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EP-4741011-A2 - TRIMODAL, PRECISION-TIMED PULSATILE RELEASE TABLET

EP4741011A2EP 4741011 A2EP4741011 A2EP 4741011A2EP-4741011-A2

Abstract

A trimodal, precision-timed pulsatile release tablet that delivers a trimodal (i.e., three pulses) release profile is provided. The tablet includes at least three stimulant layers. By providing a single tablet with multiple stimulant layers, the dosing frequency is decreased, and compliance is expected to increase since precise blood levels of the active pharmaceutical ingredient over a prolonged time period are controlled and achieved.

Inventors

  • BRAMS, Matthew
  • SILVA, Raul
  • STRAUGHN, Arthur

Assignees

  • Cingulate Therapeutics LLC

Dates

Publication Date
20260513
Application Date
20220510

Claims (13)

  1. A trimodal, pulsatile release tablet for oral administration of a stimulant comprising: (a) a first stimulant layer comprising (i) a first pulse of about 30% to about 40% of the total stimulant in the tablet, wherein the first pulse is released within about 10 to about 45 minutes after oral administration of the tablet to a patient, (ii) calcium sulfate, (iii) microcrystalline cellulose, (iv) colloidal silicon dioxide, (v) sodium starch glycolate, and (vi) sodium stearyl fumarate; (b) a second stimulant layer comprising (i) a second pulse of about 40% to about 50% of the total stimulant in the tablet, wherein release of the second pulse begins about 3 to about 5 hours following oral administration of the tablet to a patient, and release of the second pulse is sustained for about 30 to about 135 minutes, (ii) calcium sulfate, (iii) hypromellose, (iv) microcrystalline cellulose, (v) colloidal silicon dioxide, (vi) sodium starch glycolate and (vii) sodium stearyl fumarate; and (c) a third stimulant layer comprising (i) a third pulse of about 15% to about 25% of the total stimulant in the tablet, wherein the third pulse is a delayed, immediate release pulse, wherein release of the third pulse is delayed in release until about 5 hours to about 10 hours following oral administration of the tablet to a patient, (ii) calcium sulfate, (iii) microcrystalline cellulose, (iv) colloidal silicon dioxide, (v) sodium starch glycolate, and (vi) sodium stearyl fumarate; wherein the tablet is structured such that the first stimulant layer is positioned as a surface of the tablet and on an outer erosion barrier layer, the second stimulant layer is positioned between the outer erosion barrier layer and an inner erosion barrier layer such that it is surrounded by the outer and inner erosion barrier layers, and the third stimulant layer is positioned at the center of the tablet and surrounded by the inner erosion barrier layer; wherein the first stimulant layer comprises 2.5 w/w% to about 25 w/w% of stimulant, about 1 w/w% or less of calcium sulfate and about 75 w/w% to about 98 w/w% cumulatively of microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate and sodium stearyl fumarate; the second stimulant layer comprises about 5 w/w % to about 50 w/w% of stimulant, about 1 w/w% or less of calcium sulfate, about 4 w/w% to about 10 w/w% of hypromellose, and about 40 w/w% to about 90 w/w% cumulatively of microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate and sodium stearyl fumarate; the third stimulant layer comprises 2.5 w/w% to about 25 w/w% of stimulant, about 1 w/w% or less of calcium sulfate, and about 75 w/w% to about 98 w/w% cumulatively of microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate and sodium stearyl fumarate; wherein the outer and inner erosion barrier layers each comprise about 35% to about 45% by weight of glyceryl behenate, about 15% to about 25% by weight of LH-21, about 25% to about 35% by weight of LH-32 and about 4% to about 8% by weight of hydroxypropyl cellulose; and wherein the stimulant is methylphenidate or a pharmaceutically acceptable salt thereof.
  2. The tablet of claim 1, wherein: the total stimulant dose of the tablet is 50 mg; the first stimulant layer comprises 17.5 to 23.0 w/w % of stimulant, 1 w/w% or less of calcium sulfate and 76.0 to 82.0 w/w% cumulatively of microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, and sodium stearyl fumarate; the second stimulant layer comprises 43.0 to 47.0 w/w % of stimulant, 1 w/w% or less of calcium sulfate, 4.0 to 10.0 w/w% of hypromellose and 44.0 to 48.0 w/w% cumulatively of microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, and sodium stearyl fumarate; and the third stimulant layer comprises 17.5 to 23.0 w/w % of stimulant, 1 w/w% or less of calcium sulfate and 76.0 to 82.0 w/w% cumulatively of microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, and sodium stearyl fumarate.
  3. The tablet of claim 2, wherein the first pulse releases about 35% of the total stimulant in the tablet.
  4. The tablet of claim 2, wherein the second pulse releases about 45% of the total stimulant in the tablet.
  5. The tablet of claim 2, wherein the third pulse releases about 20% of the total stimulant in the tablet.
  6. The tablet of claim 1 or 2, wherein the third stimulant release layer is 1.97 - 2.03 mm thick x 4.95 - 5.05 mm in diameter with a flat-faced radius edge.
  7. The tablet of any one of claims 1-6, wherein the thickness of the outer erosion barrier layer is about 574 - 888 microns.
  8. The tablet of any one of claims 1-7, wherein the thickness of the inner erosion barrier layer is about 862 - 1071 microns.
  9. The tablet of any one of claims 1-8, wherein the tablet comprises a film coating.
  10. A tablet of any one of claims 1-9, for use in a method for extending the therapeutic duration of a stimulant, the method comprising administering the tablet to a patient in need thereof, wherein the therapeutic duration of the stimulant is effective for at least 14 hours after oral administration of the tablet to a patient.
  11. The tablet for use in a method for extending the therapeutic duration of a stimulant of claim 10, wherein the therapeutic duration of the stimulant is effective for up to 16 hours after oral administration of the tablet to a patient.
  12. A tablet of any one of claims 1-11 for use in a method of treatment of a disorder, condition, or disease for which a stimulant is generally indicated, the method comprising administering the tablet to a patient in need thereof.
  13. The tablet for use in a method of treatment of a disorder, condition, or disease of claim 12, wherein the disorder, condition, or disease is ADHD.

Description

BACKGROUND OF THE INVENTION Since the introduction of modified-release stimulant dosage forms for the treatment of conditions such Attention Deficit Hyperactivity Disorder (ADHD), the need for administering an immediate release dosage form two to three times per day has been reduced to a single daily dose. For example, patients may respond to a single daily tablet or capsule that releases the stimulant as two distinct pulses - the first pulse occurring at the time of dosing and a second pulse 3 to 5 hours later. Such modified dosage forms typically provide therapeutically effective coverage for 8 to 12 hours after administration to a patient. However, many patients still require a separate, additional "booster" dose in the afternoon to maintain adequate therapeutic coverage throughout the entire day. Furthermore, as the level of stimulant concentration in blood decreases during the latter portions of the day, patients may experience a crash or rebound effect than can result in worsening of clinical symptoms or other effects, such as irritability. There remains a need for a single, once-daily oral dosage form that delivers a stimulant drug in a manner that provides a safe and effective therapeutic response over the patient's active day. SUMMARY OF THE INVENTION A trimodal, precision-timed pulsatile release tablet that delivers a three-pulse release profile is provided. According to one embodiment, the tablet includes three stimulant layers inside the final tablet. By providing a single tablet having multiple stimulant layers, the dosing frequency is decreased, compliance is increased, and precise blood levels of the active pharmaceutical ingredient (API; e.g., the stimulant) are achieved over a prolonged time period. The trimodal, precision-timed pulsatile release tablets disclosed herein provide a pharmaceutically precise amount of stimulant initially to the patient to cause the desired pharmacological response via a first stimulant layer and deliver the remaining predetermined amounts of stimulant via second and third stimulant layers to maintain the effective therapeutic pharmacological activity for a period of time in excess of the time expected from a single, bimodal drug formulation (immediate release followed by a second, delayed release). According to one embodiment, the tablet includes a first stimulant layer having a first pulse of stimulant of about 25% to about 45% of the total stimulant in the tablet; a second stimulant layer having a second pulse of stimulant of about 35% to about 55% of the total stimulant in the tablet; and a third stimulant layer having a third pulse of stimulant of about 10% to about 30% of the total stimulant in the tablet, so that the total dose or label claim of the stimulant in the final tablet is 100%. According to one embodiment, the tablet is structured such that the first stimulant layer is positioned on the exterior of the tablet and on an outer erosion barrier layer; the second stimulant layer is positioned between the outer erosion barrier layer and an inner erosion barrier layer such that it is surrounded by the outer and inner erosion barrier layers; and the third stimulant layer is positioned at the center of the tablet and surrounded by the inner erosion barrier layer. By positioning the first stimulant layer on the exterior of the tablet, the first stimulant pulse can be released within about 10 minutes to about 45 minutes after administration to a patient. By surrounding the second and third stimulant layers with erosion barrier layers, the second and third stimulant pulses can be delayed releases. The delivery of the second stimulant pulse can be delayed until about 3 to about 5 hours following administration of the tablet to a patient. The delivery of the third stimulant pulse can be delayed until about 6 to about 10 hours following oral administration of the tablet to a patient. The outer and inner erosion barrier layers each comprise about 30% to about 50% by weight of glyceryl behenate, about 40% to about 60% by weight of two or more grades of low-substituted hydroxypropyl cellulose (L-HPC), and about 4% to about 8% by weight of hydroxypropyl cellulose. The two or more grades of L-HPC can be LH-21 and LH-32. The tablets described herein are to be administered orally in a pharmaceutically effective amount to a patient once daily to treat or prevent a variety of disorders, conditions, and diseases. According to one embodiment, administration of at least one stimulant may be carried out in order to treat any disorder, condition, or disease for which a stimulant is generally indicated in the present or the future. Such disorders, conditions, and diseases include, for example, ADHD, narcolepsy, acute depression, obesity and other eating disorders, including binge eating disorder. Stimulants may also be used in the treatment of individuals suffering from cognitive decline associated with AIDS, or AIDS-related conditions, or traumatic brain injury (TBI), mood