also highly correlated ("Level 2") clinical features with PSP can be slowed vertical saccade velocity, tendency to fall on pull test within 3 years, parkinsonism, mainly axial akinesia, and levodopa tolerance and frontal cognitive / behavioral presentation. Also significantly but less correlated ("Level 3" clinical features) are frequent gross rectangular eye movements or "eye opening apraxia", more than two steps backward on pull test within 3 years, tremor and / or asymmetry and / or levodopa responsiveness, and Parkinson's disease with corticobasal syndrome. Patients treatable with the compositions described herein may have at least one Level 1 or Level 2 clinical feature. Many patients may have a combination of clinical features drawn from Level 1, Level 2, and Level 3 clinical features. Patients with various types of corticobasal degeneration may be treated with compositions according to the present disclosure. Patients with presumed corticobasal syndrome and / or presumed corticobasal degeneration may be treated.

[0077] Argyrophilic grain dementia (AGD) may exist without any unique clinical features. AGD may be considered clinically identical to AD, as AGD may present as AD, but there is evidence that patients lack amyloid pathology. Amyloid pathology may be discounted by examining CSF levels of β-amyloid 42 and / or by using β-amyloid PET imaging. AGD may lack acetylated tau in inclusions compared to other 4R tauopathies. Similar to AGD, globular glial tauopathy (GGT) may lack a defined clinical syndrome, presenting a combination of frontotemporal dementia, motor neuron disease, and / or extrapyramidal features. Identifying GGT patients may include using imaging, biomarkers, and differential diagnosis to exclude other pathologies. Wandering in male or female human patients suspected of having dementia due to stroke can be treated with the compositions described herein. Dementia associated with a cerebrovascular accident (CVA, or stroke) may be referred to as vascular dementia.

[0078] Wandering or other symptoms in male or female human patients suspected of having dementia resulting from traumatic brain injury (TBI) can be treated with the compositions described herein. TBI is an environmental risk factor for dementia. There may also be a genetic component that influences dementia resulting from TBI. A history of TBI and inheritance of the APOE ε4 allele may be associated with a 10-fold increased risk of dementia, whereas APOE ε4 in the absence of TBI may result in only a two-fold increased risk. Autopsy studies have shown that β-amyloid plaques and neurofibrillary tangles (NFTs) were present in up to one-third of patients who had extended survival after a single TBI. Patients who have experienced multiple TBIs, such as professional athletes who have suffered multiple concussions, may experience dementia associated with chronic traumatic encephalopathy (CTE), previously known as dementia puberta or dementia pugilistica. Autopsies of CTE show global atrophy of the brain, with thinning of the corpus callosum and dilation of the ventricles and cavum septum pellucidum.

[0079] The taste masking compositions of the present disclosure can be used to treat wandering or other symptoms in patients diagnosed with amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. Other motor neuron diseases include, for example, X-linked spinal-bulbar muscular atrophy (Kennedy's disease), adult Tay-Sachs disease, spinal muscular atrophy, multifocal motor neuropathy with conduction block, primary lateral sclerosis, and familial spastic paraplegia. Upper neuron degeneration and lower neuron degeneration may be present. Symptoms of ALS and other motor neuron diseases may depend on the degree of degeneration, whether corticospinal neurons, lower motor neurons, or both are affected. Symptoms may include, for example, wrinkling of muscles of the arms, legs, shoulders, or tongue, muscle spasms, muscle stiffness (spasticity), muscle weakness affecting the arms, legs, neck, or diaphragm, slurred speech and nasal voice, or difficulty chewing or swallowing, or any combination thereof. The compositions of the present disclosure may further comprise or be administered in conjunction with one or more additional APIs, such as riluzole, edaravone, or both, to a patient diagnosed with ALS or another motor neuron disease.

[0080] The present disclosure also encompasses a method for producing the taste masking composition of the present disclosure. Any suitable manufacturing process can be used to produce the composition. The aqueous taste masking composition can be produced as a concentrate and then diluted before administration. A dry concentrate or a liquid concentrate can be produced. The composition can be produced in a separate mixture for mixing before administration to a patient. The use of a rho kinase inhibitor to produce a composition is also provided by the present disclosure, for example, to treat one or more neurodegenerative diseases. The use of a rho kinase inhibitor in a composition to treat one or more neurodegenerative diseases of the present disclosure is also provided by the present disclosure. EXAMPLES

[0081] The present disclosure is further defined by the following non-limiting examples which are illustrative of compositions of the present disclosure.

[0082] Example 1 The solubility and stability of aqueous compositions containing fasudil were evaluated. Fasudil hydrochloride hemihydrate was dissolved in water (unbuffered) to obtain concentrations ranging from 16.15 to 19.77 mg / ml and adjusted to various pHs using 0.05 M HCl (HCl was not used for F22). Samples were stored at 60°C for 42 days. As shown in Table 1, there was no significant change in fasudil concentration or pH in any of the samples. These results indicate that unbuffered fasudil at 16-20 mg / ml is stable within the range of pH 4 to pH 6. [Table 3]

[0083] Example 2 The stability of aqueous compositions of Fasudil containing citrate buffer and EDTA was evaluated. The following formulations were prepared to evaluate the effect of EDTA on Fasudil stability in 0.05M citrate buffer. Samples were stored at 60°C for 36 days. As seen in Table 3, samples with and without EDTA showed no change in pH or Fasudil concentration. These results indicate that Fasudil is compatible with EDTA in citrate buffer. [Table 4] [Table 5]

[0084] Example 3 The use of sweeteners in aqueous compositions was evaluated. After tasting various Fasudil solutions, the drug was found to have a bitter taste that was very unpleasant. To prepare a more palatable pharmaceutical formulation, various approaches were evaluated. The formulations described in Table 4 were prepared to contain sweeteners (acesulfame potassium) and strawberry flavor. [Table 6]

[0085] The formulation was still bitter, but the bitter taste was tolerable by one subject who tested it. The bitter taste eventually disappeared. There was no sensation of nausea or vomiting due to the bitter taste. The formulation was stored at 60°C for 28 days and tested for impurities. The total impurities were 0.10% when stored at 60°C for 28 days, indicating that Fasudil is compatible with the various ingredients in the formulation. The formulation was adjusted to the desired thickness to obtain the formulation in Table 5. [Table 7]

[0086] Both formulations were further adjusted for pH using 1N NaOH to obtain the pH values ​​in Table 6. These four samples were tested and the majority of subjects were unable to tolerate the taste. These results indicate that the sweetener is not sufficient to effectively mask the taste. [Table 8]

[0087] Example 4 Bitterness-masking agents were evaluated. 1.6 g of Fasudil was dissolved in water to make 100 mL of stock solution (16 mg / mL, Formulation 35A). 3.0 mL of sample was dispensed into vials and various agents were added as shown in Table 7. Each sample was tasted and ranked from 1 to 10, with 10 being the most bitter. [Table 9]

[0088] Based on the data, SBEBCD and glycine appeared promising and were further tested as described in Table 8. [Table 10]

[0089] The addition of different amounts of glycine and SBEBCD did not show any significant change in bitterness. With glycine, some bitterness remained in the mouth after rinsing with water. A combination of SBEBCD and glycine (formulation 36A, Table 9) was tested to see if a mixture of the two best agents identified could provide better masking. [Table 11]

[0090] Formulation 36A was dispensed into vials and tested by a panel. The bitterness ranking was 2, qualitatively tasting better than formulations 33A or 34A, but a readily discernible bitter taste was still present.

[0091] Additional bitterness masking approaches were explored. Alginic acid formulations were evaluated. Alginic acid was used as an ion-pairing agent and gel-forming agent for taste masking by first preparing the composition in Table 10 (Formulation 38). [Table 12]

[0092] A matching placebo formulation (without fasudil) was made and both formulations were tasted. Formulation 38 tasted much better than any previous formulation, but was easily distinguishable from the placebo.

[0093] The next step was to increase the sweetener and alginate content, remove sodium chloride, and explore different pHs. The bitter taste was still evident. In some examples, formulation 49A is 3 mg / mL, so 10 mL would be used to deliver 30 mg. For at least one tester, it was a very pleasant taste. The two 6 mg / mL formulations were slightly bitter, much better than the 16 mg / mL, but not significantly different from each other. Table 11 shows the formulations with increased alginate and sweetener. [Table 13]

[0094] Ion exchange resins were investigated. It was clear that alginate alone was not sufficient to mask the bitter taste. Strong cation exchange resins were investigated. A 100 g sample of cation exchange resin (same chemistry as AMBERLITE IRP 69 but with sulfonic acid as the exchange site) was used to form the drug-resin complex in situ. Table 12 shows formulations 51A-52A formulated with ion exchange resin. [Table 14]

[0095] The panel of tasters agreed that these formulations were a great improvement over the previous formulations and that they considered them palatable. Feedback on these formulations included that colorants were not needed as the current colors looked "medical". Additionally, flavorings were not needed and the flavor was already acceptable. All considered formulation 52A to be too viscous. One person had an aftertaste with both formulations. One person tasted a bitter taste with formulation 51A but not with formulation 52A. This person also liked the texture of 52A. The alginate may have pulled some of the fasudil out of the resin in formulation 51A and exposed it to the solvent. A "with and without alginate" comparison and an attempt to match the viscosities were then considered. The data are presented in the following tables. Table 13 lists formulations 53-55 with increased xanthan gum content and removal of alginate. Table 14 lists the viscosity values ​​for formulations 53-55. Table 15 lists another study of xanthan gum content. Table 16A lists the viscosity values ​​of various xanthan gum contents (IDDSI syringe test). Table 16B shows the viscosity values ​​of various xanthan gum contents (Cannon viscometer). [Table 15] [Table 16] [Table 17] [Table 18-1] [Table 18-2]

[0096] Based on the viscosity data, 0.3% to 0.4% xanthan gum appears to provide an acceptable viscosity with good palatability. Higher drug loadings were investigated while varying the resin content and keeping the xanthan gum in the 0.3% to 0.4% range. Table 17 describes the drug loading studies for taste masking. [Table 19]

[0097] The majority of feedback deemed formulations 61-63 (drug loading 0.3%-2.4%) to be palatable. However, it was observed that the formulations sedimented during storage and did not redisperse well. Hence, neutral suspending formulations (suspending agents) were investigated. Table 18 lists the formulations for which suspending agents were investigated. [Table 20]

[0098] The formulations were stored overnight at 60° C. and then observed for sedimentation and redispersion. Table 19 shows the effect of suspending agents on physical stability. [Table 21]

[0099] Based on the data in Table 19, methylcellulose appeared promising. The following approaches were then explored: Dissolve the drug in water. Add resin to the solution. Adjust pH to 4. Filter and dry the resin. Measure drug concentration on the filtrate. Resins were used to make suspensions (a) MC, (b) xanthan gum, and (c) 5% crospovidone and 5% glycerol to determine if sedimentation was reduced or eliminated. Formulations were also made with crospovidone without filtration and compared. Formulations 72-76 for the effect of suspending agents on physical stability are shown in Table 20. [Table 22]

[0100] The procedure for making formulations 72-76 was as follows: First water was weighed in a beaker (approximately 5 ml), then the drug was dissolved in the water (18 mg / ml). Approximately 90 mg of drug was weighed. Resin was then added to the solution (resin:drug ratio 2.5). Approximately 225 mg of resin was added. The pH was adjusted to 4. The solution was filtered using 0.45 micron filter paper. The drug concentration was measured on the filtrate. The drug-resin complex was resuspended. The drug-resin complex was used to make suspensions with a) methylcellulose (MC), b) xanthan gum, and c) 5% crospovidone and 5% glycerol to see if the sediment was reduced or removed. All formulations were split into two vials, one stored at 60°C and the other at room temperature. Observations were as follows: The formulation with crospovidone showed precipitation, but no sticky sediment formed. The resin-drug complex could be easily resuspended. No gel was formed, so the combination of methylcellulose and crospovidone was considered. The previous batch of MC was too viscous, so the reduction rate of MC in the formulation was examined. Two formulations were prepared with different percentages of MC and crospovidone. The resin to drug ratio was set at 2.5, and the drug concentration was set at 18 mg / mL. Table 21 shows the effect of methylcellulose and crospovidone content on the physical stability of the formulation. [Table 23]

[0101] After 4 days, the 60°C sample turned light yellow. The 25°C sample was white. All four samples showed settling of the resin, but the resin could be resuspended upon shaking. The bottom of the vial became clear. Formulation 78A showed adhesion of the resin to the inside wall of the vial.

[0102] Weak cation exchange resins were investigated. AMBERLITE resin samples were obtained from Coloron: AMBERLITE Sulfonate IRP 69 (strong resin, same chemistry as the resin used previously, but with sodium sulfonate groups), AMBERLITE Polacrylin Potassium IRP 88 (weak resin, -COOK), and AMBERLITE Polacrylin IRP 64 (-COOH). Testing of the AMBERLITE resins (vendor: Colorcon, manufacturer: DuPont) is listed in Table 22. [Table 24]

[0103] Fasudil binding to the resins was investigated. Both IRP 69 and IRP 64 bind >99% of fasudil when the resin:API w / w ratio is 3 or higher, while IRP 88 binds >92% under the same conditions. IRP69 is darker in color. It was observed that the formulation containing IRP69 discolored, deposited, and was not easy to redisperse (forming a sticky deposit). Formulations with IRP 64 and 88 were easy to redisperse after overnight storage at 60°C. Further formulation development was explored using these two resins. IRP 64 and IRP 88 are weak cation exchange resins with carboxylic acid groups, and therefore pH may affect their ion exchange capacity. A pH of at least 6 was considered to fully utilize their capacity, with formulation pH targeted at 6-7. [Table 25]

[0104] The formulation containing MC (81) was more viscous compared to the formulation containing crospovidone (82). The formulation vials were sealed and stored at 60°C. After overnight storage, formulation 82 showed powder settling and formulation 81 was a good suspension. IRP 88 was then focused on. Upon gentle shaking, the suspensions mixed well in both formulations 81 and 82 with no sticky deposits observed at the bottom. As formulation 81 was viscous, some powder was attached to the inside surface of the vial at the bottom. This vial was compared to a vial of formulation 79, which has both MC and crospovidone. The crospovidone appeared to aid in dispersing the powder in the formulation. Both formulations were vortexed and sonicated during preparation, however formulation 81 showed only minor small gel clumps. A homogenizer (84) was used and compared to using a vortex (83).

[0105] IDDSI flow testing (https: / / iddsi.org / IDDSI / media / images / Testing_Methods_IDDSI_Framework_Final_31_July2019.pdf) was performed on formulations 83 and 84. The plunger was removed from a 10-mL syringe (61.5 mm from the zero line to the 10 mL line) and then the syringe was filled with the formulation when the nozzle was blocked. After 10 seconds of free flow, the volume of liquid remaining in the syringe was determined. In the case of formulation 83, the flow stopped due to a blockage by a small gel mass at one reading. The average volumes of formulations 83 and 84 were 4.7 mL and 5.1 mL, respectively. The dynamic viscosity of the formulations was determined using a Canon viscometer #300. The viscosity values ​​of formulations 83 and 84 were found to be 78 cSt and 112 cSt, respectively.

[0106] Formulation 84 was tasted with no bitterness observed. It had a smooth gel-like feel. Formulation 83 showed few gel clumps. In both, the insoluble material was well suspended and did not settle out quickly. A sample of Formulation 83 was stored at 60° C. Formulation 84 was stored at 5° C., 25° C., and 60° C. Physical stability appears acceptable. Formulation 84 appears to be a satisfactory formulation. Preliminary studies were performed to investigate the levels of methylcellulose, crospovidone, and IRP 88, and the drug loading was maintained at 18 mg / mL.

[0107] Tests were performed to investigate the suspending agent and resin content. Crospovidone and methylcellulose (MC), a neutral suspending agent, showed the most promising formulation in terms of sedimentation and redispersion. Low and high settings (proposed): Crospovidone: 0.5%-2.0%, MC: 0.8%-1.4%, AMBERLITE IRP 88: 4.5%-6.3%. Drug loading is 1.8% (18mg / mL), pH=6. Samples were placed at 60°C to check physical stability. The effect of pH is considered to be minimal when the pH is between pH6-7. [Table 26]

[0108] Example 6 Another study was carried out to investigate resins and suspending agents: three resins (A-IRP 64, polacrilin, COOH), (B-IRP 88, polacrilin potassium, COOK) and (IRP-69, sulfonate) and three different types of thickeners (a-1.2% methylcellulose, MC), (d-0.3% xanthan gum, XG), and (f-1.2% MC + 0.5% pividine 90F) were investigated. [Table 27]

[0109] The formulations listed in the table above were prepared and tested by the IDDSI (syringe) flow test. During the test, the plunger was removed from a 10 mL plastic syringe (61.5 mm from the zero line to the 10 mL line). The syringe nozzle was covered and the syringe was filled with 10 mL of formulation. The nozzle was released and the flow stopped in 10 seconds. The remaining formulation was measured in the syringe. The syringe was also used to measure the deposition behavior of the formulation. The test results of the syringes and measuring cylinders after pH adjustment are listed in Table 26. The pH of the polacrilin and polacrilin potassium samples was adjusted to about 6.2. The pH of the sulfonate salt samples was adjusted to about 4.0. [Table 28]

[0110] The higher the viscosity of the solid layer, the more sedimentation there was. Ideally, everything should remain as one cloudy layer. However, sedimentation results in a bottom solid layer, a middle cloudy layer, and a top clear layer. All samples with MC showed resin sediment as a solid sediment layer. The cloudy layer was less white compared to the layer with XG. The top clear layer was much larger in samples with MC and povidone. The sulfonate samples showed only two layers, a bottom sediment layer and a top clear layer. Based on the IDDSI (syringe) test, all samples with MC were "mildly viscous" and samples with XG were "slightly viscous." Despite the high viscosity of the MC samples, the resin settled in the samples with MC. The vials of these samples showed similar sedimentation. All vials were gently shaken 10 times. In all samples with MC, the bottom solid layer did not redisperse. In samples with XG, the sedimentation layer easily redispersed and the bottom of the vial was visible. To avoid sedimentation problems, the use of a mixture of MC and XG was considered. [Table 29]

[0111] IDDSI flow test results for FAS formulations 95, 96, and 97 are shown in Table 28. Values ​​are the volume (mL) of formulation remaining in the syringe after 10 seconds. [Table 30]

[0112] Additional formulations using a xanthan gum / MC combination as a suspending agent were prepared as described in Table 29. [Table 31]

[0113] Formulations 98A-100A were stored at 5° C. and 40° C. for 3 days and tested for physical stability. [Table 32]

[0114] Based on the data, formulations 101A and 102A were prepared and tested for stability. [Table 33]

[0115] The pH was adjusted using 1N NaOH. The final pH after homogenization was 6.22 and 6.34 for formulations 101A and 102A, respectively. 100 mL of each formulation was prepared. 20 mL type I glass injection vials were used to fill 10 mL of the formulation. Nine vials were filled for each formulation for stability testing. Stability data up to 3 months under 25°C / 60% RH and 40°C / 75% RH indicate that the formulations are chemically stable. Table 32 shows the stability of the suspension at 25°C / 60% RH. Table 33 shows the stability of the suspension at 40°C / 75% RH. [Table 34] [Table 35]

[0116] Microbial growth was observed, but this could be addressed by including an antimicrobial agent in the formulation. At 5 months, 101A (xanthan gum only) settled as a cake and was not easily redispersed. 102A (xanthan gum / MC combination) was easily redispersed. Based on these results, a formulation containing xanthan gum and methylcellulose with a preservative is prepared.

[0117] Example 7 Effect of pH on the binding of fasudil to AMBERLITE IRP 69 resin, an ion exchange resin containing sulfate functional groups. Batches of IRP 69 and IRP 64 resins were prepared at drug concentrations of 25mg / mL and 50mg / mL. The resin was added to the drug solution and stirred for 30 minutes. The pH of the supernatant was observed to be 7.55 and 2.75, respectively. The drug concentration in the supernatant of IRP 69 resin was very low, about 250ug / mL, suggesting strong binding of FAS to the IRP resin. The drug:resin ratio was 1:4. The reduced fasudil binding to the resin at higher pH is attributed to fasudil protonation. Table 34 shows the composition of the various samples used in the study. The results are illustrated in Figure 1. The pH effect on fasudil binding to IRP 64 resin is illustrated in Figure 2. At lower pH, the resin is not fully deprotonated, thus reducing the binding efficiency. [Table 36]

[0118] Extraction of fasudil from AMBERLITE IRP 69 using the modified method was tested. Tests were performed in duplicate. Approximately 125 mg of drug-resin complex was added to a 100 mL volumetric flask and 500 mg of NaCl, 50 mL of diluent containing 40% acetonitrile, and 60% 0.01 N sodium hydroxide were added. The flask was placed on a wrist shaker and shaken for 30 minutes. The sample was removed and centrifuged prior to HPLC analysis. Both flasks were shaken for an additional 30 minutes. Shaking of the drug solution in the flask was vigorous. Table 35 lists the extraction values ​​for both samples. Extraction appears satisfactory and wrist shaking for 30 minutes appears to be sufficient. Table 35 shows the extraction of fasudil from sulfonate resin by wrist shaking method. [Table 37]

[0119] The S1 (4:1 resin:drug complex) formulation is listed in Table 36 below. [Table 38]

[0120] Table 37 lists the various parameters for the test. Table 38 lists the different dissolution media for the test. [Table 39] [Table 40]

[0121] The release data is shown in Figure 3, which shows a graph of the dissolution of fasudil-containing sprinkles over time under two different conditions. The low release in aqueous media was due to the lack of ions to exchange with the fasudil ion, which remained bound to the resin.

[0122] Example 8 The taste threshold concentrations of Fasudil were tested. Table 39 lists the concentrations of the aqueous Fasudil compositions and their taste by a first taster. Table 39 lists the concentrations of the aqueous Fasudil compositions and their taste by a second taster. [Table 41] [Table 42]

[0123] Example 9 An example of making a liquid suspension is provided. Co-solvents can be used as an aid to gel formation. The production of gels using xanthan gum, methylcellulose, carbomer, and other polymers can be a labor-intensive process. The procedure described herein can reduce the processing time to make the gel and subsequently the suspension formulation. Co-solvents, such as PEG300, PEG300, propylene glycol, glycerin, and ethanol, can be used as an aid to gel formation. Dry xanthan gum and polymers were first wetted with the co-solvent, and water was added with constant stirring. These can include one or more humectants, and the gums are essentially thickeners. Examples of humectants that can be used include glycerin and alcohol. For example, a 2% ethanol solution can be used. The addition of the co-solvent prevented the formation of lumps and the gel formed quickly. When water and other additives were added and stirred, the gel broke down and a suspension was formed. This product is an example of an oral suspension formulation. The oral suspension formulation can be in the form of a thickened solution.

[0124] A "one-pot" process, or a "two-pot" process, or both, can be used. In a one-pot process, the drug, gum, and resin are combined together using a single vessel. In a two-pot process, the drug and resin are first combined in a first pot and then transferred to a second pot where they are mixed with the other ingredients. Thus, the formulation can be prepared by a batch process using either a one-pot process or a two-pot process. In a one-pot process, the product can be prepared in one tank. First, the gum and polymer can be wetted with a co-solvent and then a gel can be prepared. Water, drug, resin, and other additives are added to the same vessel. In a two-pot process, in a first tank, the drug solution can be mixed with the resin to load the drug onto the resin. In a second tank, a gel of xanthan gum and a polymer, such as a cellulose ether, is prepared. The contents of the two tanks are mixed to obtain the final drug product. The product can be successfully prepared using either process.

[0125] One or more resins can be used as is or can be activated with acid, base, or both. The resin has carboxylic acid groups, which can be activated using hydrochloric acid. The acid opens up binding sites on the surface of the resin particles and present within the pores of the resin. The resin can be neutralized using, for example, sodium hydroxide. Activation of the resin also serves to strengthen the interaction between the resin and the drug. Even if the resin is not activated, the drug molecules can eventually bind to the binding sites on the resin and a satisfactory formulation can be prepared. The advantage of these methods is that they can result in effective drug binding relatively independent of the particle size of the resin. The resin particles can be insoluble in water. The resin particles are porous. The binding sites on the resin can be on the surface and primarily inside the pores. As a result, no significant effect of resin particle size on drug loading and release was observed.

[0126] Soluble additives with carboxylic acid groups can be used in the formulation. These additives are in addition to the carboxylic acid or sulfonate-containing resins used for drug binding. An example of such an additive is carbomer. The resin has either a carboxylic acid group or a sulfonate group with which the fasudil drug is ion-paired. There are many additives with ionizable carboxylic acid groups, such as sodium carboxymethylcellulose, alginic acid, polyacrylic acid, polymethacrylic acid, and carbomer. Drugs have been observed to bind with these cation exchange polymers. Their addition to the formulation serves two purposes: increasing viscosity through a gelling effect, and reducing the amount of resin required to mask the bitter taste.

[0127] Example 10 Drug:resin ratios were examined to determine their effect on the total binding of drug to the resin. Generally, there is some amount of drug in solution and not bound to the resin. There is free drug in the supernatant, which can result in a bitter taste. Advantageously, this can be kept to a minimum, for example, by using a soluble additive, e.g., carbomer. Carbomer can act as a second taste masking agent, for example. Alginate can be used in addition to or instead of alginate. The use of a second taste masking agent can mean less use of the first taste masking agent. Drug to resin ratio is a parameter of taste masking effectiveness. Different drug:resin ratios were evaluated. Amberlite IRP 64 Polarilex resin has a loading capacity of 10 meq / g or more (DuPont® AmberLite® Ion Exchange Resin Product Data Sheet, April 2021). This is equivalent to a w / w ratio of about 3:1 fasudil:resin. In practice, even more resin can be used to mask the taste of Fasudil. Drug:resin ratios ranging from about 1:2 to about 1:4.5 by weight can be used, with a ratio of 1:3 generally providing acceptable results.

[0128] Example 11 For these exemplary formulations, the resin was used as is without activation for formulation 142. The drug was loaded into lots 157 and 163 after activating the resin with 0.1N HCl. All three lots 142, 157 and 163 were prepared by a two-pot process. For formulation 142, the gums and methylcellulose can be slightly higher due to the lower strength and resin content. For formulation 157, the opposite is true. The amount of gums and methylcellulose can be reduced. For formulation 163, it is almost right. In some cases, the taste threshold of the supernatant can be 0.3-0.4 mg / mL. Example formulations are listed in Table 41. [Table 43]

[0129] Example 12 Another example of a suspension formulation produced in accordance with the present disclosure is set forth in Table 42 for formulation 172. Formulation 172 shows that xanthan gum is not the only gum that can be used to achieve a stable and palatable formulation. [Table 44]

[0130] These concentrations are merely examples, and taste threshold concentrations may be selected based on a variety of factors described herein and otherwise understood in the art.

[0131] Example 13 Ion exchange resins are used to mask the taste of fasudil. Different immediate and sustained release oral solid dosage forms can be produced from the drug loaded ion exchange resin. For example, sprinkles can be produced. After loading fasudil onto the ion exchange resin, the resulting drug-resin complex can be sprinkled onto soft foods. Drug loading onto the resin can be accomplished by batch or column processes. The drug:resin ratio can be 3:1 to 1:10. The drug-resin complex can be dried by any conventional drying process. The dried drug-resin complex can be administered as a sprinkle onto soft foods. The drug-resin complex can be granulated to create granules or beads to increase the particle size of the sprinkles. The granules or beads can be coated. Colorants and flavorings may also be added. Table 43 lists examples of sprinkle formulations of fasudil that have been prepared. [Table 45]

[0132] The drug-resin complex microparticles can be coated to achieve sustained release properties. Table 44 lists examples of sustained release fasudil microparticle formulations. [Table 46]

[0133] A dispersion of ethyl cellulose and polyvinyl alcohol in alcohol can be prepared. The dispersion can be sprayed onto the drug-resin particles in a fluid bed dryer. The particles can be coated and dried at the same time. The polyvinyl alcohol acts as a pore former and helps to slowly release the drug. Various types of coatings can be used to provide controlled release of the drug from the drug-resin particles. Lactose, sugar, sorbitol powder, etc. can be used as pore formers instead of polyvinyl alcohol.

[0134] The following procedure was used to generate microparticles of fasudil resin complex: 2 grams of fasudil HCl hemihydrate was dissolved in 20 mL of water to which 1, 2, or 4 grams of resin IRP 64 was added. The pH was adjusted to 6.5 with hydrochloric acid. The composition was stirred and the pH was adjusted until the pH was constant. The resin was then filtered and dried. The resulting drug-resin complexes contained 60%, 50%, and 33% drug, respectively. The drug loading in the drug-resin complex can be further increased by increasing the input drug:resin ratio.

[0135] Example 14 A powder for suspension was produced. The drug-resin complex may be further formulated to provide a powder for suspension formulation. In this case, the powder formulation may be added to water to form a suspension. The drug-resin complex is water insoluble. The formulation thickens the water to suspend the drug-resin particles. Powders for pharmaceutical dosage forms in suspension contain a suspending agent and may contain sweeteners, flavorings, and colorings. Preservatives can be added so that the suspension is stable for short periods of time, such as 1 day to 4 weeks. Lubricants can be added to aid in powder flow and mixing. Table 45 lists examples of compositions of powders for suspension formulations. When 20 mL and 50 mL of water were added to Formulation 1 and Formulation 2, respectively, the resulting suspensions had IDDSI flow test results of Level 2. The powders may be filled into glass / plastic bottles or supplied in pouches. [Table 47]

[0136] Example 15 Fast disintegrating tablets can be produced according to the present disclosure.Fast disintegrating tablets (FDT) are another dosage form suitable for patients with dysphagia.The tablet disintegrates quickly on a spoon or other container with a small amount of water or in the mouth without adding water.The FDT can be, for example, an orally disintegrating tablet (ODT).

[0137] Fast disintegrating tablets can be produced by conventional processes, such as dry / wet granulation, direct compression, etc. Table 46 lists examples of several FDT formulations prepared according to the present disclosure. The resulting tablets disintegrated within 1 minute. Formulation 9 is an example of an ODT. [Table 48]

[0138] Example 16 Effervescent tablets (ET) are another example of a solid dosage form that can be produced according to the present disclosure. Fasudil drug-resin complex can be incorporated into effervescent tablets. Table 47 lists the weight percentages of the compositions of effervescent fasudil tablets prepared according to the present disclosure. [Table 49]

[0139] Effervescent tablets can be prepared by conventional processes. The above examples were prepared by dry granulation and compression. The effervescence helped to disintegrate the tablets.

[0140] Example 17 Chewable tablets are an example of a solid dosage form that can be produced. Resins absorb water easily and swell. Therefore, the resin% used in chewable tablets can be less than 20%. Table 48 lists examples of the composition of chewable fasudil tablets that can be produced according to the present disclosure. Chewable tablets can be prepared, for example, by wet granulation process. [Table 50]

[0141] The present disclosure includes the following aspects / embodiments / features in any order and / or in any combination. 1. A taste masking composition comprising: a rho kinase inhibitor, wherein the rho kinase inhibitor has a bitter taste and is present at a concentration above the taste threshold concentration; A taste masking agent to hide the bitterness, and at least one pharma- ceutically acceptable excipient. 2. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the rho kinase inhibitor comprises fasudil, a pharma- ceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof. 3. The taste masking composition of any one of the preceding or following embodiments / features / aspects, further comprising water and having a taste threshold concentration of about 0.3 mg / mL. 4. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein fasudil is present in an amount of about 0.5% w / v to about 5.0% w / v of the composition. 5. The taste masking composition according to any one of the preceding or following embodiments / features / aspects, wherein the weight ratio of taste masking agent to rho kinase inhibitor is from about 10:1 to about 1:10. 6. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking agent comprises a bitter taste masking agent. 7. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the bitterness masking agent comprises a binding agent that binds to the rho kinase inhibitor to mask the bitterness. 8. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is aqueous and the binder comprises an ion exchange resin. 9. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the ion exchange resin comprises a cation exchange resin. 10. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the binding agent binds to at least 50% of the rho kinase inhibitor. 11. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is an aqueous composition and the free concentration of the rho kinase inhibitor is less than about 5.0 mg / mL. 12. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the rho kinase inhibitor is fasudil, a pharma- ceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof. 13. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking agent comprises one or both of a sweetener and a flavoring agent. 14. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is aqueous and further comprises a suspending agent. 15. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is aqueous and the suspending agent comprises a viscosity modifier. 16. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the suspending agent comprises a cellulose ether. 17. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the suspending agent comprises a non-cellulose polysaccharide. 18. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the suspending agent comprises a gum. 19. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the suspending agent comprises a plurality of suspending agents. 20. The taste masking composition of any one of the preceding or following embodiments / features / aspects, further comprising a humectant, moisturizer, chelating agent, antioxidant, or preservative, or any combination thereof. 21. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is aqueous and comprises a solution, suspension, emulsion, gel, or colloid, or any combination thereof. 22. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is aqueous and wherein the taste masking composition further comprises a buffer. 23. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is an aqueous composition and has a pH of about 5.5 to about 7.5. 24. The taste masking composition of any one of the preceding or following embodiments / features / aspects, having a viscosity of about 50 cSt to about 2,500 cSt. 25. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the rho kinase inhibitor is present in an amount sufficient to treat a neurodegenerative disease. 26. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the neurodegenerative disease comprises Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis (ALS), motor neuron disease, Parkinson's disease, Huntington's disease, multiple sclerosis, progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS), or any combination thereof. 27. A method of treating a neurodegenerative disease comprising administering to a patient a taste masking composition of any one of the preceding or following embodiments / features / aspects in an amount sufficient to treat the neurodegenerative disease. 28. The method of any one of the preceding or following embodiments / features / aspects, further comprising diagnosing the neurodegenerative disease prior to administering the composition to the patient. 29. The method of any one of the preceding or following embodiments / features / aspects, wherein treating the neurodegenerative disease comprises alleviating a symptom of the neurodegenerative disease. 30. The method of any one of the preceding or following embodiments / features / aspects, wherein the symptom comprises wandering. 31. A taste-masking composition comprising: Fasudil, or hydroxyfasudil, or both A taste masking composition comprising a taste masking agent. 32. The taste masking composition according to any one of the preceding or following embodiments / features / aspects, wherein the composition is selected from the group consisting of a solution, a suspension, a gel, a jelly, a film, a tablet, a coated tablet, an uncoated tablet, a minitablet, a coated minitablet, an uncoated minitablet, a bilayer tablet, a coated bilayer tablet, an uncoated bilayer tablet, a slurry, a capsule, a granule, a coated granule, an uncoated granule, a dissolving tablet, a multiparticulate, a powder, and a spray. 33. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is an aqueous liquid and wherein fasudil, or hydroxyfasudil, or both, are present in a concentration of at least about 0.3 mg / mL. 34. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the fasudil, or hydroxyfasudil, or both, are present in an amount of about 0.5% w / v to about 5.0% w / v of the composition. 35. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the weight ratio of the taste masking agent to fasudil, or hydroxyfasudil, or both, is from about 10:1 to about 1:10. 36. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the bitterness masking agent comprises a binding agent that binds to fasudil, or hydroxyfasudil, or both, to mask the bitter taste. 37. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the binding agent binds at least 50% of the fasudil, or hydroxyfasudil, or both. 38. The taste masking composition of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is an aqueous composition and has a free concentration of fasudil, or hydroxyfasudil, or both, less than about 5.0 mg / mL. 39. A method of treating a patient having a neurodegenerative disease, comprising administering to the patient a taste masking composition comprising fasudil, or hydroxyfasudil, or both, and a taste masking agent, wherein the fasudil, or hydroxyfasudil, or both, are present in an amount sufficient to treat the neurodegenerative disease. 40. The method of any one of the preceding or following embodiments / features / aspects, wherein the taste masking composition is formulated for a subject diagnosed with a swallowing disorder. 41. The method of any one of the preceding or following embodiments / features / aspects, wherein the taste-masking composition is an aqueous liquid and the fasudil, or hydroxyfasudil, or both, are present in a concentration of at least about 0.3 mg / mL. 42. The method of any one of the preceding or following embodiments / features / aspects, wherein the fasudil, hydroxyfasudil, or both are present in an amount of about 0.5% w / v to about 5.0% w / v of the composition. 43. The method of any one of the preceding or following embodiments / features / aspects, wherein the weight ratio of the taste-masking agent to fasudil, or hydroxyfasudil, or both, is from about 10:1 to about 1:10. 44. A method for treating a neurodegenerative disease, comprising administering to a subject with a swallowing disorder a taste masking composition formulated for subjects diagnosed with a swallowing disorder, wherein the composition comprises fasudil, hydroxyfasudil, or both in an amount sufficient to treat the neurodegenerative disease.

[0142] All references cited or otherwise mentioned herein are incorporated herein by reference in their entirety for any relevant aspect of this disclosure. Variations of the embodiments described herein are also part of this disclosure. One or more elements of an embodiment can be combined with one or more elements of another while still falling within this disclosure. The order of steps can be changed while still falling within this disclosure. The amounts, percentages, and ratios described herein can be changed while still falling within this disclosure. Ranges between any two values ​​described herein and any intervening values ​​are also included in this disclosure. Equivalents of the embodiments described herein are also included in this disclosure.

Claims

1. A taste masking composition comprising: a rho-kinase inhibitor, the rho-kinase inhibitor having a bitter taste and present at a concentration above a taste threshold concentration; A taste masking agent for masking the bitterness; and at least one pharma- ceutically acceptable excipient.

2. 2. The taste masking composition of claim 1, wherein the rho kinase inhibitor comprises fasudil, a pharma- ceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof.

3. 3. The taste masking composition of claim 2, further comprising water, wherein the taste threshold concentration is about 0.3 mg / mL.

4. 4. The taste masking composition of claim 3, wherein fasudil is present in an amount of about 0.5% to about 5.0% w / v of the composition.

5. 2. The taste masking composition of claim 1, wherein the weight ratio of the taste masking agent to the rho kinase inhibitor is from about 10:1 to about 1:

10.

6. The taste masking composition of claim 1 , wherein the taste masking agent comprises a bitter taste masking agent.

7. 7. The taste masking composition of claim 6, wherein the bitter taste masking agent comprises a binding agent that binds to the rho kinase inhibitor to mask the bitter taste.

8. 8. The taste masking composition of claim 7, wherein the taste masking composition is aqueous and the binder comprises an ion exchange resin.

9. 9. The taste masking composition of claim 8, wherein the ion exchange resin comprises a cation exchange resin.

10. 8. The taste masking composition of claim 7, wherein the binding agent binds at least 50% of the rho kinase inhibitor.

11. 8. The taste masking composition of claim 7, wherein the taste masking composition is an aqueous composition and the free concentration of the rho kinase inhibitor is less than about 5.0 mg / mL.

12. 9. The taste masking composition of claim 8, wherein the rho kinase inhibitor is fasudil, a pharma- ceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, a substituted derivative thereof, or a metabolite thereof, or any combination thereof.

13. 10. The taste masking composition of claim 1, wherein the taste masking agent comprises one or both of a sweetener and a flavoring agent.

14. 10. The taste masking composition of claim 1, wherein the taste masking composition is aqueous and further comprises a suspending agent.

15. 15. The taste masking composition of claim 14, wherein the taste masking composition is aqueous and the suspending agent comprises a viscosity modifier.

16. 15. The taste masking composition of claim 14, wherein the suspending agent comprises a cellulose ether.

17. 15. The taste masking composition of claim 14, wherein the suspending agent comprises a non-cellulosic polysaccharide.

18. 15. The taste masking composition of claim 14, wherein the suspending agent comprises a gum.

19. 15. The taste masking composition of claim 14, wherein the taste masking composition comprises a plurality of suspending agents.

20. 10. The taste masking composition of claim 1, further comprising a humectant, a moisturizer, a chelating agent, an antioxidant, or a preservative, or any combination thereof.

21. 10. The taste masking composition of claim 1, wherein the taste masking composition is aqueous and comprises a solution, a suspension, an emulsion, a gel, or a colloid, or any combination thereof.

22. 10. The taste masking composition of claim 1, wherein the taste masking composition is aqueous, and wherein the taste masking composition further comprises a buffer.

23. 10. The taste masking composition of claim 1, wherein the taste masking composition is an aqueous composition and has a pH of about 5.5 to about 7.

5.

24. 22. The taste masking composition of claim 21 having a viscosity of about 50 cSt to about 2,500 cSt.

25. 10. The taste masking composition of claim 1, wherein the rho kinase inhibitor is present in an amount sufficient to treat a neurodegenerative disease.

26. 26. The taste masking composition of claim 25, wherein the neurodegenerative disease comprises Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis (ALS), motor neuron disease, Parkinson's disease, Huntington's disease, multiple sclerosis, progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS), or any combination thereof.

27. 26. A method of treating a neurodegenerative disease comprising administering to a patient the taste masking composition of claim 25 in an amount sufficient to treat the neurodegenerative disease.

28. 28. The method of claim 27, further comprising diagnosing the neurodegenerative disease prior to administering the composition to the patient.

29. 28. The method of claim 27, wherein treating the neurodegenerative disease comprises alleviating a symptom of the neurodegenerative disease.

30. 30. The method of claim 29, wherein the symptom comprises wandering.

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