US-20260124145-A1 - LITHIUM SALT EXTENDED-RELEASE FORMULATIONS; METHODS OF MAKING; AND METHODS OF USE THEREOF

Abstract

Disclosed are high dose gastric retentive, extended-release lithium salt dosage forms suitable for once a day administration.

Inventors

• Ripal Gaudana
• Raghav Gupta
• Rama Yarasani

Assignees

• ALMATICA PHARMA LLC

Dates

Publication Date

20260507

Application Date

20260107

Claims (9)

1. 1 . A method of treating a pediatric subject in need thereof, comprising: administering an extended-release, bilayer oral tablet once daily with food to the pediatric subject to treat depression or mania; the extended-release, bilayer oral tablet comprises a first layer comprising an extended-release polymer matrix portion comprising about 600 mg or about 900 mg of lithium carbonate and a controlled-release polymer; and a second layer comprising a gastroretentive portion comprising a swellable polymer; wherein the extended-release polymer matrix portion to the gastroretentive portion has a weight ratio of about 4:1 to about 1.5:1.
2. 2 . The method of claim 1 , wherein the pediatric subject is an adolescent aged 7 to <18 years receiving up to 1800 mg daily maximum dose, or a child weighing 20 to <30 kg receiving up to 1500 mg daily maximum dose.
3. 3 . The method of claim 1 , wherein the weight ratio of the extended-release polymer matrix portion to the gastroretentive portion is about 3.5:1 to about 2.5:1.
4. 4 . The method of claim 1 , wherein the lithium carbonate is present in an amount of about 60 to about 90 wt % based on the total weight of the extended-release polymer matrix portion.
5. 5 . The method of claim 1 , wherein the controlled-release polymer is present in the extended-release polymer matrix portion in an amount of about 8 to about 40 wt % based on the total weight of the extended-release polymer matrix portion.
6. 6 . The method of claim 1 , wherein the controlled-release polymer is a cellulose ether.
7. 7 . The method of claim 1 , wherein the gastroretentive portion comprises about 75 to about 99 wt % swellable polymer.
8. 8 . The method of claim 1 , wherein the swellable polymer is a high molecular weight polyethylene oxide, a cellulose ether, or a combination thereof.
9. 9 . The method of claim 1 , wherein administering the extended-release, bilayer oral tablet once daily with food to the subject reduces or eliminates fluctuations in trough and peak lithium plasma concentrations compared to 2 or 3 times a day dosing at equivalent total daily doses of lithium carbonate.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. patent application Ser. No. 18/751,410, filed Jun. 24, 2024, which claims the benefit of U.S. Provisional Application No. 63/522,883, filed Jun. 23, 2023, each of which is hereby incorporated by reference in its entirety for all purposes. BACKGROUND Lithium carbonate was originally approved in the United States (U.S.) in 1970 as a 300 mg oral capsule. Other solid oral dosage forms of immediate-release lithium carbonate (i.e., tablets) as well as an oral syrup (as lithium citrate) have also been approved and marketed in the U.S. Extended-release lithium carbonate products have been approved in the U.S., including ESKALITH CR® (450 mg lithium carbonate extended-release tablet; NDA 018152; discontinued), LITHOBID® (300 mg lithium carbonate extended-release tablet; NDA 018027). LITHOBID and the ANDA-approved 450 mg lithium carbonate extended-release tablet product marketed by Hikma Pharmaceuticals USA Inc. (ANDA 076691). Lithium is recognized as having a narrow therapeutic index (NTI) (Drug Bank DBCAT003972), and the prescribing information for lithium carbonate products marketed in the U.S. carry a Black Box Warning regarding lithium toxicity being closely related to serum lithium levels and which can occur at doses close to therapeutic levels. The therapeutic range for lithium is identified as 0.8-1.2 mEq/L and the toxic concentration of lithium is understood to be >1.5 mEq/L. Currently for treatment of acute mania 1800 mg of lithium carbonate per day is prescribed and the same is achieved by administering 3 tablets of LITHOBID® ER 300 mg in the morning and 3 tablets in the evening. Thus, patients need to take 6 tablets, while for long term control, 900-1200 mg/day is required. Again, this requires administration of multiple tablets as well as twice daily dosing using currently approved products. Using the 450 mg extended-release tablet also requires multiple tablets and twice daily dosing to achieve 900 mg and greater strengths required for either long term control or acute mania. Due to lithium having a NTI, close monitoring of patients serum level lithium is required and the existing immediate release formulations are prescribed for closer titration. Therefore, there remains a need in the art for a higher strength lithium salt formulation that exhibits an extended-release profile for reduced number of administrations per day with fewer dosage units per administration for simpler and more convenient dosing. SUMMARY Disclosed herein is an extended-release oral tablet, comprising an extended-release polymer matrix portion comprising lithium carbonate and a controlled-release polymer; and a gastroretentive portion comprising a swellable polymer; wherein the tablet contains greater than 450 mg lithium carbonate per tablet. In an embodiment, the tablet is in the form of a layered tablet comprising a first layer comprising the extended-release polymer matrix portion and a second layer comprising the gastroretentive portion. In an embodiment, the tablet comprises 900 mg lithium carbonate. In another embodiment, a method of preparing an extended-release tablet comprises providing a first blend comprising lithium carbonate and a controlled-release polymer; providing a second blend comprising a swellable polymer; and compressing the first blend and the second blend to form a bilayer tablet comprising greater than 450 mg lithium carbonate per tablet. In an embodiment, the tablet comprises 900 mg lithium carbonate. In another embodiment, a method of treating a subject in need thereof comprises administering the tablet described herein to a subject in need thereof to treat depression or mania. The above described and other features are exemplified by the following detailed description. DETAILED DESCRIPTION Disclosed herein are higher strength, extended-release oral lithium salt formulations that require fewer doses per day than immediate release or currently available extended release tablet formulations, which require multiple doses per day. The formulation satisfies an unmet medical need for a once a day oral lithium dosage form and would greatly benefit patients currently taking multiple tablets twice a day. Patient compliance is improved with a reduced number of administrations and reduced pill burden. In an embodiment, the lithium salt is lithium carbonate and the formulation is a gastroretentive, extended release tablet formulation providing therapeutic lithium levels for 24 hours. It has been found that a layered tablet comprising a first layer comprising the extended-release polymer matrix portion and a second layer comprising the gastroretentive portion advantageously provides 24 hour extended release due to the absorption window of lithium. A single layer extended release/gastroretentive formulation did not work well as it slows down the dissolution. A single layer extended release/non gastroretentive formulation does no