Claims for Patent: 10,881,617

Summary for Patent: 10,881,617

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:	US16/908,855
Patent Claims:	1. A gastroretentive dosage form comprising an immediate release layer and an extended release component; wherein the immediate release layer comprises between about 10 mg and about 60 mg pyridostigmine bromide; and the extended release component comprises a core, a permeable elastic membrane surrounding the core, and an orifice passing through the permeable elastic membrane, wherein the core comprises between about 50 mg and about 400 mg pyridostigmine bromide, hypromellose in an amount of between about 5 wt % and about 40 wt % based on the total weight of the core, succinic acid, a carbonate salt, and a bicarbonate salt, wherein the permeable elastic membrane comprises a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), wherein the copolymer is present in an amount of between about 70 wt % and about 95 wt % of the membrane composition, wherein the plasticizer is present in an amount of between about 5 wt % and about 25 wt % of the membrane composition, and wherein the dosage form provides an extended release of pyridostigmine bromide for at least about 14 hours. 2. The dosage form of claim 1, wherein the dosage form provides an in vitro release of between about 5% and about 35% of the pyridostigmine bromide within about 2 hours of dissolution in a dissolution medium comprising pH 4.5 acetate buffer with 100 mM NaCl, using USP Apparatus I (Custom Basket), at 100 rpm and 37° C. 3. The dosage form of claim 1, wherein the dosage form provides an in vitro release of between about 5% and about 30% of the pyridostigmine bromide within about 2 hours of dissolution in a dissolution medium comprising pH 5.0 acetate buffer with 150 mM NaCl, using USP Apparatus I (Custom Basket), at 100 rpm and 37° C. 4. The dosage form of claim 1, wherein the dosage form floats in about 40 minutes or less in a dissolution medium comprising pH 4.5 acetate buffer with 100 mM NaCl, using USP Apparatus I (Custom Basket), at 100 rpm and 37° C. 5. 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. 6. The dosage form of claim 5, wherein the dosage form maintains its integrity in a swollen state for a period of at least about 14 hours. 7. The dosage form of claim 1, wherein the core further includes crospovidone as a wicking agent. 8. The dosage form of claim 1, wherein the carbonate and bicarbonate salts comprise CaCO3 and NaHCO3, respectively. 9. 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. 10. The dosage form of claim 1, wherein the dosage form is a tablet suitable for once daily administration and is administered as a single tablet/day. 11. The dosage form of claim 1, wherein the hypromellose is a mixture of a low viscosity hypromellose and a high viscosity hypromellose. 12. The dosage form of claim 11, wherein the low viscosity hypromellose has a viscosity of between about 80 mPa·s and about 120 mPa·s. 13. The dosage form of claim 11, wherein the high viscosity hypromellose has a viscosity of between about, 2,700 mPa·s and about 5,040 mPa·s. 14. The dosage form of claim 1, wherein the copolymer has a glass transition temperature (Tg) of about 63° C. 15. A gastroretentive dosage form comprising an immediate release layer and an extended release component; wherein the immediate release layer comprises between about 10 mg and about 60 mg pyridostigmine bromide; and the extended release component comprises a core, a permeable elastic membrane surrounding the core, and an orifice passing through the permeable elastic membrane, wherein the core comprises between about 50 mg and about 400 mg pyridostigmine bromide, hypromellose in an amount of between about 5 wt % and about 40 wt % based on the total weight of the core, succinic acid, a carbonate salt, and a bicarbonate salt, wherein the permeable elastic membrane comprises a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), wherein the copolymer is present in an amount of between about 70 wt % and about 95 wt % of the membrane composition, wherein the plasticizer is present in an amount of between about 5 wt % and about 25 wt % of the membrane composition, and wherein the dosage form, when administered into a dissolution medium comprising 0.001 N HCl and 10 mM NaCl, exhibits about 100% volume gain within about 30 minutes post-administration of the tablet into the dissolution medium. 16. A gastroretentive dosage form comprising an immediate release layer and an extended release component; wherein the immediate release layer comprises between about 10 mg and about 60 mg pyridostigmine bromide; and the extended release component comprises a core, a permeable elastic membrane surrounding the core, and an orifice passing through the permeable elastic membrane, wherein the core comprises between about 50 mg and about 400 mg pyridostigmine bromide, hypromellose in an amount of between about 5 wt % and about 40 wt % based on the total weight of the core, succinic acid, a carbonate salt, and a bicarbonate salt, wherein the permeable elastic membrane comprises a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), wherein the copolymer is present in an amount of between about 70 wt % and about 95 wt % of the membrane composition, wherein the plasticizer is present in an amount of between about 5 wt % and about 25 wt % of the membrane composition, and wherein the dosage form, when administered into a dissolution medium comprising 0.001 N HCl and 10 mM NaCl, can withstand a compression force of at least 15N for about 8 hours post-administration, and can withstand a compression force of about ION or less at about 14 hours post-administration. 17. A gastroretentive dosage form comprising an immediate release layer and an extended release component; wherein the immediate release layer comprises between about 10 mg and about 60 mg pyridostigmine bromide; and the extended release component comprises a core, a permeable elastic membrane surrounding the core, and an orifice passing through the permeable elastic membrane, wherein the core comprises between about 50 mg and about 400 mg pyridostigmine bromide, hypromellose in an amount of between about 5 wt % and about 40 wt % based on the total weight of the core, succinic acid, a carbonate salt, and a bicarbonate salt, wherein the permeable elastic membrane comprises a plasticizer, and a copolymer based on ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (1:2:0.2), wherein the copolymer is present in an amount of between about 70 wt % and about 95 wt % of the membrane composition, wherein the plasticizer is present in an amount of between about 5 wt % and about 25 wt % of the membrane composition, and wherein the dosage form, when administered into a dissolution medium comprising pH 4.5 acetate buffer and 10 mM NaCl, exhibits at least about 150% volume gain on floatation.