Claims for Patent: 11,229,606

Summary for Patent: 11,229,606

Title:	Extended release compositions comprising pyridostigmine
Abstract:	Extended release pyridostigmine dosage forms, suitable for maintaining stable plasma concentrations with reduced or minimized initial burst release/dose dumping of pyridostigmine, are provided. The dosage forms include matrix tablets, gastroretentive tablets, and pellets, the latter being suitable for dosing in capsules, tablets, and sachets, as well as for sprinkling on foodstuffs. The disclosure also provides methods for improving patient compliance by administering once-a-day extended release pyridostigmine bromide dosage forms that provide a superior controlled drug release.
Inventor(s):	Siva Ram Kiran Vaka, Namdev B. Shelke, Dipen Desai, Wantanee Phuapradit, Navnit H. Shah
Assignee:	Kashiv Biosciences LLC, Amneal Complex Products Research LLC
Application Number:	US16/609,397
Patent Claims:	1. A gastroretentive dosage form comprising an immediate release portion and an extended release portion, wherein the immediate release portion comprises an immediate release drug layer containing pyridostigmine or a pharmaceutically acceptable salt thereof, wherein the extended release portion comprises a core, and a permeable elastic membrane comprising at least one orifice and surrounding the core, wherein the core comprises pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable water-soluble hydrophilic polymer, wherein the permeable elastic membrane comprises a plasticizer and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride, wherein the copolymer is present in an amount of from about 70 wt % to about 95 wt % based on the total weight of the membrane. 2. The dosage form of claim 1, wherein the dosage form provides an in vitro release of less than about 35 wt % of the pyridostigmine or a pharmaceutically acceptable salt thereof, within 2 hours of dissolution in a 900 ml dissolution medium comprising pH 5 buffer and about 150 mM of NaCl, measured using USP Apparatus I, at 100 rpm and 37° C. 3. The dosage form of claim 1, wherein the dosage form floats in about 40 minutes or less in 50 mM of pH 4.5 buffer with 100 mM NaCl. 4. The dosage form of claim 1, wherein the dosage form, when in contact with gastric fluid, swells in about 60 minutes or less to a size that prevents its passage through pyloric sphincter. 5. The dosage form of claim 4, wherein the dosage form provides extended release of pyridostigmine or a pharmaceutically acceptable salt thereof for at least about 14 hours. 6. The dosage form of claim 1, wherein the plasticizer is present in an amount of from about 5 wt % to about 25 wt % of the membrane. 7. The dosage form of claim 1, wherein the immediate release drug layer comprises from about 10 mg to about 60 mg pyridostigmine or a pharmaceutically acceptable salt thereof, and the core comprises from about 50 mg to about 400 mg pyridostigmine or a pharmaceutically acceptable salt thereof. 8. The dosage form of claim 1, wherein the swellable water-soluble hydrophilic polymer in the core is hydroxypropyl methylcellulose. 9. The dosage form of claim 8, wherein the hydroxypropyl methylcellulose is present in an amount of from about 5 wt % to about 35 wt %, based on the total weight of the core. 10. The dosage form of claim 1, wherein the gas-generating agent is selected from the group consisting of sodium bicarbonate, sodium carbonate, magnesium carbonate, calcium carbonate, and mixtures thereof. 11. The dosage form of claim 1, wherein the plasticizer is selected from the group consisting of triethyl citrate, triacetin, polyethylene glycol, propylene glycol, dibutyl sebacate, and mixtures thereof. 12. An extended release gastroretentive pyridostigmine tablet comprising a core, and a permeable elastic membrane containing at least one orifice and, surrounding the core, wherein the core comprises pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable water-soluble hydrophilic polymer, wherein the permeable elastic membrane comprises a plasticizer and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride, wherein the copolymer is present in an amount of from about 70 wt % to about 95 wt % based on the total weight of the membrane. 13. The tablet of claim 12, wherein the tablet provides extended release of pyridostigmine or a pharmaceutically acceptable salt thereof for at least about 14 hours. 14. The tablet of claim 12, wherein the swellable water-soluble hydrophilic polymer is hydroxypropyl methylcellulose. 15. The tablet of claim 14, wherein the hydroxypropyl methylcellulose is present in an amount of from about 5 wt % to about 35 wt %, based on the total weight of the core. 16. The tablet of claim 12, wherein the gas-generating agent is selected from the group consisting of sodium bicarbonate, sodium carbonate, magnesium carbonate, calcium carbonate, and mixtures thereof. 17. A therapeutic method for treating myasthenia gravis, the method comprising orally administering to a subject in need thereof a gastroretentive pyridostigmine tablet, wherein the tablet comprises an immediate release portion and an extended release portion, wherein the immediate release portion comprises an immediate release drug layer containing pyridostigmine or a pharmaceutically acceptable salt thereof, wherein the extended release portion comprises a core, and a permeable elastic membrane comprising at least one orifice and surrounding the core, wherein the core comprises pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable, water-soluble hydrophilic polymer, wherein the permeable elastic membrane comprises a plasticizer and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride, wherein the copolymer is present in an amount of from about 70 wt % to about 95 wt % based on the total weight of the membrane. 18. A method for reducing GI side effects in a patient in need of a pyridostigmine composition, the method comprising: administering to the patient a gastroretentive pyridostigmine composition comprising an immediate release portion and an extended release portion, as a single tablet/day, wherein the immediate release portion comprises an immediate release drug layer containing pyridostigmine or a pharmaceutically acceptable salt thereof, wherein the extended release portion comprises a core, and a permeable elastic membrane containing at least one orifice surrounding the core, wherein the core comprises pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable, water-soluble hydrophilic polymer, wherein the permeable elastic membrane comprises a plasticizer and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride, wherein the copolymer is present in an amount of from about 70 wt % to about 95 wt % based on the total weight of the membrane, wherein the composition provides an extended release of pyridostigmine or a pharmaceutically acceptable salt thereof for at least about 14 hours, and wherein the composition releases less than about 35% of pyridostigmine or a pharmaceutically acceptable salt thereof, within two hours of dissolution of the composition in 900 ml of dissolution medium comprising pH 5 buffer and 150 mM NaCl, measuring using USP Apparatus I, at 100 rpm and 37° C.