Claims for Patent: 11,478,425

Summary for Patent: 11,478,425

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):	Namdev B. Shelke, Siva Ram Kiran Vaka, Dipen Desai, Wantanee Phuapradit, Navnit H. Shah
Assignee:	Amneal Complex Products Research LLC
Application Number:	US17/153,090
Patent Claims:	1. A gastroretentive dosage form comprising a core, a permeable elastic membrane surrounding the core, and at least one orifice passing through the permeable elastic membrane, wherein the core comprises a blend comprising pyridostigmine or a pharmaceutically acceptable salt thereof, a swellable water-soluble hydrophilic polymer, an acid, and a gas-generating agent, wherein the permeable elastic membrane comprises a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride, 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, bicarbonate salts and mixture 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 in vitro release of less than about 35 wt % of pyridostigmine or a pharmaceutically acceptable salt thereof, within about 2 hours of dissolution in a 900 ml dissolution medium comprising 50 mM pH 4.5 acetate buffer and 100 mM NaCl, measured using USP Apparatus I at 100 rpm and 37° C. 2. The dosage form of claim 1, wherein the dosage form further comprises an immediate release layer covering at least a portion of the permeable elastic membrane, wherein the immediate release layer comprises pyridostigmine or a pharmaceutically acceptable salt thereof. 3. The dosage form of claim 1, wherein the core comprises from about 50 mg to about 400 mg of pyridostigmine bromide. 4. The dosage form of claim 1, wherein the dosage form, on coming in contact with a 200 ml dissolution medium comprising 50 mM of pH 4.5 acetate buffer and 100 mM NaCl, floats in about 40 minutes or less, measured using Rotating Bottle method at 5 rpm and 37° C. 5. The dosage form of claim 1, wherein the plasticizer is selected from the group consisting of triethyl citrate, triacetin, polyethylene glycol, propylene glycol, and dibutyl sebacate. 6. A gastroretentive tablet dosage form comprising a core, a permeable elastic membrane surrounding the core, and at least one orifice passing through the permeable elastic membrane, wherein the core comprises a blend comprising pyridostigmine or a pharmaceutically acceptable salt thereof, a swellable water-soluble hydrophilic polymer, an acid, and a gas-generating agent, wherein the permeable elastic membrane comprises a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride, 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, bicarbonate salts and mixture 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, comprises a long axis and a short axis, wherein the long axis is about 12 mm to about 22 mm, and the short axis is about 8 mm to about 11 mm and wherein the tablet dosage form provides an in vitro release of less than about 35 wt % of pyridostigmine or a pharmaceutically acceptable salt thereof, within about 2 hours of dissolution in a 900 ml dissolution medium comprising 50 mM pH 4.5 acetate buffer and 100 mM NaCl, measured using USP Apparatus I at 100 rpm and 37° C. 7. A gastroretentive dosage form comprising an immediate release layer and an extended release component; wherein the immediate release layer comprises pyridostigmine or a pharmaceutically acceptable salt thereof; and the extended release component comprises a core, a permeable elastic membrane surrounding the core, and at least one orifice passing through the permeable elastic membrane, wherein the core comprises a blend comprising pyridostigmine or a pharmaceutically acceptable salt thereof, a water-soluble hydrophilic polymer, an acid, and a gas generating agent, wherein the permeable elastic membrane comprises a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride, 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, bicarbonate salts and mixture 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 in vitro release of less than about 35 wt % of pyridostigmine or a pharmaceutically acceptable salt thereof, within about 2 hours of dissolution in a 900 ml dissolution medium comprising 50 mM pH 4.5 acetate buffer and 100 mM NaCl, measured using USP Apparatus I at 100 rpm and 37° C. 8. The dosage form of claim 7, 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. 9. The dosage form of claim 7, wherein the dosage form, on coming in contact with a 200 ml dissolution medium comprising pH 4.5 acetate buffer and 100 mM NaCl, floats in about 40 minutes or less, measured using Rotating Bottle method at 5 rpm and 37° C. 10. A method for treatment of myasthenia gravis, postoperative bowel bloating, or urinary retention, the method comprising once-a-day administration of a gastroretentive dosage form comprising an immediate release layer and an extended release component; wherein the immediate release layer comprises pyridostigmine or a pharmaceutically acceptable salt thereof; and the extended release component comprises a core, a permeable elastic membrane surrounding the core, and at last one orifice passing through the permeable elastic membrane, wherein the core comprises a blend comprising pyridostigmine or a pharmaceutically acceptable salt thereof, a water-soluble hydrophilic polymer, an acid, and a gas generating agent, wherein the permeable elastic membrane comprises a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride, 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, bicarbonate salts and mixture 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 in vitro release of less than about 35 wt % of pyridostigmine or a pharmaceutically acceptable salt thereof, within about 2 hours of dissolution in a 900 ml dissolution medium comprising 50 mM pH 4.5 acetate buffer and 100 mM NaCl, measured using USP Apparatus I at 100 rpm and 37° C. 11. The method of claim 10, 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. 12. The method of claim 10, wherein the dosage form, on coming in contact with a 200 ml dissolution medium comprising 50 mM pH 4.5 acetate buffer and 100 mM NaCl, floats in about 40 minutes or less, measured using Rotating Bottle method at 5 rpm and 37° C. 13. A method for pre-treatment of organophosphorus or Soman nerve gas poisoning injuries, the method comprising once-a-day administration of a gastroretentive dosage form comprising a core, a permeable elastic membrane surrounding the core, and at least one orifice in the permeable elastic membrane, wherein the core comprises a blend comprising pyridostigmine or a pharmaceutically acceptable salt thereof, a swellable water-soluble hydrophilic polymer, an acid, and a gas-generating agent, wherein the permeable elastic membrane comprises a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride, 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, bicarbonate salts and mixture 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 in vitro release of less than about 35 wt % of pyridostigmine or a pharmaceutically acceptable salt thereof, within about 2 hours of dissolution in a 900 ml dissolution medium comprising 50 mM pH 4.5 acetate buffer and 100 mM NaCl, measured using USP Apparatus I at 100 rpm and 37° C.