Modified-release tolcapone formulation

Abstract

A modified-release tablet dosage form containing tolcapone is disclosed. The tablet dosage form provides a pulsatile, pH-dependent release profile of tolcapone to both the gastric cavity and the small intestine. Methods for treating or preventing a disease selected from transthyretin amyloidosis (ATTR), Parkinson's disease, and obsessive-compulsive disorder using the dosage form are provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 414,655, filed October 10, 2022, the contents of which are incorporated herein by reference.

[0002] The present disclosure relates to modified-release tablets of tolcapone. [Background technology]

[0003] Transthyretin amyloidosis (ATTR) is an example of a group of amyloid diseases specifically associated with the transthyretin (TTR) protein. TTR is a 55-kD homotetramer of 127 amino acid residues that is primarily produced in the liver and secreted into plasma. Dissociation of TTR tetramers at the T4 binding interface generates monomers that misfold and aggregate to form amyloid fibrils. These fibrils, along with unstable fibril precursors, cause cell death and tissue damage.

[0004] ATTR is characterized by the deposition of misfolded proteins in one or more organ systems (e.g., peripheral nervous system, autonomic nervous system, heart, brain, and eyes). Symptoms typically begin to appear at ages ranging from 20 to 70 years. ATTR is progressive, and some types can be fatal within a few years of onset. Treatment options include supportive and symptomatic care, which slow or halt the progressive decline in functional status but do not alter the pathological process. Liver transplantation is available for selected patients, but it is subject to limited organ supply, requires lifelong immunosuppression, and may be complicated by progressive cardiac and neuronal amyloid deposition. Importantly, liver transplantation does not alter the natural history of central nervous system amyloid disease. Life expectancy is generally 5 to 15 years after diagnosis.

[0005] TTR dissociation can be the result of genetic mutations (hereditary ATTR), aging (wt ATTR), or both. There are over 120 known amyloidogenic mutations in TTR, resulting in diverse clinical manifestations, including hATTR-polyneuropathy (familial amyloid polyneuropathy [FAP]) and hATTR-cardiomyopathy (familial amyloid cardiomyopathy [FAC]). Often, hereditary ATTR (hATTR) causes a mixture of progressive neurological and cardiac disorders. hATTR-leptomeningeal syndrome (hATTR-leptomeningeal syndrome) is a poorly recognized, progressive, and fatal disease caused by the accumulation of mutant transthyretin (TTR) expressed by the choroid plexus in the brain, resulting in central nervous system (CNS) dysfunction.

[0006] Tolcapone is one of several small molecules that can stabilize the tetrameric structure of TTR and reduce or prevent dissociation (Sant'Anna R. et al. Nature Communications volume 7, Article number: 10787 (2016)). Tolcapone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of Parkinson's disease and crosses the blood-brain barrier.

[0007] A recent proof-of-concept study in patients with hATTR-leptomeningeal disease, in which patients received 100 mg of tolcapone orally three times daily for 14 days, followed by 200 mg of tolcapone orally three times daily for another 14 days, demonstrated that tolcapone is a potent TTR stabilizer in both plasma and cerebrospinal fluid (CSF). Tolcapone normalized plasma TTR concentrations, with an overall mean increase in plasma TTR tetramer concentrations of 55%. Significant concentrations of the drug penetrated into the CSF, where it reduced monomeric TTR concentrations by an average of 48% when measured under semi-denaturing conditions. (Berk J., Kaku, M., Alosco, M., Lazzari, V., Brueckner, C., Doros, G., Glidden, P., Roberts, M., Tolcapone Levels and TTR Stabilization in Cerebrospinal Fluid of Patients with Leptomeningeal Amyloid TTR Mutations, XVII International Symposium on Amyloidosis, Abstract PW020, September 2020).

[0008] However, tolcapone is eliminated fairly rapidly, with an elimination half-life of 1.6 to 3.4 hours (Keating GM, Lyseng-Williamson KA. Tolcapone: a review of its use in the management of Parkinson's disease. CNS Drugs. 2005; 19(2):165-84). Therefore, immediate-release dosage forms are not suitable for the treatment of ATTR, as 4 to 6 doses per day are required to consistently stabilize TTR (e.g., overnight). Patient compliance with such dosing regimens is problematic, thereby reducing efficacy.

[0009] Initial attempts to manufacture a modified-release tolcapone formulation utilized established wet granulation technology with an HPMC binder. 300 mg tablets were developed containing (i) an intragranular portion containing tolcapone (37.50 wt%), HPMC E50 (22.0 wt%), HPMC K100LV (10.0 wt%), and anhydrous dicalcium phosphate (24.75 wt%), and (ii) an extragranular component containing Aerosil 200 (0.50 wt%) and magnesium stearate (1.0 wt%). Phase I studies in healthy subjects unexpectedly demonstrated low bioavailability and minimal extended release (Figure 1).

[0010] Further studies revealed that exposure to the low pH of the stomach altered the tablet's properties, making it rubbery and gelatinous and not dissolving after transition to the higher pH of the small intestine. It also revealed that the solubility of tolcapone itself is highly pH-dependent, with low pH reducing tolcapone's solubility and physically changing its appearance from a crystalline structure to a longer, hair-like structure. It has been hypothesized that the reconstituted hair-like form of tolcapone has lower solubility and slows dissolution in the low pH environment of the stomach, resulting in poor drug release. Summary of the Invention [Problem to be solved by the invention]

[0011] Thus, there remains a need for a modified-release oral dosage form of tolcapone that can be used in twice-daily dosing and that can provide sustained TTR stabilization. [Means for solving the problem]

[0012] Disclosed herein is a tablet dosage form of tolcapone that provides a pulsatile release profile useful for treating conditions such as ATTR and can be administered twice daily for consistent TTR stabilization.

[0013] The tablets disclosed herein include: (i) a tablet core comprising a first portion of tolcapone and optionally at least one binder, filler, glidant and / or lubricant; (ii) an optional film coating layer surrounding the tablet core and comprising at least one cellulosic polymer; (iii) an enteric coating layer encapsulating the core or film coating layer and comprising a copolymer of acrylic acid and methacrylic acid and, optionally, at least one additive; (iv) an immediate-release layer encapsulating the enteric coating layer and comprising a second portion of tolcapone and at least one cellulosic polymer; and (v) An optional topcoat that encapsulates the immediate release layer.

[0014] Also provided is a method of treating a disease in a patient, comprising orally administering to a patient in need thereof a tablet as disclosed herein. In particular, the tablet as disclosed herein can be used to treat any disease or condition for which tolcapone is indicated, including ATTR and Parkinson's disease.

[0015] In typical embodiments, patients receive no more than two doses per day, each dose containing from about 100 mg to about 600 mg of tolcapone, more preferably from about 100 mg to about 300 mg of tolcapone. Each dose can be one or more tablets as disclosed herein.

[0016] ATTR is selected from hereditary ATTR (hATTR), hATTR-polyneuropathy (hATTR-PN), hATTR-cardiomyopathy (hATTR-CM), ATTR-cardiomyopathy (ATTR-CM), hATTR-leptomeningeal (hATTR-Lepto) and mixed phenotypes thereof. [Brief explanation of the drawings]

[0017] [Figure 1]1 is a graph showing the release profile of (i) Tasmar® in the fasted state (circles), and (ii) a prototype modified-release tablet containing tolcapone according to Example 1 in the fasted state (diamonds). [Figure 2] FIG. 1 is an illustration of one of the tablets of the present invention. [Figure 3] 1 is a graph showing the change in plasma concentration of tolcapone over time in Part 1 of the PK study (Example 4). [Figure 4] 1 is a graph showing the mean fraction of initial (FOI) over time and the mean plasma concentration over time for prototype 1 (Example 5). [Figure 5] 1 is a flow chart illustrating the preparation of tablets described herein (Example 3). DETAILED DESCRIPTION OF THE INVENTION

[0018] definition "AUC" refers to the area under the curve obtained by plotting time on the x-axis and the concentration of a substance (e.g., tolcapone) in blood or plasma on the y-axis over a specified period (e.g., 0-24 hours). AUC is generally expressed in units of ng·hr / ml.

[0019] "Mean C" refers to the average of two or more individual C values ​​measured across a group of subjects. For example, when multiple subjects are dosed as described herein, each of the multiple subjects may have different individual C values. The calculated average of these different C values ​​is the "mean C" for the group.

[0020] "Mean C" means the average of two or more individual C values ​​measured across a group of subjects. For example, when multiple subjects are dosed as described herein, each of the multiple subjects may have different individual C values. The calculated average of these different C values ​​is the "mean C" for the group.

[0021] "Disease" means a disease, disorder, illness, or any symptom thereof.

[0022] "Gastrointestinal tract" or "GI tract" refers to the digestive tract, a muscular-membrane tube approximately 30 feet in length that runs from the mouth to the anus. As used herein, the term "upper gastrointestinal tract" refers to the oral cavity, pharynx, esophagus, stomach, and small intestine. As used herein, the term "lower gastrointestinal tract" refers to the large intestine and rectum.

[0023] "Immediate release" means in In vitro and in vivo Immediate release refers to a formulation or dosage form that is rapidly dissolving in the stomach or upper gastrointestinal tract and is intended to be completely dissolved and absorbed in the stomach or upper gastrointestinal tract. An immediate release formulation can release at least 90% of the active ingredient or precursor thereof within about 15 minutes, about 30 minutes, about 1 hour, or about 2 hours after administration of the immediate release dosage form.

[0024] By "patient" or "subject" is meant a mammal, for example, a human.

[0025] "Modified release" (used interchangeably with "sustained release" or "delayed release" or "controlled release") refers to the release of a drug from a dosage form in which the release of the drug occurs over a period of time. Modified release can mean that the release of the drug from the dosage form is longer than that from an immediate release dosage form, i.e., over at least several hours. In some embodiments, the release of tolcapone in vivo The release occurs over a period of about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours.

[0026] "Small intestine" means that portion of the gastrointestinal tract consisting of the duodenum, jejunum, and ileum, ie, that portion of the intestine immediately adjacent to the upper proximal duodenal sphincter and adjacent to the large intestine.

[0027] "Treating" or "treatment" with respect to any disease means reversing, alleviating, preventing, or ameliorating the disease or at least one clinical symptom of the disease, reducing the risk of acquiring at least one clinical symptom of the disease, inhibiting the progression of the disease or at least one clinical symptom of the disease, or reducing the risk of developing at least one clinical symptom of the disease. "Treating" or "treatment" also means inhibiting the disease physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both, and inhibiting at least one physical parameter that may or may not be discernible to the patient. In certain embodiments, "treating" or "treatment" means protecting against or delaying the onset of at least one or more symptoms of the disease in a patient.

[0028] Detailed Description I. Tablets In preferred embodiments, the tablets of the present invention, when administered to a subject, provide a pulsatile, pH-dependent release profile of tolcapone into both the gastric cavity and, after a delay period, the small intestine. Such a release profile requires the appropriate selection of multiple coating layers.

[0029] The immediate-release layer of the tablet described herein becomes soluble or dissolves in the gastric cavity at gastric pH (pH 1-3). At this stage, the portion of tolcapone present in the immediate-release layer is released. The enteric coating is not soluble at gastric pH and therefore protects the core (and the portion of tolcapone contained therein) at this stage. There is then a lag time before the remainder of the tablet enters the small intestine. The enteric coating and core become soluble or dissolve at the neutral or slightly alkaline pH of the small intestine (pH 6 in the duodenum, pH 6-7.5 in the jejunum and ileum), thereby releasing the portion of tolcapone in the core and providing a second pulse of active ingredient to the subject.

[0030] A. Tablet Core The tablets disclosed herein include a tablet core containing tolcapone. The tolcapone in the tablet core is present in an amount of about 10% to about 95% by weight of the total tablet weight, for example, about 10% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 20% by weight, or about 20% to about 95% by weight. , about 20% to about 90% by weight, about 20% to about 80% by weight, about 20% to about 70% by weight, about 20% to about 60% by weight, about 20% to about 50% by weight, about 20% to about 40% by weight %, about 20% to about 30% by weight, about 30% to about 95% by weight, about 30% to about 90% by weight, about 30% to about 80% by weight, about 30% to about 70% by weight, about 30% to about 60% by weight %, about 30% to about 50% by weight, about 30% to about 40% by weight, about 40% to about 95% by weight, about 40% to about 90% by weight, about 40% to about 80% by weight, about 40% to about 70% by weight Amount%, about 40% to about 60% by weight, about 40% to about 50% by weight, about 50% to about 95% by weight, about 50% to about 90% by weight, about 50% to about 80% by weight, about 50% to about 70% by weight %, about 50% to about 60% by weight, about 60% to about 95% by weight, about 60% to about 90% by weight, about 60% to about 80% by weight, about 60% to about 70% by weight, about 70% to about 95% by weight, about 70% to about 90% by weight, about 70% to about 80% by weight, about 80% to about 95% by weight, about 80% to about 90% by weight, or about 90% to about 95% by weight.

[0031] In one particular embodiment, the tolcapone in the tablet core is present in an amount of about 20% to about 30% by weight of the total tablet weight.

[0032] The tablet core contains tolcapone in an amount of about 10% to about 95% by weight of the total weight of the tablet core, for example, about 10% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 20% by weight, or about 20% to about 95% by weight. Amount%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40 Weight%, about 20% to about 30%, about 30% to about 95%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60 Weight%, about 30% to about 50%, about 30% to about 40%, about 40% to about 95%, about 40% to about 90%, about 40% to about 80%, about 40% to about 7 0% by weight, about 40% to about 60% by weight, about 40% to about 50% by weight, about 50% to about 95% by weight, about 50% to about 90% by weight, about 50% to about 80% by weight, about 50% to about 7 0% by weight, about 50% to about 60% by weight, about 60% to about 95% by weight, about 60% to about 90% by weight, about 60% to about 80% by weight, about 60% to about 70% by weight, about 70% to about 95% by weight, about 70% to about 90% by weight, about 70% to about 80% by weight, about 80% to about 95% by weight, about 80% to about 90% by weight, or about 90% to about 95% by weight.

[0033] In one particular embodiment, the tablet core comprises tolcapone in an amount of about 40% to about 50% by weight of the tablet core weight.

[0034] Tolcapone may be micronized or non-micronized tolcapone. In preferred embodiments, the tolcapone is micronized.

[0035] Compressed tablet cores containing tolcapone can be manufactured using well-known techniques, such as those described in Remington: The Science and Practice of Pharmacy, 21st Edition, edited by University of the Sciences in Philadelphia (2005). Such tablet cores can contain one or more known tableting excipients, such as binders, fillers, disintegrants, flow agents, lubricants, surfactants, plasticizers, anti-adherents, buffers, disintegrants, wetting agents, emulsifiers, thickeners, colorants, sustained-release agents, or any combination thereof.

[0036] A binder may be included in the tablet core to hold the ingredients of the tablet core together. Typical binders include alginic acid and its salts; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), microcrystalline cellulose (e.g., Avicel®), and the like; microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth; dextrin; sugars such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, and the like; natural or synthetic gums such as acacia, tragacanth, ghatti gum, and mucilage of isapol shells. isapol husks), polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, wax, sodium alginate, and any combination thereof.

[0037] In certain embodiments, the binder is hydroxypropyl methylcellulose. There are many different grades of hydroxypropyl methylcellulose, depending, for example, on its molecular weight, degree of etherification, viscosity, etc. Examples of hydroxypropyl methylcellulose include the "E," "F," and "K" chemical products available from Dow Chemical Company under the trade name METHOCEL®. Each hydroxypropyl methylcellulose is available in various viscosities. A typical commercially available hydroxypropyl cellulose is available, for example, from JRS Pharma under the trade name VIVAPHARM® HPMC-E.

[0038] In one particular embodiment, the hydroxypropyl methylcellulose has a viscosity (mPa·s) of 3.0 to 5.0 when measured in an aqueous solution containing 2% by weight of dry HPMC at 20° C. In another particular embodiment, the binder is HPMC-E.

[0039] The at least one binder in the tablet core is present in an amount of about 1% to about 10% by weight of the total tablet weight, for example, about 2% to about 6% by weight.

[0040] Fillers may be added to increase the volume of the dosage form. Examples of fillers include, for example, dibasic calcium phosphate, dibasic calcium phosphate dihydrate, calcium sulfate, dicalcium phosphate, tricalcium phosphate, lactose, cellulose such as microcrystalline cellulose, mannitol, sodium chloride, dry starch, pregelatinized starch, compressible sugar, mannitol, and combinations thereof. Fillers may be water-insoluble, water-soluble, or a combination thereof. Examples of useful water-insoluble fillers include starch, dibasic calcium phosphate dihydrate, calcium sulfate, dicalcium phosphate, tricalcium phosphate, powdered cellulose, microcrystalline cellulose, and combinations thereof. Examples of water-soluble fillers include water-soluble sugars and water-soluble sugar alcohols, such as lactose, glucose, fructose, sucrose, mannose, dextrose, galactose, their corresponding sugar alcohols, and other sugar alcohols (e.g., mannitol, sorbitol, xylitol), and combinations thereof. In particular embodiments, the at least one filler is microcrystalline cellulose.

[0041] The at least one filler in the tablet core is present in an amount of about 5% to about 50% by weight of the total tablet weight, for example, about 5% to about 40% by weight, about 5% to about 30% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, or about 5% to about 10% by weight. In one particular embodiment, the at least one filler in the tablet core is present in an amount of about 20% to about 30% by weight of the total tablet weight.

[0042] The tablet core may contain a glidant or anti-adhesion agent to reduce the adhesive effect during processing, film formation, and / or drying.Examples of useful glidants include talc, glycerol monostearate, colloidal silicon dioxide, precipitated silicon dioxide, fumed silicon dioxide, and combinations thereof.In one particular embodiment, the glidant is fumed silicon dioxide.

[0043] The at least one fluidizing agent is present in an amount of about 0.1% to about 1% by weight of the total tablet weight, for example, about 0.1% to about 0.5% by weight.

[0044] Lubricants and antistatic agents may be included to aid processing. Examples of lubricants include calcium stearate, glyceryl monostearate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, sodium lauryl sulfate, stearic acid, talc, vegetable oil, zinc stearate, and combinations thereof. In certain embodiments, the lubricant is magnesium stearate.

[0045] The at least one lubricant in the tablet core is present in an amount of about 0.1% to about 1% by weight of the total tablet weight, for example, about 0.1% to about 0.5% by weight.

[0046] Disintegrants may be included in the tablet core, for example, to cause the tablet core to break down due to the expansion of the disintegrant when exposed to water. Examples of useful disintegrants include water-swellable substances such as croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, and combinations thereof.

[0047] In various embodiments, the tablet core comprises an immediate release formulation of tolcapone.

[0048] In other embodiments, the tablet core may also be a sustained-release formulation. Such tablets provide extended release throughout the small and large intestines. Examples of polymeric materials for achieving sustained release include, but are not limited to, cellulose-based polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethyl cellulose. Any combination of these polymers may also be used.

[0049] B. Film coating layer A film coating layer optionally encapsulates the tablet core. The film coating can fill any imperfections in the tablet core and provide a smooth surface for application of the enteric coating.

[0050] In one embodiment, the film coating layer comprises at least one cellulose polymer.Typical examples of cellulose polymers include, but are not limited to, methyl cellulose, ethyl cellulose, propyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate butyrate, cellulose acetate propionate, methyl cellulose, methyl cellulose acetate, methyl cellulose propionate, methyl cellulose butyrate, cellulose acetate ethyl cellulose, ethyl cellulose propionate, ethyl cellulose butyrate, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose propionate, hydroxypropyl methyl cellulose butyrate, and their corresponding salts and esters.In certain embodiments, the film coating comprises hydroxypropyl methyl cellulose.

[0051] In one particular embodiment, the cellulosic polymer of the film coating layer is a member of the Opadry® and / or OPAGLOS® 2 film coating systems manufactured by Colorcon, Inc. of West Point, Pa. Opadry® I and / or Opadry® II are preferred.

[0052] The film coating is present in an amount of about 0.1% to about 10% by weight of the total tablet weight, for example, about 1% to about 5% by weight or about 1% to about 3% by weight.

[0053] C. Enteric Coating Layer The enteric coating layer encases the tablet core or the optional film coating layer. The enteric polymer coating operates on the principle of pH-dependent solubility; that is, it is insoluble in the low pH conditions of the stomach but soluble in the near-neutral pH environment of the proximal small intestine. The enteric coating begins to dissolve in aqueous solutions with a pH above 5.0, 5.5, 6.0, or 6.5. The enteric coating layer protects the contents of the tablet core, preventing disintegration and / or release of tolcapone from the tablet core in the acidic environment of the stomach and preventing gelation of the tablet during the pH transition from the stomach to the small intestine.

[0054] The enteric coating layer comprises at least one of the following polymers: shellac, gelatin, methacrylic acid copolymer type C NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (PMCAS), and polymers and copolymers of acrylic acid (acrylic acid copolymers are typically formed from methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate to produce copolymers of acrylic acid and methacrylic acid esters), acrylic acid and methacrylic acid copolymers. Copolymers of methacrylic acid, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), copolymers of methacrylic acid and alkylamides, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers, ammonioalkyl methacrylate copolymers, and methacrylic resins commercially available under the trade name Eudragit® (e.g., Eudragit® L, Eudragit® S, Eudragit® E, Eudragit® RL, Eudragit® RS). In certain embodiments, the polymer is a copolymer based on methacrylic acid and ethyl acrylate, such as Eudragit® L or Eudragit® L30 D55 from Evonik Industries AG.

[0055] The enteric coating polymer is present in an amount of about 0.5% to about 10% by weight of the total tablet weight, for example, about 0.5% to about 5%, about 0.5% to about 3.0%, about 0.5% to about 2.0%, or about 1.0% to about 2.0% by weight. In one particular embodiment, the enteric coating is present in an amount of about 1.0% to about 7% by weight of the total tablet weight.

[0056] The enteric coating layer can further comprise at least one additive (e.g., an anti-tack agent, a plasticizer, and a stabilizer). Typical examples of anti-tack additives include the PlasACRYL® family, i.e., a 20% aqueous emulsion of glycerol monostearate, as an anti-tack agent, and triethyl citrate as a plasticizer and stabilizer. PlasACRYL® HTP20 is designed for Eudragit® L30 D55 formulation. PlasACRYL® T20 is designed for Eudragit® FS 30 D formulation. In certain embodiments, the at least one additive is PlasACRYL® HTP20.

[0057] The at least one additive in the enteric coating layer is present in an amount of about 0.1 wt % to about 1.0 wt % of the total tablet weight, for example, about 0.1 wt % to about 4.0 wt %, about 0.1 wt % to about 3.0 wt %, about 0.1 wt % to about 2.0 wt %, or about 0.1 wt % to about 1.0 wt %.

[0058] D. Immediate release layer The immediate-release layer encapsulates the enteric coating. The immediate-release layer contains tolcapone and provides immediate release of tolcapone and absorption of tolcapone after the enteric coating dissolves in the small intestine.

[0059] Tolcapone in the immediate release layer is present in an amount of about 10% to about 95% by weight of the total tablet weight, for example, about 10% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 20% by weight, about 20% to about 95% by weight Weight%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40 Weight%, about 20% to about 30%, about 30% to about 95%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60 Weight%, about 30% to about 50%, about 30% to about 40%, about 40% to about 95%, about 40% to about 90%, about 40% to about 80%, about 40% to about 70 Weight%, about 40% to about 60%, about 40% to about 50%, about 50% to about 95%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70 %, about 50% to about 60% by weight, about 60% to about 95% by weight, about 60% to about 90% by weight, about 60% to about 80% by weight, about 60% to about 70% by weight, about 70% to about 95% by weight, about 70% to about 90% by weight, about 70% to about 80% by weight, about 80% to about 95% by weight, about 80% to about 90% by weight, or about 90% to about 95% by weight.

[0060] In certain embodiments, the tolcapone in the immediate release layer is present in an amount of about 20% to about 30% by weight of the total tablet weight.

[0061] Tolcapone is suspended or solubilized with at least one cellulose-based polymer and then film-coated onto the enteric coating layer. The at least one cellulose-based polymer may be the same as or different from the at least one cellulose-based polymer used in the optional film-coating layer. In some embodiments, the at least one cellulose-based polymer comprises hydroxypropyl methylcellulose. In one particular embodiment, the cellulose-based polymer is one of the Opadry® and / or OPAGLOS® 2 film coating systems manufactured by Colorcon, Inc., West Point, Pennsylvania. Opadry® I and / or Opadry® II are preferred.

[0062] The at least one cellulosic polymer in the immediate release layer is present in an amount of about 5% to about 20% by weight of the total tablet weight, for example, about 5% to about 15% by weight, about 5% to about 10% by weight, or about 10% to about 15% by weight.

[0063] The tablet contains tolcapone in an amount of about 100 mg to about 1,000 mg, for example, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, and about 100 mg to about 200 mg. Tolcapone is contained in the core (first portion) and the immediate-release layer (second portion).

[0064] The amount of tolcapone in the core (first portion) is selected from the range of about 50 mg to about 900 mg, for example, from about 50 mg to about 500 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, or about 50 mg to about 100 mg.

[0065] The amount of tolcapone in the immediate-release layer (second portion) is selected from the range of about 50 mg to about 900 mg, for example, about 50 mg to about 500 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, or about 50 mg to about 100 mg.

[0066] The weight ratio of the first portion of tolcapone to the second portion of tolcapone is selected from the range of about 1:5 to about 5:1, e.g., about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, or about 1:1. In one particular embodiment, the weight ratio is about 1:1.

[0067] The total tablet weight is selected from the range of 100 mg to about 1,000 mg, for example, from the ranges of about 100 mg to about 300 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg, about 200 mg to about 500 mg, about 300 mg to about 500 mg, and about 400 mg to about 500 mg.

[0068] E. Top Coat The tablet optionally comprises a topcoat that can be spray-dried on the immediate-release layer. Typical topcoat materials include at least one cellulose-based polymer (e.g., hydroxypropyl methylcellulose, Opadry®, etc.), HPC, Eudragit® RL, Eudragit® E100, Eudragit® E 12.5, Eudragit® E PO, Eudragit® NE, and combinations thereof. In one particular embodiment, the topcoat comprises hydroxypropyl methylcellulose.

[0069] The topcoat is present in an amount of about 0.1% to about 10% by weight of the total tablet weight, for example, about 0.1% to about 7.0% by weight, about 0.1% to about 5.0% by weight, about 0.1% to about 3.0% by weight, about 0.1% to about 2.0% by weight, or about 0.1% to about 1.0% by weight. In one particular embodiment, the topcoat is present in an amount of about 0.1% to about 3.0% by weight of the total tablet weight.

[0070] In one exemplary embodiment, the tablet of the invention comprises: (i) a tablet core comprising a first portion of tolcapone and optionally at least one binder, filler, glidant and / or lubricant; (ii) an optional film coating layer surrounding the tablet core and comprising at least one cellulosic polymer; (iii) an enteric coating layer encapsulating the core or film coating layer and comprising a copolymer of acrylic acid and methacrylic acid and, optionally, at least one additive; (iv) an immediate-release layer encapsulating the enteric coating layer and comprising a second portion of tolcapone and at least one cellulosic polymer; and (v) An optional topcoat that encapsulates the immediate release layer.

[0071] In one more particular embodiment, the tablet of the present invention comprises: (i) A tablet core comprising a first portion of tolcapone, and optionally comprising: a. at least one binder, wherein the binder, if present, is hydroxypropyl methylcellulose; b. at least one filler, wherein the filler, if present, is microcrystalline cellulose; c. at least one fluidizing agent, where the fluidizing agent, if present, is fumed silicon dioxide, and / or d. at least one lubricant, where the lubricant, if present, is magnesium stearate; (ii) an optional film coating layer surrounding the tablet core and comprising at least one cellulosic polymer; (iii) an enteric coating layer encapsulating the core or optional film coating layer, the enteric coating layer comprising a copolymer of acrylic acid and methacrylic acid, and optionally at least one additive comprising an aqueous suspension of an anti-blocking agent, a plasticizer, and a stabilizer; (iv) an immediate-release layer encapsulating the enteric coating layer and comprising a second portion of tolcapone and at least one cellulosic polymer; and (v) An optional topcoat that encases the immediate release layer and comprises at least one cellulosic polymer.

[0072] In one more particular embodiment, the tablet of the present invention comprises the following in the following weight amounts: (i) A tablet core comprising a first portion of tolcapone, wherein the first portion of tolcapone is present in an amount of about 10% to about 95% by weight, optionally comprising: a. at least one binder in an amount of about 1% to about 10% by weight; b. at least one filler in an amount of about 5% to about 50% by weight; c. at least one flow agent in an amount of about 0.1% to about 1% by weight, and / or at least one lubricant in an amount of about 0.1% to about 1% by weight; (ii) an optional first film coating layer encapsulating the tablet core and comprising at least one cellulosic polymer, wherein the at least one cellulosic polymer is present in an amount of about 0.1% to about 10% by weight; (iii) an enteric coating layer encapsulating the core or an optional film coating layer, the enteric coating layer comprising a copolymer of acrylic acid and methacrylic acid, the copolymer being present in an amount of about 0.5% to about 10% by weight, and optionally at least one additive in an amount of about 0.1% to about 10% by weight; (iv) an immediate-release layer encapsulating the enteric coating layer and comprising a second portion of tolcapone and at least one cellulosic polymer, wherein the second portion of tolcapone is present in an amount of about 10% to about 95% by weight and the at least one cellulosic polymer is present in an amount of about 5% to about 20% by weight; and (v) an optional topcoat encapsulating the immediate release layer and comprising at least one cellulosic polymer, the topcoat being present in an amount of about 0.1% to about 10% by weight.

[0073] In one more particular embodiment, the tablet of the present invention comprises the following in the following weight amounts: (i) A tablet core comprising a first portion of tolcapone, wherein the first portion of tolcapone is present in an amount of about 20% to about 30% by weight, optionally comprising: a. at least one binder in an amount of about 2% to about 10% by weight; b. at least one filler in an amount of about 20% to about 30% by weight; c. at least one flow agent in an amount of about 0.1% to about 0.5% by weight, and / or at least one lubricant in an amount of about 0.1% to about 0.5% by weight; (ii) an optional film coating layer encapsulating the tablet core and comprising at least one cellulosic polymer, wherein the at least one cellulosic polymer is present in an amount of about 1% to about 3% by weight; (iii) an enteric coating layer encapsulating the core or an optional film coating layer, the enteric coating layer comprising a copolymer of acrylic acid and methacrylic acid, the copolymer being present in an amount of about 1.0% to about 4.0% by weight, and optionally at least one additive in an amount of about 0.1% to about 1.0% by weight; (iv) an immediate-release layer encapsulating the enteric coating layer and comprising a second portion of tolcapone and at least one cellulosic polymer, wherein the second portion of tolcapone is present in an amount of about 20% to about 30% by weight, and the at least one cellulosic polymer is present in an amount of about 5% to about 15% by weight; and (v) an optional topcoat encapsulating the immediate release layer and comprising at least one cellulosic polymer, the topcoat being present in an amount of about 0.1% to about 3.0% by weight.

[0074] In one exemplary alternative embodiment, the tablet of the invention comprises: (i) a tablet core comprising a first portion of tolcapone and at least one sustained-release polymer, and optionally at least one binder, filler, glidant, and / or lubricant; (ii) an optional film coating layer surrounding the tablet core and comprising at least one cellulosic polymer; (iii) an enteric coating layer encapsulating the core or film coating layer and comprising a copolymer of acrylic acid and methacrylic acid and, optionally, at least one additive; (iv) an immediate-release layer encapsulating the enteric coating layer and comprising a second portion of tolcapone and at least one cellulosic polymer; and (v) An optional topcoat that encases the immediate release layer and comprises at least one cellulosic polymer.

[0075] The tablets of the present invention can provide immediate release of tolcapone (from the immediate-release layer) in the gastric cavity, followed by subsequent release (immediate or sustained release) of tolcapone from the tablet core in the small intestine. The tablet structure prevents gelation and related release problems observed with conventional tolcapone formulations.

[0076] in In vitro The dissolution rate is in In vitro1 shows how the amount of tolcapone dissolved changes over time when subjected to a dissolution test. in In vitro The higher (faster) the dissolution rate, the greater the amount of tolcapone released in a given period of time. in In vitro The lower (slower) the dissolution rate under the same conditions, the in In vitro This means that when subjected to a dissolution test, a smaller amount of tolcapone is released in the same time period.

[0077] Tablets in In vitro Dissolution can be measured by placing a tablet in 1000 mL of dissolution medium (phosphate buffer containing 0.5% SLS and having a pH of 6.8), stirring at 75 rpm at 37±0.5°C, and then periodically (e.g., every 15 minutes for up to 24 hours) taking samples and measuring the tolcapone concentration using HPLC.

[0078] In typical embodiments, the tablets disclosed herein release at least 95% of the tolcapone within about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours when placed in a dissolution medium. In a preferred embodiment, the tablets release at least 95% of the tolcapone within about 1-5 hours, about 1-4 hours, about 2-5 hours, about 3-5 hours, about 2-4 hours, or about 3-4 hours when placed in a dissolution medium.

[0079] II. Therapeutic applications The tablets disclosed herein can be administered to patients suffering from any disease (including disorders, illnesses, or conditions) for which tolcapone is known or will be found to be effective in treating. Examples of indications for which tolcapone is expected to be effective include ATTR, Parkinson's disease, schizophrenia, polycystic kidney disease, and obsessive-compulsive disorder.

[0080] The present disclosure provides a method of treating a disease in a patient comprising administering to a patient in need of such treatment a tablet as disclosed herein, which, after administration to a patient, can provide a therapeutically or prophylactically effective plasma and / or blood concentration of tolcapone.

[0081] The tablets disclosed herein can be administered in an amount and using a dosing schedule appropriate for the treatment of a particular disease. For example, the daily dose of tolcapone may be in the range of about 0.01 mg / kg to about 50 mg / kg, such as about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 20 mg / kg, or about 1 mg / kg to about 10 mg / kg.

[0082] In certain embodiments, the daily dosage of tolcapone ranges from about 2 mg / kg to about 10 mg / kg, about 3 mg / kg to about 10 mg / kg, about 4 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 6 mg / kg to about 10 mg / kg, about 7 mg / kg to about 10 mg / kg, about 8 mg / kg to about 10 mg / kg, or about 9 mg / kg to about 10 mg / kg.

[0083] In certain embodiments, tolcapone can be administered at a dosage of about 1 mg to about 1 g, about 100 mg to about 600 mg, about 300 mg to about 600 mg, or about 100 mg to about 300 mg per day. The appropriate dosage of tolcapone can be determined based on several factors, including the weight and / or condition of the patient being treated, the severity of the disease being treated, the incidence and / or severity of side effects, the mode of administration, and the judgment of the prescribing physician. Appropriate dosage ranges can be determined by methods known to those of skill in the art.

[0084] Each dose can be one tablet or multiple tablets, and if multiple tablets are administered, each dosage form may contain the same or different amounts of tolcapone.

[0085] In some embodiments, the patient is administered twice daily. In preferred embodiments, the patient is administered no more than twice daily.

[0086] Administration can be in a fed or fasted state. In some embodiments, administration is in a fasted state. In other embodiments, administration is in a fed state.

[0087] In certain embodiments, a therapeutically effective dose of tolcapone can provide therapeutic benefit without causing substantial toxicity, including adverse side effects.

[0088] The mean maximum plasma concentration (mean Cmax) of tolcapone provided by administration of the tablets disclosed herein is in the range of about 1,000 ng / mL to about 10,000 ng / mL, for example, about 1,000 ng / mL to about 8,000 ng / mL, 1,000 ng / mL to about 5,000 ng / mL, 1,000 ng / mL to about 3,000 ng / mL, 5,000 ng / mL to about 10,000 ng / mL, 5,000 ng / mL to about 8,000 ng / mL, about 7,000 ng / mL to about 10,000 ng / mL, or about 8,000 ng / mL to about 10,000 ng / mL.

[0089] Administration of the tablets disclosed herein provides a mean minimum plasma concentration (mean Cmin) of tolcapone of 200 ng / mL or greater at 12 hours post-dose, 500 ng / mL or greater at 12 hours post-dose, or 800 ng / mL or greater at 12 hours post-dose.

[0090] In certain embodiments, administration provides a mean minimum plasma concentration (mean Cmin) of about 200 ng / mL to about 800 ng / mL 12 hours after administration.

[0091] The area under the plasma tolcapone concentration versus time curve (AUC) provided by administration of the tablets disclosed herein 0-inf) is in the range of at least about 3,200 ng·hr / ml, e.g., about 3,500 ng·hr / ml to about 4,000 ng·hr / ml. 0-inf is about 3,500 ng hr / ml to about 4,000 ng hr / ml when administered in the fasted state. 0-inf is approximately 3,200 ng·hr / ml to approximately 3,500 ng·hr / ml when administered in the fed state.

[0092] In certain embodiments, administration of the tablets of the invention to a patient results in release of 60% or less of the tolcapone contained in the tablet within 2 hours after administration, e.g., release of 50% or less of the tolcapone within 2 hours after administration, release of 40% or less of the tolcapone within 2 hours after administration, or release of 30% or less of the tolcapone within 2 hours after administration.

[0093] In certain embodiments, administration of the tablet of the present invention to a patient results in release of 90% or more of the tolcapone contained in the tablet within 8 hours after administration, or release of 95% or more of the tolcapone within 8 hours after administration.

[0094] In certain embodiments, administration of the tablet of the present invention to a patient results in release of 60% or less of the tolcapone contained in the tablet within 2 hours and release of 90% or more of the tolcapone contained in the tablet within 9 hours.

[0095] The tablets of the present invention provide a first pulse of tolcapone upon dissolution of the immediate-release layer, which occurs 0-4 hours after administration. A second pulse of tolcapone is released upon dissolution of the enteric coating when the remainder of the tablet reaches the small intestine, approximately 5-6 hours after administration. In preferred embodiments, release is complete after about 8 hours.

[0096] A. Transthyretin amyloidosis (ATTR) In one particular embodiment, a method of treating transthyretin amyloidosis (ATTR) in a patient comprises administering to the patient at least one tablet disclosed herein comprising an effective amount of tolcapone.

[0097] In one embodiment, ATTR is hereditary ATTR, i.e., ATTR caused by one or more pathogenic mutations, mainly in the TTR gene. Generally, hATTR affects the nerves, heart, kidney, eye, and brain. The proportion of cardiac and neurological lesions depends on the underlying TTR mutation.

[0098] In one particular embodiment, the one or more pathogenic mutations in the TTR gene are selected from single nucleotide substitutions, deletions, or duplications. The specific mutations may be homogeneous or heterogeneous. In some embodiments, ATTR is caused by one or more pathogenic mutations. In one embodiment, the one or more pathogenic mutations affect the CD loop of the TTR protein.

[0099] In one particular embodiment, the one or more pathogenic mutations are selected from the group consisting of Gly6Ser, Cys10Arg, Leu12Pro, Leu12Val, Met13Ile, Asp18Asn, Asp18Gly, Asp18Glu, Ala19Asp, Val20Ile, Arg21Gln, Ser23Asn, Pro24Ser, Ala25Ser, Ala25Thr, Val28Met, Val28Ser, Val30Leu, Val30Met, Val30Ala, Val30Gly, Val30Leu, Val32Ala, Val32Gly, Phe33Ile, Phe33Leu, Phe3 3Val, Phe33Cys, Arg34Gly, Arg34Thr, Lys35Asn, Lys35Thr, Ala36Asp, Ala36Pro, Asp38Ala, Asp38Val, Thr40Asn, Trp41Leu, Glu42Gly, Glu42A sp, Phe44Tyr, Phe44Ser, Phe44Leu, Ala45Ser, Ala45Thr, Ala45Asp, Ala45Gly, Gly47Arg, Gly47Glu, Gly47Val, Thr49Ala, Thr49Pro, Thr49Ile , Thr49Ser, Ser50Arg, Ser50Ile, Glu51Gly, Glu51_Ser52dup, Ser52Pro, Gly53Arg, Gly53Glu, Gly53Ala, Glu54Leu, Glu54Lys, Glu54Gly, Glu 54Asp, Glu54Gln, Leu55Gln, Leu55Arg, Leu55Pro, His56Arg, Gly57Arg, Leu58Arg, Leu58His, Thr59Arg, Thr59Lys, Thr60Ala, Thr60Ile, Glu61 Lys, Glu61Gly, Glu61Ala, Glu62Lys, Phe64Ile, Phe64Leu, Phe64Ser, Phe64Val, Gly67Arg, Gly67Glu, Ile68Leu, Tyr69His, Tyr69Ile, Lys70As n, Val71Ala, Glu72Gly, Ile73Val, Asp74His, Ser77Phe, Ser77Tyr, Tyr78Phe, Ala81Thr, Ala81Val, Gly83Arg, Ile84Asn, Ile84Ser, Ile84Thr,His88Arg, Glu89Gln, Glu89Lys, His90Asn, His90Asp, Ala91Ser, Gln92Lys, Val93Met, Val94Ala, A la97Ser, Ala97Gly, Gly101Ser, Pro102Arg, Arg103Ser, Arg104Cys, Arg104His, Ile107Val, Ile10 7Phe, Ile107Met, Ala109Ser, Ala109Thr, Ala109Val, Leu111Met, Ser112Ile, Pro113Thr, Tyr114Cys, Tyr114His, Tyr114Ser, Tyr116Ser, Thr116Met, Ala120Ser, Val122del, Val122Ile, Val122Ala and Pro125Ser.

[0100] In one particular embodiment, the pathogenic mutation underlying hereditary ATTR is Val30Met (i.e., a substitution of valine with methionine at position 30 of the transthyretin protein). Sousa A, et al. Am J Med Genet. 1995;60:512-521.

[0101] In particular embodiments, the subject treated according to the present invention has asymptomatic hATTR due to Val30Met, early-onset hATTR due to Val30Met, or late-onset hATTR due to Val30Met.

[0102] In a specific embodiment, ATTR is hATTR-polyneuropathy (hATTR-PN). hATTR-PN is generally caused by genetic mutations (i.e., point mutations) in the transthyretin gene, with V30M being the most common mutation. The age at onset of hATTR-PN can vary widely, from early (> about 40 years old) to late (> about 50 years old). hATTR-PN is clinically heterogeneous with respect to mutations and the geographic origin of patients. hATTR-PN usually presents as length-dependent sensory polyneuropathy with autonomic neuropathy. Examples of peripheral neuropathy symptoms include, for example, tingling, pins and needles in the feet and hands; weakness and pain in the arms and legs; loss of sensation (numbness); and loss of temperature sensation in the feet. Symptoms of autonomic neuropathy include, for example, orthostatic hypotension; bowel dysfunction, nausea, vomiting; urinary retention; impotence; and decreased sweating. The average survival time after symptom onset is approximately 10 years. As patients age, central symptoms begin to appear.

[0103] In another specific embodiment, ATTR is hATTR-cardiomyopathy (hATTR-CM). hATTR-CM clinically manifests as heart disease (restrictive cardiomyopathy) and sometimes carpal tunnel syndrome, the latter often occurring several years before the former. In one specific embodiment, the mutant TTR is V122I. Examples of symptoms of hATTR-CM include chest pain (angina), shortness of breath; palpitations and arrhythmia; ankle swelling (edema), fatigue; nausea; weight loss; and dizziness.

[0104] In another embodiment, ATTR is primarily caused by wild-type (wt) transthyretin and more specifically manifests clinically as ATTR-cardiomyopathy (ATTR-CM). Exemplary symptoms include slowly progressive loss of energy, exercise intolerance, weight loss, and gastrointestinal (GI) complaints, as well as left and right ventricular congestive heart failure (CHF) with normal systolic function and pronounced diastolic dysfunction, and arrhythmias.

[0105] In another embodiment, ATTR is hATTR-leptomeningeal (hATTR-Leptо), which is primarily caused by ultra-rare genetic mutations in TTR that cause primarily central pathology through amyloid deposition in the leptomeningeal areas of the brain.

[0106] The duration of treatment can vary. In one embodiment, treatment is administered for at least 3 months, e.g., 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In one particular embodiment, patients treated according to the methods disclosed herein exhibit a slowing of disease progression or improvement in disease as measured by the patient's Neuropathic Impairment Score (NIS) or modified Neuropathic Impairment Score (mNIS).

[0107] In one particular embodiment, patients treated according to the methods disclosed herein exhibit a slowing of disease progression or improvement in disease as measured by patient-reported Transient Focal Neurological Episodes (TFNEs).

[0108] In one particular embodiment, patients treated according to the methods disclosed herein exhibit a slowing of disease progression or improvement in disease as measured by the patient's Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score. The patient-reported Norfolk QOL-DN assessment includes the following domains: physical function / large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy.

[0109] In one particular embodiment, a patient treated according to the methods disclosed herein exhibits a slowing of disease progression or improvement in disease as measured by the patient's Kansas City Cardiomyopathy Questionnaire (KCCQ).

[0110] In another embodiment, patients treated according to the methods described herein show a lack of clinically significant changes in most clinical, biochemical, electrocardiographic, and echocardiographic parameters, consistent with delayed cardiac disease progression.

[0111] In another particular embodiment, a patient treated according to the methods described herein exhibits an improvement in the patient's modified body mass index (mBMI) compared to a reference patient treated with conventional (immediate-release) tolcapone. In one particular embodiment, the patient's mBMI is improved by an amount between about 1% and about 20%, more particularly by an amount between about 1% and about 10%, and more particularly by an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%.

[0112] In another particular embodiment, patients treated according to the methods described herein exhibit an improvement in the patient's 6-minute walk test or "6MWT" (a test that measures the distance a patient can rapidly walk in 6 minutes (6MWD) on a flat, hard surface) compared to a reference patient treated with conventional (immediate-release) tolcapone. In one particular embodiment, the patient's 6-minute walk test is improved by about 1% to about 20%, more particularly by about 1% to about 10%, and more particularly by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%.

[0113] In one particular embodiment, patients treated according to the methods described herein exhibit a slowing of disease progression or improvement in disease as measured by a reduction in hospitalizations or deaths.

[0114] In yet a specific embodiment, patients treated according to the methods disclosed herein exhibit at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60% TTR tetramer stabilization for at least 10 hours after administration, e.g., from about 10 hours to about 14 hours, or from about 10 hours to about 12 hours. By stabilizing the tetrameric form, TTR amyloid formation is reduced or prevented.

[0115] TTR stabilization can be measured using an immunoturbidity assay, as described in Gamez, J., et al., “Transthyretin stabilization activity of the catechol-O-methyltranslferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study”, Amyloid 2019.

[0116] In another particular embodiment, patients treated according to the methods disclosed herein exhibit one or more of the following characteristics after administration compared to reference patients treated with conventional tolcapone: (i) increased levels of tetrameric TTR, (ii) decreased levels of monomeric TTR, and / or (iii) an increased ratio of tetrameric to monomeric TTR.

[0117] B. Parkinson's disease In one embodiment, a method of treating Parkinson's disease in a patient comprises administering to the patient at least one tablet disclosed herein comprising an effective amount of tolcapone.

[0118] Parkinson's disease is a slowly progressive neurodegenerative disorder characterized by tremors when muscles are at rest (resting tremor), slowness of voluntary movements, and increased muscle tone (rigidity). In Parkinson's disease, neurons in the basal ganglia, including the substantia nigra, degenerate, resulting in a decrease in dopamine production and a decrease in the number of connections between neurons in the basal ganglia. As a result, the basal ganglia are unable to smoothly smooth muscle movements and coordinate postural changes as they normally do, resulting in tremors, loss of coordination, and slow and reduced movement (bradykinesia) (Blandini, et al., Mol. Neurobiol. 1996, 12, 73-94).

[0119] The efficacy of the tablets disclosed herein for treating Parkinson's disease can be evaluated using animal and human models of Parkinson's disease, as well as in clinical studies.

[0120] C. Obsessive-compulsive disorder Grant, R. et al. recently reported that tolcapone may improve obsessive-compulsive disorder (Grant, R., et al., Tolcapone in obsessive-compulsive disorder: a randomized double-blind placebo-controlled crossover trial; Int Clin Psychopharmacol. 2021 Sep 1; 36(5):225-229).

[0121] In one embodiment, a method of treating obsessive-compulsive disorder (OCD) in a patient comprises administering to the patient at least one tablet disclosed herein.

[0122] The primary symptoms of obsessive-compulsive disorder are recurrent obsessions (i.e., repetitive and intrusive thoughts, images, or urges that cause marked anxiety) and / or compulsions (i.e., repetitive behaviors or mental actions performed to relieve the anxiety caused by the obsessions) that are severe enough to cause distress, be time-consuming, or significantly interfere with normal daily activities and lifestyles. Anxiety is an associated feature of the disorder. For example, patients with the disorder may phobic-avoid situations that trigger the obsessions. Typical obsessions involve contamination, doubt (including self-doubt), and disturbing sexual or religious thoughts. Typical compulsions include cleaning, checking, ordering, and counting.

[0123] A pervasive pattern of preoccupation with orderliness, perfectionism, and psychological and interpersonal control at the expense of flexibility, openness, and effectiveness begins by early adulthood and is present across a variety of contexts, as indicated by four (or more than five) of the following:

[0124] 1. Preoccupied with details, rules, lists, sequences, organizations, or schedules to the extent that the main point of the activity is lost. 2. Exhibiting perfectionism that prevents task completion. 3. Excessive dedication to work and productivity to the exclusion of leisure activities and friendships (not explained by obvious economic necessity). 4. Overly conscientious, scrupulous, and inflexible on matters of morality, ethics, or values. 5. You can't throw away worn-out or worthless items, even if they have no sentimental value. 6. I am reluctant to delegate tasks or work with others unless they follow my exact way of doing things. 7. They adopt a stingy spending style with both themselves and others, viewing money as something to be saved for future catastrophes. 8. Demonstrate strictness and stubbornness.

[0125] Thus, obsessive-compulsive disorder may be characterized by at least four, five, six, seven, or all eight of these features.

[0126] In one embodiment, the method of the present invention comprises administering at least one tablet of the present invention and an additional therapeutic agent. Typical examples of additional therapeutic agents include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine, sertraline, fluoxetine, escitalopram, and fluvoxamine), tricyclic antidepressants (clomipramine), benzodiazepines, and atypical antipsychotics (e.g., olanzapine, quetiapine, and risperidone). The tablet of the present invention and the additional therapeutic agent can be administered together or sequentially.

[0127] The methods of the present invention can result in a reduction of one or more behaviors associated with obsessive-compulsive disorder.

[0128] Example The following examples illustrate various aspects of the present disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure. [Example]

[0129] Modified-release tablets containing 300 mg of tolcapone as described in Table 1 were prepared.

[0130] [Table 1]

[0131] The dissolution profile of the tablets was measured under the following conditions.

[0132]

number

[0133] The concentration of tolcapone was measured under the following HPLC conditions: HPLC column: Kromasil, C18, 4 x 250 mm, 100 A, 5 μm Column temperature: 40℃ Sample temperature: ambient temperature UV detection: UV 271nm Flow rate: 1.0mL / min Injection volume: 5.0μL Mobile phase: 25:40:35 acetonitrile:methanol:phosphate buffer, 5 mM, pH 2.0 Needle wash: 100% methanol Run Time: 15 minutes

[0134] The dissolution profile was promising, demonstrating that 80% drug release was achieved within 12–13 hours. This would have allowed for the possibility of once-daily dosing if the pharmacokinetics had been promising. However, a phase 1 study in fasted and fed patients demonstrated a significant lack of tolcapone absorption (Figure 1). It was hypothesized that the poor bioavailability was due, at least in part, to tolcapone retention in the formulation. Another concerning hypothesis was that local absorption could prevent the sustained-release formulation from being an appropriate delivery system. [Example]

[0135] 375±10 mg of micronized tolcapone was added to 150 mL of each buffer solution for solubility evaluation to yield 2.5 mg of tolcapone per mL. Two aliquots of each sample were taken at 1 and 2 hours. One aliquot was used for assay and related substance analysis by reverse-phase HPLC, and the other aliquot was used for microscopic imaging using 5.5x magnification, polarized and unpolarized light. Additionally, a representative photograph of each n=1 sample at the 1 hour time point was taken for information. The pH of each sample was measured at 2 hours.

[0136] Visual observation At pH 2.0, the appearance of the solutions in both replicates changed from clear and colorless (before tolcapone addition) to highly cloudy and bright yellow within the first 5 minutes (after tolcapone addition). No further changes in appearance were observed.

[0137] At pH 4.5, the appearance of the solutions in both replicates changed from clear and colorless (before tolcapone addition) to highly cloudy and yellow within the first 5 minutes (after tolcapone addition). No further changes in appearance were observed.

[0138] At pH 5.5, the appearance of the solutions in both replicates changed from clear and colorless (before tolcapone addition) to highly cloudy and bright orange within the first 5 minutes (after tolcapone addition). No further changes in appearance were observed.

[0139] At pH 6.8, the appearance of the solutions in both replicates changed from clear and colorless (before tolcapone addition) to clear and dark red within the first 5 minutes (after tolcapone addition). No visible solids were observed. Both solutions then became opaque by the 45 minute time point, and a significant amount of precipitation was observed by the 1 hour time point. No further changes in appearance were observed.

[0140] At pH 7.4, the appearance of the solutions in both replicates changed from clear and colorless (before tolcapone addition) to highly cloudy and orange within the first 5 minutes (after tolcapone addition). No further changes in appearance were observed.

[0141] The solubility of tolcapone measured by HPLC is shown in Table 2.

[0142] [Table 2]

[0143] Both visual and HPLC measurements indicate that the solubility of tolcapone is pH dependent: tolcapone is poorly soluble under acidic conditions, but solubility improves around pH 6.8.

[0144] Lower pH was also associated with differences in the microscopic physical appearance of tolcapone crystals. Specifically, lower pH promoted a form of the drug with a longer, hair-like crystal structure. It was hypothesized that rearrangement into hair-like crystals under acidic conditions provided a less soluble form, thereby making tablets containing tolcapone resistant to disintegration and erosion for drug release. [Example]

[0145] Tablets of the present invention were prepared with the ingredients shown in Table 3.

[0146] [Table 3]

[0147] Tolcapone was divided between the core (50% by weight) and the immediate release layer (50% by weight).

[0148] Tablet cores were prepared using wet granulation according to the process outlined in FIG. [Example]

[0149] A Phase I, open-label, randomized, crossover study was conducted to evaluate the bioavailability of different tolcapone modified-release prototype formulations and compare them with Tasmar® (tolcapone immediate-release tablets) at 300 mg doses in the fasted and fed states in healthy subjects. The study was conducted in two sequential parts.

[0150] Part 1 (Periods 1-6): Part 1 was a randomized, six-period, six-arm, six-treatment crossover design. Prior to study entry, subjects attended a screening visit to establish eligibility within 28 days prior to study drug administration. Subjects were admitted to the Clinical Research Unit (CRU) on Day 1 and administered one of six study treatments under fasting conditions in a randomized fashion on Days 1 (Period 1), 3 (Period 2), 5 (Period 3), 7 (Period 4), 9 (Period 5), and 11 (Period 6). Administration of study drug in each period was separated by a 48-hour (±30-minute) washout period.

[0151] Part 2 (Periods 7-8): Part 2 was a randomized, two-period, two-arm, two-treatment crossover design. Prior to study entry, subjects attended a screening visit to establish eligibility within 28 days prior to study drug administration. Subjects were admitted to the CRU on Day 1 and administered one of two study treatments on Days 1 (Period 7) and 3 (Period 8) in a randomized fashion under fed conditions. Administration of study drug in each period was separated by a 48-hour (±30-minute) washout period.

[0152] There was an approximately 3-week interval between Parts 1 and 2, which was the time required to conduct the interim PK analysis of Part 1. The total study duration (Parts 1 and 2) was approximately 40 days. Patients were permitted to leave the clinic during their stay. This was always supervised by clinical staff and was limited to the surrounding grounds of the clinic to ensure compliance with the protocol.

[0153] Subjects were healthy, non-smoking adults of both sexes, aged 18 years or older, with a body mass index (BMI) of 18.5 kg / m 2 Over 30.0 kg / m 2 The subjects were required to be under 18 years of age and to have a body weight of 50.0 kg or more for men and 45.0 kg or more for women.

[0154] During each Part 1 period, subjects received a single oral dose of one of the following treatments:

[0155]

number

[0156] Prototype 1 and Prototype 2

[0157] [Table 4]

[0158] The first manufacturing step was high shear (wet) granulation. Three sub-batches of 68 wt. % tolcapone granulation were produced in a GMX high shear granulator equipped with a 4-liter bowl. The three individual sub-batches were passed through a Comil equipped with a 0.375-inch sieve screen to de-lump the wet mass. The material was dried to a moisture level of less than 3.0% (loss on drying) using an FLM-1 fluid bed. The dried granules were then blended together in a 1 cubic foot V-blender. After blending, the dried granules were passed through a Comil equipped with a 0.075-inch screen.

[0159] The granules were divided into two portions and further blended with extragranular excipients: one portion was blended with excipients in an 8-quart V-blender to produce an immediate-release (IR) tablet blend, and the other portion was blended in the same shell with different excipients to produce an extended-release (ER) tablet blend.

[0160] Compression of the IR and ER blends was performed on a rotary Piccola B / D Tablet Press equipped with 6.5 x 12.5 mm caplet-shaped tooling. The target weight was 300 mg, providing a tablet core with a 50% drug load. The target hardness was 10 kp for each compression run.

[0161] Each set of tablet cores was subcoated in a CompuLab Pan Coater equipped with a 15-inch pan insert. A single spray gun was used to spray the subcoat suspension. A target weight gain of 3% was applied to the tablets.

[0162] A delayed release (DR) layer was then applied to each set of tablets using the same equipment settings. A target weight gain of 3.5% was applied to the tablets to prevent disintegration of the tablet core in the gastric environment.

[0163] An immediate release (IR) layer was then sprayed onto the tablets with a target weight gain of 62.5%. This layer provided an additional 150 mg of tolcapone to the formulation, bringing the total tablet strength to 300 mg.

[0164] Prototype 3 and Prototype 4 Prototypes 3 and 4 are similar in size, shape, and aspect. The only difference is that Prototype 3 contains a higher amount of hypromellose per tablet. This difference results in a slower dissolution profile for the controlled-release layer of Prototype 3 than for Prototype 4.

[0165] [Table 5]

[0166] All ingredients except magnesium stearate are mixed together in a container, and then the magnesium stearate is added to the previously prepared mixture and mixed in the same container.The mixture is then tableted using a Styl'One compression simulator.

[0167] Blood collection: Blood collection for PK: Blood samples were collected 16 times in total: before administration and at 0.5, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 7.00, 8.00, 9.00, 10.0, 12.0, 16.0, and 24 hours after administration.

[0168] Blood collection for PD: Blood samples were collected 10 times: pre-dose and 1.00, 2.00, 4.00, 6.00, 8.00, 10.0, 12.0, 16.0, and 24.0 hours after administration. PD samples were collected and stored for future analysis.

[0169] Evaluation criteria: Pharmacokinetics: The following PK parameters were calculated by standard non-compartmental methods for tolcapone: AUC 0-t , AUC 0-inf , residual area, Cmax, Tmax, T1 / 2 el, Kel.

[0170] Safety: Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), vital signs, ECG measurements (in triplicate), physical examination, and standard laboratory assessments.

[0171] Statistical methods: Pharmacokinetic analysis: AUC 0-t , AUC 0-inf Parametric ANOVA for residual area, Cmax, T1 / 2 el, Kel; AUC 0-t , AUC 0-inf , and geometric confidence intervals (CI) for Cmax; Wilcoxon nonparametric test for Tmax. · Factors in the ANOVA model: sequence, subjects within sequence, period, and treatment. Ln transformation parameter: AUC 0-t , AUC 0-inf , Cmax.

[0172] result: Pharmacokinetics: The release profiles of prototypes 1-4 and Tasmar® are shown in Table 6. Mean and geometric mean values ​​for 10 subjects are shown for each treatment type.

[0173] [Table 6]

[0174] The PK parameters of each prototype are shown in Tables 7 to 13.

[0175] [Table 7]

[0176] [Table 8]

[0177] [Table 9]

[0178] The bioavailability of tolcapone in the prototype tablets was compared to treatment E (Tasmar®).

[0179] [Table 10]

[0180] [Table 11]

[0181] [Table 12]

[0182] [Table 13]

[0183] Treatment A demonstrated the highest bioavailability among the prototypes and showed similar bioavailability compared to the reference product (Tasmar®). No difference in half-life was observed under fasted conditions, suggesting that twice-daily dosing maintains therapeutically effective plasma concentrations. Prototype 1 demonstrated the advantage of delayed absorption under fasted conditions, but its half-life was not significantly longer. Therefore, Prototype 1 was selected for Part 2 of the study by dosing under fed conditions.

[0184] [Table 14]

[0185] For the administration of the reference formulations (Treatment E and Treatment H), the administration time was set to the same time that the subject received the first tablet. If the subject was unable to swallow three tablets with 240 mL of water, an additional 60 mL of water was administered and recorded. The complete administration procedure had to be completed within 2 minutes.

[0186] An investigator assistant was present for drug administration and until 4 hours after the last subject received study drug.

[0187] The release profiles of Prototype 1 and Tasmar® under fed conditions are shown in Figure 3. The pharmacokinetic results were as follows:

[0188] [Table 15]

[0189] Treatment G (test) vs. Treatment H (reference) - under feeding conditions When Treatment G (Prototype 1) was administered, tolcapone absorption was slightly slower, with median peak concentrations observed at 5.996 hours post-dose compared to 1.996 hours post-dose for Treatment H. The extent and rate of tolcapone absorption (AUC and Cmax) were similar, with AUC and Cmax approximately 15% lower after administration of Treatment G (Prototype 1) compared to Treatment H, as expected given the formulation differences. The resulting mean T 1 / 2 el was similar for both formulations, 2.17 hours and 1.74 hours.

[0190] The ratio of geometric means (treatment G (prototype 1) vs. treatment H) and 90% confidence intervals (CI) are given for AUC 0-t , AUC 0-inf and 101.68% (89.54% vs. 115.47%), 98.72% (87.29% vs. 111.65%), and 85.37% (71.47% vs. 101.97%) for Cmax, respectively.

[0191] Treatment G (fed state) vs. Treatment A (fasted state) When Treatment G (fed state) was administered, tolcapone absorption was slightly slower, with median peak concentrations observed at 5.996 hours post-dose compared with 2.999 hours post-dose for Treatment A (fasted state). Compared with Treatment A (fasted state), the extent (AUC) of tolcapone absorption after Treatment G (fed state) was approximately 17% and 14% lower, and the rate (Cmax) was approximately 25% lower. The resulting mean T 1 / 2 el was similar for both formulations, 2.17 hours and 1.74 hours.

[0192] The ratio of geometric means (treatment G (fed state) vs. treatment A (fasted state)) and 90% confidence intervals (CI) are given for AUC 0-t , AUC 0-inf and 82.55% (66.62% vs. 102.29%), 85.97% (68.36% vs. 108.11%), and 74.33% (49.90% vs. 110.73%) for Cmax, respectively.

[0193] ANOVA did not detect statistically significant differences between treatments for all AUC and Cmax.

[0194] Treatment H (fed state) vs. Treatment E (fasted state) When Treatment H (fed state) was administered, tolcapone absorption was slightly slower, with median peak concentrations observed at 1.996 hours post-dose compared with 1.753 hours post-dose for Treatment E (fasted state). Compared with Treatment E (fasted state), the extent (AUC) of tolcapone absorption after Treatment H (fed state) was approximately 19% and 21% lower, and the rate (Cmax) was approximately 28% lower. The resulting mean T 1 / 2 el was similar for both formulations, 1.74 and 1.94 hours.

[0195] The ratio of geometric means (treatment H (fed state) vs. treatment E (fasted state)) and 90% confidence intervals (CI) are given for AUC 0-t , AUC 0-inf and 81.73% (74.93% vs. 89.15%), 78.83% (73.72% vs. 84.29%), and 71.53% (49.43% vs. 103.52%) for Cmax, respectively.

[0196] ANOVA detected statistically significant differences between treatments for all AUCs, but not for Cmax.

[0197] The extent and rate of absorption of Prototype 1 when administered in the fed state was lower than when administered in the fasted state (approximately 15% lower and approximately 25% lower, respectively). The extent and rate of absorption of Tasmar® was also lower when administered in the fed state compared to when administered in the fasted state (approximately 19% lower and approximately 28% lower, respectively).

[0198] Overall, single oral doses of tolcapone were safe and well tolerated in healthy subjects. Considering twice-daily dosing, prototype 1 was the most suitable. [Example]

[0199] TTR stabilization was measured along with mean plasma tolcapone concentrations 12 hours after administration of Prototype 1. Fraction of initial tetramer concentration (FOI) was determined according to Gamez, J., et al., “Transthyretin stabilization activity of the catechol-O-methyltranslferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study,” Amyloid 2019. Results are shown in Figure 4. Near-complete TTR stabilization occurred over 12 hours, with robust stabilization observed at all time points. Near-complete stabilization is expected after repeated administration.

Claims

1. Tablets containing: (i) a tablet core comprising a first portion of tolcapone and optionally at least one binder, filler, glidant, and / or lubricant; (ii) an optional film coating layer surrounding the tablet core and comprising at least one cellulosic polymer; (iii) an enteric coating layer encapsulating the core or film coating layer and comprising a copolymer of acrylic acid and methacrylic acid and, optionally, at least one additive; (iv) an immediate-release layer encapsulating the enteric coating layer and comprising a second portion of tolcapone and at least one cellulosic polymer; and (v) An optional topcoat that encapsulates the immediate release layer.

2. 10. The tablet of claim 1, wherein the first portion of tolcapone is present in an amount of about 10% to about 95% by weight of the tablet core.

3. 10. The tablet of claim 1, wherein the at least one cellulosic polymer of the optional film coating layer is present in an amount of about 0.1% to about 10% by weight of the total tablet weight.

4. 10. The tablet of claim 1, wherein the polymer of the enteric coating is present in an amount of about 0.5% to about 10% by weight of the total tablet weight.

5. 10. The tablet of claim 1, wherein the second portion of tolcapone is present in an amount of about 10% to about 95% by weight of the total tablet weight.

6. 10. The tablet of claim 1, wherein the at least one cellulosic polymer of the immediate release layer is present in an amount of about 5% to about 20% by weight of the total tablet weight.

7. 10. The tablet of claim 1, comprising: (i) A tablet core comprising a first portion of tolcapone, wherein the first portion of tolcapone is present in an amount of about 10% to about 95% by weight, optionally comprising: a. at least one binder in an amount from about 1% to about 10% by weight; b. at least one filler in an amount from about 5% to about 50% by weight; c. at least one flow agent in an amount from about 0.1% to about 1% by weight, and / or at least one lubricant in an amount from about 0.1% to about 1% by weight; (ii) an optional film coating layer encapsulating the tablet core and comprising at least one cellulosic polymer, wherein the at least one cellulosic polymer is present in an amount of about 0.1% to about 10% by weight; (iii) an enteric coating layer encapsulating the core or film coating layer, the enteric coating layer comprising a copolymer of acrylic acid and methacrylic acid, the copolymer being present in an amount of about 0.5% to about 10% by weight, and optionally at least one additive in an amount of about 0.1% to about 10% by weight; (iv) an immediate-release layer encasing the enteric coating layer and comprising a second portion of tolcapone and at least one cellulosic polymer, wherein the second portion of tolcapone is present in an amount of about 10% to about 95% by weight and the at least one cellulosic polymer is present in an amount of about 5% to about 20% by weight; and (v) an optional topcoat encapsulating the immediate release layer, the topcoat comprising at least one cellulosic polymer present in an amount of about 0.1% to about 10% by weight.

8. 10. The tablet of claim 1, comprising: (i) A tablet core comprising a first portion of tolcapone, wherein the first portion of tolcapone is present in an amount of about 20% to about 30% by weight, optionally comprising: a. at least one binder in an amount from about 2% to about 10% by weight; b. at least one filler in an amount from about 20% to about 30% by weight; c. at least one glidant in an amount from about 0.1% to about 0.5% by weight, and / or at least one lubricant in an amount from about 0.1% to about 0.5% by weight; (ii) an optional film coating layer encapsulating the tablet core and comprising at least one cellulosic polymer, wherein the at least one cellulosic polymer is present in an amount of about 1% to about 3% by weight; (iii) an enteric coating layer encapsulating the core or an optional film coating layer, the enteric coating layer comprising a copolymer of acrylic acid and methacrylic acid, the copolymer being present in an amount of about 1.0% to about 7.0% by weight, and optionally at least one additive in an amount of about 0.1% to about 1.0% by weight; (iv) an immediate-release layer encapsulating the enteric coating layer and comprising a second portion of tolcapone and at least one cellulosic polymer, wherein the second portion of tolcapone is present in an amount of about 20% to about 30% by weight, and the at least one cellulosic polymer is present in an amount of about 5% to about 15% by weight; and (v) an optional topcoat encapsulating the immediate release layer, the topcoat comprising at least one cellulosic polymer present in an amount of about 0.1% to about 3.0% by weight.

9. 10. The tablet of claim 1, comprising from about 100 mg to about 600 mg of tolcapone.

10. A method for treating or preventing a disease selected from transthyretin amyloidosis (ATTR), Parkinson's disease, and obsessive-compulsive disorder in a patient in need thereof, comprising orally administering the tablet of claim 1.

11. 11. The method of claim 10, wherein the tablet comprises from about 100 mg to about 600 mg of tolcapone.

12. 11. The method of claim 10, wherein the tablet is administered no more than twice daily.

13. 11. The method of claim 10, wherein the tablet is administered in the fasted or fed state.

14. 11. The method of claim 10, wherein the administration provides a plasma concentration (mean Cmax) of tolcapone of about 1,000 ng / mL to about 10,000 ng / mL.

15. 11. The method of claim 10, wherein the administration provides a plasma concentration (mean Cmin) of tolcapone of preferably 200 ng / mL or more 12 hours after administration.

16. 11. The method of claim 10, wherein the administration provides a plasma concentration (mean Cmin) of tolcapone of about 200 ng / mL to about 800 ng / mL 12 hours after administration.

17. 11. The method of claim 10, wherein after administration to a patient, no more than 60% of the tolcapone is released within 2 hours.

18. 11. The method of claim 10, wherein at least 90% of the tolcapone is released within 8 hours after administration to a patient.

19. 16. The method of claim 15, wherein the ATTR is selected from hereditary ATTR (hATTR), hATTR-polyneuropathy (hATTR-PN), hATTR-cardiomyopathy (hATTR-CM), ATTR-cardiomyopathy (ATTR-CM), hATTR-leptomeningeal (hATTR-Lepto), and mixed phenotypes.

20. 16. The method of claim 15, wherein administration provides one or more of the following, compared to a reference patient treated with immediate-release tolcapone: (i) an increase in the level of tetrameric TTR, (ii) a decrease in the level of monomeric TTR, and / or (iii) an increase in the ratio of tetrameric to monomeric TTR.

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