Claims for Patent: 10,835,488

Summary for Patent: 10,835,488

Title:	Stable orally disintegrating pharmaceutical compositions
Abstract:	Described herein are stable orally disintegrating tablets containing a proton pump inhibitor, methods for making the same, and methods for treating subjects in need thereof. In particular, the orally disintegrating tablets are composed of a plurality of coated units admixed with a disintegrant that demonstrate decreased friability and increased hardness.
Inventor(s):	Pevzner; Victor (Hadera, IL), Moses-Heller; Sheera (Atlit, IL)
Assignee:	DEXCEL PHARMA TECHNOLOGIES LTD. (Or-Akiva, IL)
Application Number:	16/130,494
Patent Claims:	1. A compressed orally disintegrating tablet comprising a disintegrant and a plurality of units comprising: i) a plurality of cores comprising a therapeutically effective amount of a proton pump inhibitor; ii) an enteric coating over the cores; and iii) a coating comprising a reverse enteric polymer in an amount of 5% to 15% by weight of a total tablet weight over the enteric coating; wherein the disintegrant and the plurality of units are compressed to an orally disintegrating tablet having a friability of 0.75% or less when 10 kN to 50 kN of a compression force is applied during manufacturing of the tablet. 2. The tablet of claim 1, wherein each core comprises an inert seed coated with an active ingredient coating comprising a proton pump inhibitor. 3. The tablet of claim 2, wherein the inert seed comprises a granule, a pellet, a bead, or a powder. 4. The tablet of claim 1, wherein each unit further comprises a subcoating between the plurality of cores and the enteric coating. 5. The tablet of claim 4, wherein the subcoating comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol or a mixture or combination thereof. 6. The tablet of claim 1, wherein the enteric coating comprises one or more of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate, cellulose acetate trimellitate, shellac, polymethacrylic acid, polymethyl methacrylate, polyethyl methacrylate, polyethyl acrylate or a mixture or combination thereof. 7. The tablet of claim 1, wherein the coating comprising a reverse enteric polymer comprises a (meth)acrylate polymer or copolymer. 8. The tablet of claim 1, wherein the reverse enteric polymer comprises a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer. 9. The tablet of claim 1, wherein the reverse enteric polymer is in an amount of 70% to 100% of the total reverse enteric coating mass. 10. The tablet of claim 1, wherein the weight percentage ratio of the coating comprising a reverse enteric polymer to the enteric coating is 0.4:1. 11. The tablet of claim 1, wherein the disintegrant comprises one or more of crospovidone, croscarmellose sodium, a cellulose derivative, cross-linked derivatives of starch, pregelatinized starch, crosslinked sodium carboxymethyl cellulose, low substituted hydroxypropylcellulose or a mixture or combination thereof. 12. The tablet of claim 1, further comprising one or more pharmaceutically acceptable excipients selected from a binder, a filler, a diluent, a surfactant, a glidant, a lubricant, a plasticizer, an anti-tacking agent, an alkaline substance, a tonicity enhancing agent, a wetting agent, a buffering substance, a preservative, a sweetener, an opacifier, a colorant, and a mixture or combination thereof. 13. The tablet of claim 1 having a hardness of 20 N to 100 N. 14. The tablet of claim 1, which substantially disintegrates in an oral cavity of a subject within less than 60 seconds after administration. 15. The tablet of claim 1, wherein the disintegrant is in an amount of 2% to 25% by weight of a total tablet weight; or wherein the plurality of cores is in an amount of 5% to 25% by weight of a total tablet weight; or wherein the enteric coating is in an amount of 10% to 30% by weight of a total tablet weight. 16. The tablet of claim 4, wherein the subcoating is in an amount of 2% to 15% by weight of the total tablet weight. 17. A process of manufacturing the tablet of claim 1 comprising: a) generating a plurality of cores comprising a therapeutically effective amount of a proton pump inhibitor; b) applying a solution or dispersion comprising an enteric polymer to the plurality of cores of step (a) thereby obtaining a plurality of enteric coated cores; c) applying a solution or dispersion comprising a reverse enteric polymer to the enteric coated cores of step (b) thereby obtaining a plurality of units; d) mixing the plurality of units of step (c) with at least one tablet excipient comprising a disintegrant thereby obtaining a blend; and e) compressing the blend of step (d) thereby obtaining the compressed orally disintegrating tablet. 18. The process of claim 17, wherein step (a) comprises applying a solution or dispersion comprising a therapeutically effective amount of a proton pump inhibitor to a plurality of inert seeds. 19. The process of claim 17, further comprising an additional step prior to the step (b) comprising: a1) applying a solution or dispersion comprising one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol or a mixture or combination thereof to the plurality of cores of step (a) thereby obtaining a subcoating between the cores and the enteric coating. 20. A compressed orally disintegrating tablet prepared by a process comprising the following steps: a) generating a plurality of cores comprising a therapeutically effective amount of a proton pump inhibitor; b) applying a solution or dispersion comprising an enteric polymer to the plurality of cores of step (a) thereby obtaining a plurality of enteric coated cores; c) applying a solution or dispersion comprising a reverse enteric polymer to the enteric coated cores of step (b) thereby obtaining a plurality of units; d) mixing the plurality of units of step (c) with at least one tablet excipient comprising a disintegrant thereby obtaining a blend; and e) compressing the blend of step (d) thereby obtaining the compressed orally disintegrating tablet, wherein the coating comprising a reverse enteric polymer is in an amount of 5% to 15% by weight of a total tablet weight; and wherein a friability of the compressed tablet is 0.75% or less when 10 kN to 50 kN of a compression force is applied during manufacturing of the tablet. 21. A method of treating a subject having a gastric disorder comprising gastric reflux, gastroesophageal reflux disease, laryngopharyngeal reflux, laryngitis, dyspepsia, Barrett's esophagus, eosinophilic esophagitis, gastritis, gastrinomas, Zollinger-Ellison syndrome, peptic ulcers, or excessive Helicobacter pylori or combinations thereof, the method comprising administering the tablet of claim 1 to the subject. 22. A method for increasing a compressibility of a compressed orally disintegrating tablet comprising a disintegrant and a plurality of units comprising: i) a plurality of cores comprising a therapeutically effective amount of a proton pump inhibitor; and ii) an enteric coating over the cores; the method comprising the step of applying a coating comprising a reverse enteric polymer in an amount of 5% to 15% by weight of a total tablet weight to the enteric coated cores, wherein the increased compressibility comprises one or more of a decreased friability or an increased hardness compared to a compressed orally disintegrating tablet not comprising a coating comprising a reverse enteric polymer when a substantially identical compression force is applied during manufacturing of the tablet. 23. The method of claim 22, wherein the decreased friability is 0.75% or less, or wherein the increased hardness is 20 N to 100 N when 10 kN to 50 kN of compression force is applied during manufacturing of the tablet. 24. A compressed orally disintegrating tablet comprising a disintegrant in an amount of 2% to 25% by weight of a total tablet weight, and a plurality of units comprising: i) a plurality of cores comprising a therapeutically effective amount of a proton pump inhibitor, the plurality of cores in an amount of 5% to 25% by weight of a total tablet weight; ii) a subcoating over the cores, the subcoating in an amount of 2% to 15% by weight of a total tablet weight; iii) an enteric coating over the subcoating, the enteric coating in an amount of 10% to 30% by weight of a total tablet weight; and iv) a coating comprising a reverse enteric polymer over the enteric coating, the reverse enteric coating in an amount of 5% to 15% by weight of a total tablet weight; wherein the orally disintegrating tablet optionally comprises one or more additional excipients selected from the group consisting of a binder, a filler, a diluent, a surfactant, a glidant, a lubricant, a plasticizer, an anti-tacking agent, an alkaline substance, a tonicity enhancing agent, a wetting agent, a buffering substance, a preservative, a flavoring agent, an opacifier, a colorant, an anti-oxidant or a mixture or combination thereof in an amount of not more than 50% by weight of a total tablet weight, wherein the weight of all components add to 100% (w/w), and wherein a friability of the compressed tablet is 0.75% or less when 10 kN to 50 kN of a compression force is applied during manufacturing of the tablet. 25. The tablet of claim 24, wherein the disintegrate comprises crospovidone; the plurality of cores comprises an inert seed coated with a drug layer comprising omeprazole or a pharmaceutically acceptable salt thereof, hydroxypropylmethyl cellulose, and sodium stearate; the subcoating comprises hydroxypropylmethyl cellulose, and mannitol; the enteric coating comprises hydroxypropylmethyl cellulose phthalate, cetyl alcohol, and triethyl citrate; and the reverse enteric coating comprises an amino methacrylate copolymer. 26. The tablet of claim 1 providing a delayed release profile of the proton pump inhibitor.