Claims for Patent: 10,987,311

Summary for Patent: 10,987,311

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:	Amneal Complex Products Research LLC
Application Number:	US16/445,110
Patent Claims:	1. A gastroretentive dosage form comprising an extended release portion and an immediate release portion, wherein the extended release portion comprises a core comprising from about 50 mg to about 400 mg of pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable water-soluble hydrophilic polymer; and a permeable elastic membrane surrounding the core and comprising a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), and the immediate release portion comprises an immediate release drug layer containing from about 10 mg to about 60 mg of pyridostigmine or a pharmaceutically acceptable salt thereof, wherein the permeable elastic membrane contains at least one orifice wherein the swellable water-soluble hydrophilic polymer is present in an amount of from about 5 wt % to about 35 wt %, based on the total weight of the core, wherein the acid is selected from the group consisting of succinic acid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid, tartaric acid, boric acid, benzoic acid, and mixtures thereof, wherein the gas generating agent is selected from the group consisting of carbonate salts of alkali metals, carbonate salts of alkaline earth metals, bicarbonate salts of alkali metals, bicarbonate salts of alkaline earth metals, and mixtures thereof, wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, a polyethylene oxide polymer, a carbomer, sodium alginate, and mixtures thereof, and wherein the dosage form provides an extended release, with reduced initial burst release, of pyridostigmine or a pharmaceutically acceptable salt thereof, for at least about 14 hours, and wherein the reduced initial burst release comprises an in vitro release of less than 35% of the pyridostigmine or a pharmaceutically acceptable salt thereof, within 2 hours of dissolution in a dissolution medium comprising 50 mM acetate buffer with 100 mM NaCl. 2. 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. 3. 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 the pyloric sphincter. 4. The dosage form of claim 3, wherein the dosage form maintains its integrity in a swollen state for a period of at least about 14 hours. 5. The dosage form of claim 1, wherein the dosage form provides a therapeutic plasma concentration of about 20 ng/ml of pyridostigmine or a pharmaceutically acceptable salt thereof for at least about 14 hours. 6. The dosage form of claim 1, wherein the core further includes a wicking agent selected from the group consisting of crospovidone; croscarmellose sodium; sodium starch glycolate; low-substituted hydroxypropyl cellulose; a mixture of mannitol, crospovidone, and polyvinyl acetate; a coprocessed blend of mannitol, starch, crospovidone, croscarmellose sodium, colloidal silica, and silica; microcrystalline cellulose; alginic acid; and mixtures thereof. 7. The dosage form of claim 1, wherein the gas-generating agent comprises NaHCO3, CaCO3, or a mixture thereof. 8. 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. 9. The dosage form of claim 1, wherein the dosage form further includes a seal coat between the immediate release drug layer and the permeable elastic membrane. 10. The dosage form of claim 9, wherein the seal coat comprises a water-soluble polymer selected from the group consisting of a polyvinyl alcohol-based polymer, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a mixture thereof. 11. The dosage form of claim 1, wherein the dosage form further includes an overcoat over the immediate release drug layer. 12. The dosage form of claim 11, wherein the overcoat comprises a water-soluble polymer selected from a group consisting of a polyvinyl alcohol-based polymer, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a mixture thereof. 13. The dosage form of claim 1, wherein the dosage form is a tablet. 14. The dosage form of claim 13, wherein the dosage form is suitable for once daily administration and is administered as a single tablet/day. 15. An extended release gastroretentive pyridostigmine tablet comprising a core comprising from about 50 mg to about 400 mg of pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable water-soluble hydrophilic polymer; and a permeable elastic membrane, surrounding the core, and comprising a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride wherein the swellable water-soluble hydrophilic polymer is present in an amount of from about 5 wt % to about 35 wt %, based on the total weight of the core (1:2:0.2), wherein the permeable elastic membrane contains at least one orifice, wherein the acid is selected from the group consisting of succinic acid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid, tartaric acid, boric acid, benzoic acid, and mixtures thereof, wherein the gas generating agent is selected from the group consisting of carbonate salts of alkali metals, carbonate salts of alkaline earth metals, bicarbonate salts of alkali metals, bicarbonate salts of alkaline earth metals, and mixtures thereof, wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, a polyethylene oxide polymer, a carbomer, sodium alginate, and mixtures thereof, and wherein the tablet is suitable for once daily administration and is administered as a single tablet/day and the tablet provides an extended release of pyridostigmine or a pharmaceutically acceptable salt thereof for at least about 14 hours. 16. A therapeutic method for treating myasthenia gravis, comprising orally administering to a subject in need thereof a single QD gastroretentive tablet comprising a core comprising from about 50 mg to about 400 mg of pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable water-soluble hydrophilic polymer; and a permeable elastic membrane, surrounding the core and comprising a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), wherein the permeable elastic membrane contains at least one orifice wherein the swellable water-soluble hydrophilic polymer is present in an amount of from about 5 wt % to about 35 wt %, based on the total weight of the core, wherein the acid is selected from the group consisting of succinic acid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid, tartaric acid, boric acid, benzoic acid, and mixtures thereof, wherein the gas generating agent is selected from the group consisting of carbonate salts of alkali metals, carbonate salts of alkaline earth metals, bicarbonate salts of alkali metals, bicarbonate salts of alkaline earth metals, and mixtures thereof, wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, a polyethylene oxide polymer, a carbomer, sodium alginate, and mixtures thereof, and wherein the tablet provides an extended release of pyridostigmine or a pharmaceutically acceptable salt thereof for at least about 14 hours. 17. A method for reducing GI side effects in a patient consuming a pyridostigmine composition, the method comprising: administering to the patient a gastroretentive pyridostigmine composition comprising a core comprising from about 50 mg to about 400 mg of pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable water-soluble hydrophilic polymer; and a permeable elastic membrane, surrounding the core and comprising a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), wherein the permeable elastic membrane contains at least one orifice wherein the swellable water-soluble hydrophilic polymer is present in an amount of from about 5 wt % to about 35 wt %, based on the total weight of the core, wherein the acid is selected from the group consisting of succinic acid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid, tartaric acid, boric acid, benzoic acid, and mixtures thereof, wherein the gas generating agent is selected from the group consisting of carbonate salts of alkali metals, carbonate salts of alkaline earth metals, bicarbonate salts of alkali metals, bicarbonate salts of alkaline earth metals, and mixtures thereof, wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, a polyethylene oxide polymer, a carbomer, sodium alginate, and mixtures thereof, 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 not more than 35% of pyridostigmine or a pharmaceutically acceptable salt thereof within two hours of dissolution of the composition into a dissolution medium. 18. An extended release gastroretentive pyridostigmine tablet comprising a core comprising from about 50 mg to about 400 mg of pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a water-soluble hydrophilic polymer; and a permeable elastic membrane, surrounding the core; and comprising a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), wherein the permeable elastic membrane contains at least one orifice wherein the swellable water-soluble hydrophilic polymer is present in an amount of from about 5 wt % to about 35 wt %, based on the total weight of the core, wherein the acid is selected from the group consisting of succinic acid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid, tartaric acid, boric acid, benzoic acid, and mixtures thereof, wherein the gas generating agent is selected from the group consisting of carbonate salts of alkali metals, carbonate salts of alkaline earth metals, bicarbonate salts of alkali metals, bicarbonate salts of alkaline earth metals, and mixtures thereof, wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, a polyethylene oxide polymer, a carbomer, sodium alginate, and mixtures thereof, and wherein the tablet, when in contact with gastric fluid, swells in about 60 minutes or less to a size that prevents its passage through the pyloric sphincter. 19. A method for improving patient compliance in a patient consuming a pyridostigmine composition, the method comprising: administering to the patient a gastroretentive pyridostigmine composition comprising a core comprising from about 50 mg to about 400 mg of pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable water-soluble hydrophilic polymer; and a permeable elastic membrane, surrounding the core and comprising a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), wherein the permeable elastic membrane contains at least one orifice wherein the swellable water-soluble hydrophilic polymer is present in an amount of from about 5 wt % to about 35 wt %, based on the total weight of the core, wherein the acid is selected from the group consisting of succinic acid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid, tartaric acid, boric acid, benzoic acid, and mixtures thereof, wherein the gas generating agent is selected from the group consisting of carbonate salts of alkali metals, carbonate salts of alkaline earth metals, bicarbonate salts of alkali metals, bicarbonate salts of alkaline earth metals, and mixtures thereof, wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, a polyethylene oxide polymer, a carbomer, sodium alginate, and mixtures thereof, and wherein the composition is suitable for once daily administration and is administered as a single tablet/day. 20. A gastroretentive tablet dosage form comprising a core comprising from about 50 mg to about 400 mg of pyridostigmine or a pharmaceutically acceptable salt thereof, an acid, a gas-generating agent, and a swellable water-soluble hydrophilic polymer; and a permeable elastic membrane, surrounding the core and comprising a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), wherein the permeable elastic membrane contains at least one orifice wherein the swellable water-soluble hydrophilic polymer is present in an amount of from about 5 wt % to about 35 wt %, based on the total weight of the core, wherein the acid is selected from the group consisting of succinic acid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid, tartaric acid, boric acid, benzoic acid, and mixtures thereof, wherein the gas generating agent is selected from the group consisting of carbonate salts of alkali metals, carbonate salts of alkaline earth metals, bicarbonate salts of alkali metals, bicarbonate salts of alkaline earth metals, and mixtures thereof, wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, a polyethylene oxide polymer, a carbomer, sodium alginate, and mixtures thereof, wherein the table is a horizontally compressed, oval-shaped gastroretentive tablet containing a long axis and a short axis, wherein the long axis is between about 12 mm and about 22 mm long, and the short axis is between about 8 mm and about 11 mm wide, and wherein the tablet, when in contact with media simulating gastric conditions, floats in about 30 minutes or less, and expands in about 60 minutes or less to a size that prevents its passage through a pyloric sphincter of a human.