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US-20260124146-A1 - MODIFIED RELEASE TOLCAPONE FORMULATIONS

US20260124146A1US 20260124146 A1US20260124146 A1US 20260124146A1US-20260124146-A1

Abstract

Modified release tablet dosage forms comprising tolcapone are disclosed. The tablet dosage forms provide a pulsed, pH dependent release profile of tolcapone to both the gastric space and the small intestine. Methods of treating or preventing a disease selected from transthyretin amyloidosis (ATTR), Parkinson's Disease and obsessive compulsive disorder using said dosage forms are provided.

Inventors

  • Michael Roberts
  • Harish Pimplaskar
  • Paul Glidden

Assignees

  • CORINO THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20231006

Claims (20)

  1. 1 . A tablet comprising: (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 surrounding the core or film coating layer and comprising acrylic acid and methacrylic acid copolymer, and optionally at least one additive; (iv.) an immediate release layer surrounding the enteric coating layer and comprising a second portion of tolcapone and comprising at least one cellulosic polymer; and (v.) an optional top coat surrounding the immediate release layer.
  2. 2 . The tablet of claim 1 , wherein the first portion of tolcapone is present in an amount from about 10 wt % to about 95 wt % by weight of the tablet core.
  3. 3 . The tablet of claim 1 , wherein the at least one cellulosic polymer of the optional film coating layer is present in an amount from about 0.1 wt % to about 10 wt % of the total tablet weight.
  4. 4 . The tablet of claim 1 , wherein the enteric coating polymer is present in an amount from about 0.5 wt % to about 10 wt % of the total tablet weight.
  5. 5 . The tablet of claim 1 , wherein the second portion of tolcapone is present in an amount from about 10 wt % to about 95 wt % of the total tablet weight.
  6. 6 . The tablet of claim 1 , wherein the at least one cellulosic polymer of the immediate release layer is present in an amount from about 5 wt % to about 20 wt % of the total tablet weight.
  7. 7 . The tablet of claim 1 , comprising by weight: (i.) a tablet core comprising a first portion of tolcapone, wherein the first portion of tolcapone is present in an amount from about 10 wt % to about 95 wt %, and optionally: a. at least one binder in an amount from about 1 wt % to about 10 wt %, b. at least one filler in an amount from about 5 wt % to about 50 wt %, c. at least one glidant in an amount from about 0.1 wt % to about 1 wt %, and/or at least one lubricant in an amount from about 0.1 wt % to about 1 wt %; (ii.) an optional film coating layer surrounding the tablet core and comprising at least one cellulosic polymer, wherein the at least one cellulosic polymer is present in an amount from about 0.1 wt % to about 10 wt %; (iii.) an enteric coating layer surrounding the core or film coating layer and comprising acrylic acid an methacrylic acid copolymer, wherein the copolymer is present in an amount from about 0.5 wt % to about 10 wt %, and optionally at least one additive in an amount from about 0.1 wt % to about 1.0 wt %; (iv.) an immediate release layer surrounding 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 from about 10 wt % to about 95 wt % and the at least one cellulosic polymer is present in an amount from about 5 wt % to about 20 wt %; and (v.) an optional top coat surrounding the immediate release layer and comprising at least one cellulosic polymer, wherein the top coat is present in an amount from about 0.1 wt % to about 10 wt %.
  8. 8 . The tablet of claim 1 , comprising by weight: (i.) a tablet core comprising a first portion of tolcapone, wherein the first portion of tolcapone is present in an amount from about 20 wt % to about 30 wt %, and optionally: a. at least one binder in an amount from about 2 wt % to about 10 wt %, b. at least one filler in an amount from about 20 wt % to about 30 wt %, c. at least one glidant in an amount from about 0.1 wt % to about 0.5 wt %, and/or at least one lubricant in an amount from about 0.1 wt % to about 0.5 wt %; (ii.) an optional film coating layer surrounding the tablet core and comprising at least one cellulosic polymer, wherein the at least one cellulosic polymer is present in an amount from about 1 wt % to about 3 wt %; (iii.) an enteric coating layer surrounding the core or optional film coating layer and comprising acrylic acid an methacrylic acid copolymer, wherein the copolymer is present in an amount from about 1.0 wt % to about 7.0 wt %, and optionally at least one additive in an amount from about 0.1 wt % to about 1.0 wt %; (iv.) an immediate release layer surrounding 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 from about 20 wt % to about 30 wt the cellulosic polymer is present in an amount from about 5 wt % to about 15 wt %; and (v.) an optional top coat surrounding the immediate release layer and comprising at least one cellulosic polymer, wherein the top coat is present in an amount from about 0.1 wt % to about 3.0 wt %.
  9. 9 . The tablet of claim 1 , wherein the tablet comprises from about 100 mg to about 600 mg tolcapone.
  10. 10 . A method of 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 a tablet of claim 1 .
  11. 11 . The method of claim 10 , wherein the tablet comprises from about 100 mg to about 600 mg tolcapone.
  12. 12 . The method of claim 10 , wherein the tablet is administered not more than twice daily.
  13. 13 . The method of claim 10 , wherein the tablet is administered in a fasted or fed state.
  14. 14 . The method of claim 10 , wherein administration provides a blood plasma concentration (Average Cmax) of tolcapone of about 1,000 ng/ml to about 10,000 ng/mL.
  15. 15 . The method of claim 10 , wherein administration provides a blood plasma concentration (Average Cmin) of tolcapone of preferably no less than 200 ng/ml at 12 hours after dosing.
  16. 16 . The method of claim 10 , wherein administration provides a blood plasma concentration (Average Cmin) of tolcapone from about 200 ng/ml to about 800 ng/ml at 12 hours after dosing.
  17. 17 . The method of claim 10 , wherein, following administration to a patient, no more than 60% of the tolcapone is released within 2 hours.
  18. 18 . The method of claim 10 , wherein, following administration to a patient, no less than 90% of the tolcapone is released within 8 hours.
  19. 19 . 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. 20 . 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 the level of monomeric TTR, and/or (iii) an increase the ratio of tetrameric to monomeric TTR.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No. 63/414,655, filed Oct. 10, 2022, the contents of which are incorporated by reference herein. FIELD OF THE INVENTION The present disclosure relates to modified release tablets of tolcapone. BACKGROUND Transthyretin (ATTR) amyloidosis includes a group of amyloid diseases specifically associated with transthyretin (TTR) protein. TTR is a 127 amino acid 55 KD homo-tetrameric produced primarily in the liver and secreted into the plasma. Dissociation of the TTR-tetramer at the T4-binding interface generates monomers that misfold and aggregate to form amyloid fibrils. These fibrils, together with unstable fibril precursors, produce cell death and tissue damage. ATTR is characterized by deposition of misfolded protein in one or more organ systems (including the peripheral and autonomic nervous systems, the heart, the brain and the eyes). The age at which symptoms begin to develop varies widely ranging between 20 to 70 years old. ATTR is progressive, and some variants can have a fatal outcome within a few years of presentation. Treatment options include supportive and symptomatic care that may slow or stop progressive decline in functional state but do not alter the pathological process. Liver transplant can be performed in selected patients but is limited by organ supply, requires lifelong immunosuppression, and may be complicated by progressive heart and nerve amyloid deposition. Importantly, liver transplant does not alter the natural course of central nervous system amyloid disease. Life expectancy is generally between 5 and 15 years following diagnosis. TTR dissociation can be the result of a genetic mutation (hereditary ATTR), aging (wt ATTR) or both. There are more than 120 known amyloidogenic mutations in TTR with diverse clinical manifestations, including hATTR-polyneuropathy (familial amyloid polyneuropathy (FAP)) and hATTR-cardiomyopathy (familial amyloid cardiomyopathy (FAC)). Often, hereditary ATTR (hATTR) results in a mix of progressive neurological and cardiological impairment. hATTR-leptomeningeal is an under recognized, progressive and fatal disease caused by accumulation in the brain of variant transthyretin (TTR) expressed by the choroid plexus, causing central nervous system (CNS) dysfunction. Tolcapone is one of several small molecules that can stabilize the tetrameric structure of TTR, reducing or preventing dissociation (Sant′Anna R. et al. Nature Communications volume 7, Article number: 10787 (2016). Tolcapone is FDA-approved for treatment of Parkinson's disease and crosses the blood-brain barrier. A recent proof-of-concept study of orally dosing hATTR-leptomeningeal patients three times daily with 100 mg tolcapone over 14 days and then three times daily with 200 mg tolcapone over an additional 14 days demonstrated that tolcapone is a potent TTR stabilizer in both plasma and cerebral spinal fluid (CSF). Tolcapone normalized TTR concentration in plasma with an overall mean increase in plasma TTR tetramer concentration of 55%. Significant concentrations of drug penetrated into the CSF decreasing monomeric TTR concentration by a mean of 48% as 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). However, tolcapone is eliminated fairly quickly, with an elimination half-life of 1.6 to 3.4 hours (Keating G M, Lyseng-Williamson K A. Tolcapone: a review of its use in the management of Parkinson's disease. CNS Drugs. 2005; 19 (2): 165-84). Immediate release dosage forms are therefore not suitable for treatment ATTR as 4-6 dosings a day would be required to ensure consistent TTR stabilization (e.g., at nighttime). Patient compliance with such dosing regimens would be problematic, thereby reducing efficacy. Initial attempts to formulate modified release tolcapone formulations utilized off-the-shelf technology using wet granulation with HPMC binder. A 300 mg tablet was developed containing (i) an intragranular portion containing tolcapone (37.50 wt %), HPMC E50 (22.0 wt %), HPMC K100LV (10.0 wt %), dicalcium phosphate anhydrous (24.75 wt %) and (ii) an extragranular component containing Aerosil 200 (0.50 wt %) and magnesium stearate (1.0 wt %). A Phase I study in healthy subjects unexpectedly indicated low bioavailability and minimal extended release (FIG. 1). Further investigations demonstrated that exposure to low pHs found in the stomach changed the nature of the tablet such that it became rubberized and gelatinous and resisted dissolution after transition to the higher pHs found in the small intestine. It was also found that tolcapone itself has a strong pH dependent solubility, with lower pHs associated with low tolc