WO2022020464A1 - Compositions à désintégration rapide à libération modifiée d'inhibiteurs de pompe à protons - Google Patents

Compositions à désintégration rapide à libération modifiée d'inhibiteurs de pompe à protons Download PDF

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Publication number
WO2022020464A1
WO2022020464A1 PCT/US2021/042566 US2021042566W WO2022020464A1 WO 2022020464 A1 WO2022020464 A1 WO 2022020464A1 US 2021042566 W US2021042566 W US 2021042566W WO 2022020464 A1 WO2022020464 A1 WO 2022020464A1
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Prior art keywords
week
delayed release
esomeprazole
ppi
pharmaceutical composition
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PCT/US2021/042566
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English (en)
Inventor
Jin Wang Lai
Michelle Schilling
Craig Kramer
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Ellodi Pharmaceuticals, L.P.
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Publication of WO2022020464A1 publication Critical patent/WO2022020464A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • Eosinophilic Esophagitis is an allergen/ immune-mediated disease characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa in the absence of secondary causes of eosinophilia.
  • This inflammatory condition of the esophagus causes chronic esophagitis; dysphagia for solids and food impaction are the leading symptoms in adults, whereas children present mainly with food refusal, chest and/or abdominal pain and failure to thrive.
  • Treatment of EoE is challenging with the goals of treatment including resolution of symptoms and esophageal inflammation and prevention of complications, such as strictures which can lead to food impaction [0003]
  • PPIs particularly esomeprazole and omeprazole, and pharmaceutically acceptable salts thereof, are highly susceptible to degradation in acidic conditions and hydrolysis in the presence of atmospheric moisture. Accordingly, these drugs need to be protected both during storage and passage through the acidic environment of the stomach.
  • PPIs are highly susceptible to degradation in acidic conditions and hydrolysis in the presence of atmospheric moisture.
  • the present disclosure provides stable compositions of PPI that significantly reduce degradation and/or hydrolysis of the PPI.
  • the PPI is combined with an alkaline material (e.g., the PPI and alkaline material are intimately associated), which improves the stability of the PPI compared to a similarly formulated composition that does not include the alkaline material.
  • the alkaline material is magnesium oxide (MgO).
  • the present disclosure relates to solid disintegrating or dispersing or dispersible pharmaceutical compositions, such as orally disintegrating tablets (ODTs).
  • ODTs Such disintegrating or dispersing compositions facilitate easy oral administration of PPI (such as esomeprazole).
  • PPI such as esomeprazole
  • the solid compositions of the present disclosure are easier to swallow than conventional dosage forms (e.g., tablets or capsules).
  • the present disclosure provides for pharmaceutical compositions which rapidly disintegrate or disperse on contact with saliva in the buccal cavity, thereby forming a smooth (non-gritty), easy-to- swallow, viscous suspension containing effective amount of particles comprising the PPI, such as esomeprazole.
  • the disclosure provides a delayed release pharmaceutical composition
  • a delayed release pharmaceutical composition comprising at least one proton pump inhibitor (PPI), or a pharmaceutically acceptable salt thereof, magnesium oxide, and one or more enteric polymers, wherein the PPI, or pharmaceutically acceptable salt thereof, and the magnesium oxide are present as a mixture, and wherein the amount of PPI, or pharmaceutically salt thereof in the mixture is greater than or equal to the amount of magnesium oxide (MgO) in the mixture.
  • PPI proton pump inhibitor
  • MgO magnesium oxide
  • a delayed release pharmaceutical composition comprising of at least one proton pump inhibitor (PPI), or a pharmaceutically acceptable salt thereof, magnesium oxide, and one or more enteric polymers, wherein in the mixture comprising the PPI and the magnesium oxide the amount of PPI is greater than or equal to the amount of magnesium oxide (MgO) in the mixture.
  • the delayed release pharmaceutical composition comprises an inert core, wherein the mixture of the PPI, or the pharmaceutically acceptable salt thereof, and MgO is disposed over the inert core.
  • the one or more enteric polymers are disposed over the mixture of the PPI, or the pharmaceutically acceptable salt thereof, and MgO.
  • the delayed release pharmaceutical composition comprises one or more delayed release particles, wherein the delayed release particle comprises an inert core, wherein the mixture of the PPI, or the pharmaceutically acceptable salt thereof, and the MgO is disposed over the core, and the enteric polymer is disposed over the mixture.
  • the PPI is esomeprazole, omeprazole, lansoprazole, pantoprazole, or rabeprazole, or a pharmaceutically acceptable salt thereof.
  • the PPI is esomeprazole magnesium.
  • the ratio of PPI, or the pharmaceutically acceptable salt thereof, to MgO ranges from 1:1 to about 10:1. In embodiments, the ratio of PPI, or a pharmaceutically acceptable salt thereof, to MgO ranges from 5 : 1 to about 7:1. In embodiments, the ratio of PPI, or the pharmaceutically acceptable salt thereof, to MgO ranges from 2:1 to about 10:1. In embodiments, the PPI is esomeprazole magnesium, and the ratio of PPI to MgO ranges from 5:1 to 7:1
  • the amount of PPI, or pharmaceutically acceptable salt thereof, in the delayed release particle ranges from about 10% to about 20% w/w based on the weight of the delayed release particle. In embodiments, the amount of PPI, or pharmaceutically acceptable salt thereof, in the delayed release particle is about 15% w/w based on the weight of the delayed release particle.
  • the amount of MgO in the delayed release particle ranges from about 2% to about 15% w/w based on the weight of the delayed release particle. In embodiments, the amount of MgO in the delayed release particle is about 4% to about 15% w/w, or about 4 to about 10% based on the weight of the delayed release particle.
  • the amount of the enteric polymer in the delayed release particle ranges from about 50% to about 80% w/w based on the weight of the delayed release particle. In embodiments, the amount of the enteric polymer in the delayed release particle ranges from about 60% to about 75% w/w based on the weight of the delayed release particle. In embodiments, the enteric polymer is cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive acrylate copolymers, shellac, or mixtures thereof.
  • the mixture of the PPI, or a pharmaceutically acceptable salt thereof, and MgO comprises a binder.
  • the binder is povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxy methylcellulose, hydroxyethylcellulose, gelatin, polyethylene oxide, polyethylene glycol, poly vinyl alcohol, acacia, dextrin, magnesium aluminum silicate, starch, or an aqueous acrylic system.
  • the binder is hydroxypropylcellulose.
  • the amount of binder in the delayed release particle ranges from about 2% to about 10% w/w based on the weight of the delayed release particle.
  • the pharmaceutical composition comprises a seal coating disposed over the mixture of the PPI, or pharmaceutically acceptable salt thereof, and MgO.
  • the seal coating comprises hydroxypropylcellulose, hydroxypropyl methylcellulose, low-viscosity ethylcellulose, or mixtures thereof.
  • the amount of the seal coating in the delayed release particle ranges from about 1% to about 10% w/w based on the weight of the delayed release particle.
  • the pharmaceutical composition is in the form of disintegrating composition.
  • the disintegrating composition comprises one or more pharmaceutically acceptable excipients which swell, dissolve or otherwise facilitate disintegration of the composition.
  • the one or more pharmaceutically acceptable excipients is (i) a disintegrant or (ii) a pharmaceutically acceptable acid and a carbonate salt.
  • the disintegrating composition is in the form of an orally disintegrating tablet (ODT).
  • ODT comprises delayed release particles and rapidly dispersing granules, wherein the rapidly dispersing granules comprise a mixture of (i) one or more disintegrants and (ii) one or more sugar alcohols and/or saccharides.
  • the disclosure provides an orally disintegrating tablet (ODT) comprising delayed release particles and rapidly dispersing granules, wherein the delayed release particles comprise a mixture of esomeprazole, or a pharmaceutically acceptable salt thereof, magnesium oxide (MgO) , and a delayed release coating disposed over the mixture, and wherein the ratio of esomeprazole to magnesium oxide ranges from about 2:1 to about 10:1. In embodiments, the ratio of esomeprazole, or its pharmaceutically acceptable salt, to magnesium oxide is in the range from about 5:1 to about 7:1. In some embodiments, the mixture of esomeprazole, or a pharmaceutically acceptable salt thereof, magnesium oxide (MgO) comprises a binder.
  • ODT orally disintegrating tablet
  • the binder is hydroxypropyl cellulose.
  • the delayed release coating comprises an enteric polymer.
  • the enteric polymer is a pH-sensitive acrylate copolymer.
  • the ODT comprises a seal coating.
  • the seal coating comprises hydroxypropyl cellulose.
  • the ratio of esomeprazole to magnesium oxide is about 5:1.
  • magnesium oxide is present in amount of about 2% to about 15% w/w based on the weight of the delayed release particle. In embodiments, magnesium oxide is present in amount of about 9% w/w based on the weight of the delayed release particle.
  • the delayed release particles comprise a) a core comprising esomeprazole magnesium and magnesium oxide, b) a seal coating of hydroxypropyl cellulose disposed over the core, and a c) delayed release coating comprising a pH-sensitive acrylate copolymer disposed over the seal coating, and wherein the ratio of esomeprazole to magnesium oxide is in the range of from about 2:1 to about 10:1. In embodiments, the ratio of esomeprazole to magnesium oxide is in the range of from about 5:1 to about 7:1. In embodiments, the ratio of esomeprazole to magnesium oxide is about 5:1.
  • the magnesium oxide is present in an amount ranging from 2-15% w/w, based on the weight of the delayed release particle. In embodiments, the magnesium oxide is present at about 9% w/w based on the weight of the delayed release particle.
  • the rapidly dispersing granules have an average particle size of not more than about 300 pm and comprise: a) a disintegrant and b) a sugar alcohol or a saccharide. In embodiments, each of the a) disintegrant and b) a sugar alcohol or a saccharide have a particle size is not more than about 30 pm. In embodiments, the ratio of sugar alcohol and/or saccharide to disintegrant range from about 90/10 to about 99/1. In embodiments, the ratio of the delayed release to the rapidly-dispersing granules ranges from about 6/1 to about 1/2, or from about 2/1 to about 1/1.
  • the PPI is esomeprazole, or a pharmaceutically acceptable salt thereof, and the composition comprises about 20-60 mg of the esomeprazole base per unit dose. In embodiments, the PPI is esomeprazole, or a pharmaceutically acceptable salt thereof, and the composition comprises about 20, 30, 40, 45, or 60 mg of the esomeprazole base per unit dose.
  • the pharmaceutical or ODT disintegrates in the oral cavity of a patient in less than about 60 seconds or less than about 20 seconds. In embodiments, the pharmaceutical composition or ODT disintegrates in less than about 60 second, or less than 20 seconds as measured using the USP ⁇ 701> Disintegration Test.
  • the pharmaceutical composition or ODT of any one of the preceding claims which releases at least 80% of the dose in 20 minutes in Stage-2 when tested for dissolution using USP Test-1 (Paddle, 100RPM, Stage-1: 300 mL 0.1N HC1 (2h); Stage-2: Add 700 mL of 0.086M dibasic sodium phosphate to make pH 6.8 (30 minute)) or USP Test-2 (Paddle, 100RPM, Stage-1: 300 mL 0. IN HC1 (2h), Stage-2: transfer the beads to a 1000 mL VF and Assay).
  • the pharmaceutical composition or ODT has less than 2.9% impurities under a super accelerated impurities teat at 75% humidity, 60 °C for 72 hours.
  • the composition of the present disclosure provides a modified release in vivo plasma concentration profile of PPI (such as esomeprazole) after administration.
  • PPI such as esomeprazole
  • no substantially no drug is released in the acid environment of the stomach (e.g., less than about 10%), but drug release occurs after the drug containing particles of the composition reaches the intestines.
  • the disclosure additionally provides a method of manufacturing the pharmaceutical composition comprising particles comprising PPI. It additionally may include other ingredients to facilitate disintegration or dispersion upon contact with the saliva or with a solution (such as disintegrants of different types, rapidly-dispersing microgranules).
  • the present disclosure also provides a method of treating illnesses with PPI in a subject in need thereof, comprising orally administering the pharmaceutical composition disclosed herein which can be administered in the inflammatory stages of the disease, such as EoE or variant thereof, or allergic variant thereof or EoE variants that are not responsive to steroid treatment
  • FIG. 1 shows the bitterness profiles for three orally disintegrating tablet (ODT) formulations.
  • FIG. 2 shows the chalky mouthfeel profiles for three ODT formulations.
  • FIG. 3 shows the gritty texture profiles for three ODT formulations.
  • FIG. 4 shows the tongue abrasion profile for three ODT formulations.
  • FIG. 5 shows the disintegration times for the ODTs of the disclosure.
  • the present disclosure provides stable compositions comprising a PPI (e.g., esomeprazole or a pharmaceutically acceptable salt thereof).
  • the composition is a solid rapidly disintegrating or dispersing pharmaceutical compositions.
  • the composition is appropriately formulated (e.g., with a coating or a matrix) to provide modified release of the PPI.
  • the disclosure also provides methods for making said compositions.
  • drug refers to a proton pump inhibitor (“PPI”), such as esomeprazole, any pharmaceutically acceptable salts, such as esomeprazole magnesium, or omeprazole and its salts, or other PPI, such as lansoprazole, pantoprazole, rabeprazole.
  • PPI proton pump inhibitor
  • All references to “drug”, “active”, or “active pharmaceutical ingredient”, or a particular drug, such as esomeprazole also includes solvates, hydrates, polymorphs, and prodrugs thereof.
  • Esomeprazole which is a mixture of the S- and R- isomers.
  • Esomeprazole magnesium (herein called also esomeprazole) is the S-isomer of omeprazole.
  • the chemical name of esomeprazole is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfmyl]-lHbenzimidazole-l-yl) magnesium trihydrate. Its molecular formula is (C17H18N303S)2 Mg x 3 H20 with molecular weight of 767.2 g/mol as a trihydrate and 713.1 g/mol on an anhydrous basis.
  • the magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of hydration and is very slightly soluble in water (-300 mg/1).
  • the stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C.
  • Omeprazole undergoes stereoselective metabolism, and the S-isomer esomeprazole is metabolized to a lesser degree than the R-isomer omeprazole.
  • Esomeprazole has a greater plasma exposure than omeprazole, which promotes an effective acid control.
  • Esomeprazole inhibits the H(+)-K(+)-ATPase (H(+)-K(+)-exchanging ATPase in the proton pump of gastric parietal cells. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion.
  • a polymer includes a mixture of one or more polymers.
  • coating weight is expressed as the percentage by weight of the coating, relative to the final weight of the processed particles or beads.
  • “Disposed over” refers to a coating over a substrate and denotes a relative location of the coating, e.g. a coating disposed over a substrate requires that the coating is outside of the substrate but need not be in direct contact with the substrate, i.e. another coating or material could be interposed there between.
  • a first coating “disposed over” a substrate can be in direct contact with the substrate, or one or more intervening materials or coatings can be interposed between the first coating and the substrate.
  • “Functional polymer” means a polymer comprising a group selected from a water- insoluble polymer, a water-soluble polymer, an enteric polymer, or a mixture thereof.
  • the functional polymer may, for example be applied as a coating to a particle (e.g. bead, pellet, or mini-tablet).
  • pH sensitive refers to a polymer with a pH-dependent dissolution profile.
  • a pH sensitive polymer may not dissolve in the acid environment of the stomach, but will dissolve at higher pH levels in the intestinal tract.
  • Enteric polymer refers to a pH sensitive polymer that is resistant to gastric juice (i.e. relatively insoluble at the low pH levels found in the stomach), and that dissolves at the higher pH levels found in the intestinal tract.
  • Water-insoluble polymer or “hydrophobic polymer” refers to a polymer that is insoluble or very sparingly soluble in aqueous media, independent of gastrointestinal pH, or over a broad pH range (e.g. less than 1 to 8).
  • a polymer other than an enteric (enterosoluble) or gastrosoluble (reverse enteric) polymer that may swell but does not dissolve in aqueous media is defined as “water-insoluble,” as used herein.
  • Water-soluble polymer or “hydrophilic polymer” refers to a polymer that is soluble or miscible in aqueous media, independent of gastrointestinal pH, or over a broad pH range (e.g. less than 1 to 8).
  • a polymer other than an enteric (enterosoluble) or gastrosoluble (reverse enteric) polymer that dissolves in aqueous media is defined as “water-soluble,” as used herein.
  • “Sealant layer” or “protective seal” or “under-coating” or “seal coat” refers to a protective membrane disposed over a drug-containing core particle or a functional polymer coating. The sealant layer protects the particle from abrasion and attrition during handling, and / or minimizes static during processing. In general, the sealant coating can have a stabilizing effect.
  • Particles includes beads, granules, pellets, micro-particles, micro-particulates, mini tablets, or a powder mix or blend.
  • drug micro-particulates or “drug micro-particles” refer to drug particles with particle size in the micrometer range.
  • drug layered particle or “DL particles” refers broadly to an active agent-containing crystal, bead, pellet, granule, microparticulate, microparticle or mini-tablet. In one specific embodiment the drug is layered upon an inactive core.
  • Modified release as used herein encompasses all release profiles other than immediate release. Accordingly, modified release may refer to controlled release, delayed release, extended release, or pulsatile release.
  • Delayed release particles or “DR particles” refers broadly to an active agent- containing crystal, bead, pellet, granule, microparticulate, microparticle or mini-tablet that exhibits "delayed release” properties. These DR particles comprise a coating of one or more enteric polymers which start to dissolve at about pH 5.0 or higher.
  • “Delayed release” refers to a drug release profile in which substantially no drug is released in the acid environment of the stomach (e.g., less than about 10%), but drug release occurs in the high pH environment of the intestines.
  • DR drug release profile in which substantially no drug is released in the acid environment of the stomach (e.g., less than about 10%), but drug release occurs in the high pH environment of the intestines.
  • greater than or equal to about 50% of the active such as greater than about 75% of the active, greater than about 90% of the active or greater than about 95% of the active is released within about 4 hours, 3 hours, 2 hours, or 60 minutes or less (e.g., 50, 40, 30, 20, or 10 minutes or less), following administration after the composition transitions to the intestines from the stomach.
  • the release in the buffer phase that it at least about 80% or at least about 90% (e.g. about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) of the active within about 30 minutes, when in vitro dissolution tested
  • Rapidly disintegrating solid composition or “rapidly dispersing solid composition” as used herein encompass any pharmaceutical dosage formulations of all shapes and sizes, including compressed dosage formulations, that rapidly disintegrate or disperse upon contact with a liquid, which includes saliva or a pharmaceutically acceptable liquid (e.g., an aqueous solution). Disintegration of such compositions occurs without chewing.
  • these dosage forms can rapidly disintegrate upon contact with the saliva in the oral cavity without chewing and form a viscous smooth (non-gritty), easy-to-swallow suspension, although it can be ingested with water if the patient so desires.
  • the rapidly disintegrating/dispersing solid composition includes a wafer, film, or tablet.
  • Dosage forms of the present disclosure can contain pharmaceutical ingredients that swell, dissolve or otherwise facilitate the disintegration of the composition.
  • Such ingredient can include disintegrants, or effervescent components or effervescent blend comprising a pharmaceutically acceptable acid in solid form and a carbonate and/ or hydrogen carbonate containing compound (e.g., a carbonate salt, such as sodium bicarbonate).
  • a carbonate salt such as sodium bicarbonate.
  • a carbonate salt such as sodium bicarbonate
  • disorder refers to any condition or illness, requiring medication and / or medical attention.
  • patient means a subject who has presented a clinical manifestation of a particular disorder with symptom or symptoms suggesting the need for treatment, who can be treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.
  • “Plasma concentration - time profile”, “Cmax”, “AUC”, “Tmax” and “elimination half- life” have their generally accepted meanings as defined in the FDA Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations (issued March 2003). All references to “plasma concentration - time profile”, “Cmax”, “AUC”, “Tmax”, and “elimination half-life” refer to the average values for such parameters as measured for a population of patients.
  • terapéuticaally effective plasma concentration means a plasma concentration of PPI such as esomeprazole that is sufficient to treat one or more symptoms of EoE.
  • “Therapeutically effective amount”, as used herein, means the amount of the drug to be dosed once or multiple times daily in a patient with the disorder to cause the desired therapeutic effect. “Effective amount” or “therapeutically effective amount”, as used herein, means the amount of the drug to be dosed once or multiple times daily in a patient with the disorder to cause the desired therapeutic effect.
  • Eosinophilic Esophagitis identifies an allergen/ immune-mediated disease characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa. It includes also the allergic variant.
  • the inventors have identified stable pharmaceutical compositions that disintegrate or disperse rapidly in the mouth or in a solution (such as aqueous solution) and provide modified release of the drug (PPI).
  • the solid compositions of the present disclosure are highly stable and protect the PPI from degrading in the acidic environment of the stomach and in the presence of atmospheric moisture.
  • the PPI is combined with an alkaline material, which improves the stability of the PPI compared to a similarly formulated composition that does not include the alkaline material.
  • the alkaline material is MgO.
  • an enteric polymer is disposed over the PPI and MgO to further protect the PPI from degradation in the acidic environment of the stomach.
  • the composition is a solid rapidly disintegrating / dispersing composition with modified release of PPI.
  • the composition is an orally disintegrating tablet (ODT).
  • the PPI of the composition is esomeprazole, omeprazole, lansoprazole, pantoprazole, or rabeprazole, or any pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salt may be an alkali metal salts thereof such as, sodium or potassium salts, and alkaline earth metal salts thereof such as, for example, calcium and magnesium salts.
  • the PPI may also be in the form of a single isomer, enantiomer, racemate, or mixtures thereof.
  • the proton pump inhibitor may be in any of its crystalline, polymorph, semi-crystalline, or amorphous form, or mixtures thereof.
  • the PPI is esomeprazole, or a pharmaceutically acceptable salt thereof.
  • the PPI is an esomeprazole salt, such as esomeprazole magnesium.
  • the solid pharmaceutical composition comprises a modified release component comprising at least one PPI (such as esomeprazole), magnesium oxide and a coating suitable to a provide modified release profile.
  • the solid pharmaceutical composition comprises delayed release (DR) component comprising at least one PPI (such as esomeprazole), magnesium oxide and an enteric polymer.
  • DR delayed release
  • the DR component may be in any form in which the enteric polymer and MgO is able to inhibit degradation of the PPI.
  • the DR component may be a matrix or a particle containing the enteric polymer disposed over one or more layers containing the MgO and the drug.
  • the DR component is a particle comprising a core, the PPI, MgO, and the enteric polymer.
  • the PPI e.g., esomeprazole magnesium
  • the PPI may be layered on a core.
  • the PPI may be distributed within a rapidly disintegrating matrix.
  • DR particles comprise an inert core, a layer of PPI together with an alkaline material (e.g., MgO) and a binder disposed on the core, and at least one coating layer comprising an enteric polymer which is disposed over the PPI-MgO-binder layer.
  • a solid rapidly disintegrating / dispersing composition with modified release of PPI is useful for treatment of EoE or variant thereof for the following main reasons:
  • the drug-containing component disclosed herein comprises at least one PPI (such as esomeprazole) mixed with magnesium oxide.
  • the drug containing component may be any suitable form in which the PPI is mixed with magnesium oxide (MgO) in a manner that inhibits degradation of the PPI.
  • MgO magnesium oxide
  • the PPI and MgO mixture may be in the form of, but not limited to, powder, drug-coated core particles, solid blends or dispersions, mini-tablets, and matrices.
  • the PPI and MgO mixture may be granules, microgran es, microcapsules, pellets, microspheres that are prepared by rotogranulation, high- shear granulation, spray congealing and extrusion-spheronization or compression of the drug (as mini-tablets and micro-tablets, e.g., having a diameter of about 2 mm or more or about 2 mm or less, respectively), a polymeric binder and optionally fillers/diluents [0070]
  • the drug-containing component is in the form of a particle that contain a PPI layered on an inactive (or inert) core (they may also be referred to as an active particle, drug-containing particle, or bead).
  • the core may comprise different oxides, celluloses, organic polymers and other materials, alone or in mixtures, or water soluble seeds comprising different inorganic salts, sugars, nonpareil cores and other materials, alone or in mixtures.
  • the core may be a sphere comprising sugar, microcrystalline cellulose (MCC), polyol, camauba wax, silica, lactose-starch, or lactose-cellulose.
  • the core may be a buffer crystal or an encapsulated buffer crystal, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. Buffer crystals are useful to alter the microenvironment.
  • the amount of the PPI layered onto each core is such that when a plurality of cores are combined in a solid pharmaceutical composition disclosed herein, the plurality of cores contains a therapeutically effective amount of the PPI (e.g., esomeprazole magnesium).
  • therapeutically effective amounts of a PPI may range from about 2 mg to about 100 mg, including about 2 mg, about 2.5 mg, about 5 mg, 10 mg, about 15 mg, about 20 mg, about 25, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, and 100 mg, including all values and ranges between these values.
  • therapeutically effective amounts of esomeprazole range from about 2 mg to about 75 mg, e.g., about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, and about 75 mg, including all values and ranges between these values.
  • the solid pharmaceutical compositions of the disclosure e.g., ODT
  • the solid pharmaceutical compositions of the disclosure comprise about 30 mg to about 60 mg of esomeprazole magnesium, e.g., about 30 mg, about 45 mg or about 60 mg per dose unit.
  • the solid pharmaceutical compositions of the disclosure comprise about 20 mg of esomeprazole magnesium.
  • PPI is present an amount ranging from about 30% to about 60% by weight of the total mass of the core, e.g. about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60%, including each value and subrange between these values.
  • MgO may be mixed with the PPI (e.g., esomeprazole magnesium) and the mixture of the PPI and MgO is disposed over a core (e.g., as a drug-containing layer) and/or MgO may be disposed over the drug layer.
  • MgO may be mixed with the PPI. Mixing the MgO and PPI ensures that the MgO is intimately associated with the PPI, and thereby improves the stability of the PPI.
  • the PPI and MgO mixture may be achieved by granulating MgO and the PPI together, dissolving the MgO and PPI in a solvent and spraying the mixture onto a core, and the like.
  • the MgO and PPI mixture is disposed over the core.
  • the PPI and MgO mixture is not a solid dispersion.
  • combinations of MgO and PPI are critical to the improving of the stability of the PPI in the solid dosage forms disclosed herein, and inhibits degradation of the PPI in the acidic environment of the stomach and in the presence of atmospheric moisture.
  • the amount of MgO is important to the stability of the PPI. Too little MgO and the MgO does not inhibit degradation of the PPI. Too much MgO is detrimental to the acid protection provided by the enteric polymer.
  • the MgO agent is present an amount ranging from about 1% to about 20% by weight of the total mass of the core, e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, including each value and subrange between these values.
  • MgO agent is present an amount ranging 5% to about 15%. In embodiments, MgO agent is present at about 9%.
  • compositions of the disclosure include a sufficient amount of the MgO to improve stability but the mass of MgO in the core is equal to or less than the mass of PPI.
  • the ratio of PPI (e.g., esomeprazole magnesium) to MgO ranges from about 1:1 to about 20:1 by weight of the total mass of the core, e.g., about 1:1, about 2:1, about 3:1, about 4:1, about 5:1 about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1 about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19.1, or about 20:1, including each value and subrange between these values.
  • the PPI is present in a slight excess.
  • the ratio of PPI to MgO ranges from about 2:1 to about 10:1.
  • the ratio of PPI to MgO ranges from about 5: 1 to about 7:1
  • the ratio of PPI to MgO is about 6.2: 1
  • the ratio of PPI to MgO is about 5:1.
  • MgO may be substituted for another alkaline agent.
  • Such may be chosen among, but are not limited to, substances such as the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminum hydroxide/sodium bicarbonate co-precipitate; substances normally used in antacid preparations such as aluminum, calcium and magnesium hydroxides or composite substances, such as Ai203.6Mg0.C02.12H20, (Mg6Al2(0H)i6C03.4H20), MgO. Ab O3.2SiO2.nH2O or similar compounds; organic pH- buffering substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering substances.
  • the drug-containing layer comprises a binder.
  • the binder may be hydrophilic hydroxypropylcellulose such as Klucel® LF (which is soluble in ethanol), Klucel® EF which has lower viscosity but is applicable, Eudragit® L100-55 (soluble in water/ ethanol), with HPMCAS (soluble in water/acetone), or an aqueous acrylic system (such as AcrylEze®).
  • the drug containing core may be coated with a seal layer and /or additional functional coating. In such embodiments, the seal layer polymer is disposed over the drug layer and below the enteric coating.
  • the average diameter of drug- containing core particle is less than 300 microns, e.g., about 290, about 280, about 270, about 260, about 250, about 240, about 230, about 220, about 210, about 200, about 190, about 180, about 170, about 160, about 150, about 140, about 130, about 120, about 110, or about 100 microns, including all values and subranges between these values.
  • Drug layered beads can be sieved for oversize (e.g., using 50 mesh).
  • a seal layer may be applied at a coating weight of about 1% to about 10%, for example about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, and inclusive of all ranges and sub-ranges there between.
  • the seal layer comprises one or more water-soluble (hydrophilic) polymers.
  • Non-limiting examples of suitable hydrophilic polymers useful as a sealant coating include hydrophilic hydroxypropylcellulose (e.g., KLUCEL ® LF), hydroxypropyl methylcellulose or hypromellose (e.g., OPADRY ® CLEAR or PHARMACOATTM 603), low- viscosity ethylcellulose, and mixtures thereof.
  • hydrophilic hydroxypropylcellulose e.g., KLUCEL ® LF
  • hydroxypropyl methylcellulose or hypromellose e.g., OPADRY ® CLEAR or PHARMACOATTM 603
  • low- viscosity ethylcellulose e.g., OPADRY ® CLEAR or PHARMACOATTM 603
  • an additional functional coating may be disposed over the drug- containing particles.
  • a functional coating is a polymeric coating that is soluble in gastric conditions up to pH 5.0 and swellable and permeable above pH 5.0 such as Eudragit E polymer, suitable example is Eudragit E-OP polymer.
  • Such polymers may be referred to as a “reverse enteric polymer.” Examples are described in U.S. Pat. No. 10,076,494, which is herein incorporated by reference in its entirety.
  • the drug-containing cores which include the PPI, MgO and one or more pharmaceutically acceptable excipients (e.g. a filler, a binder, etc.), may be generated through methods well-known in the pharmaceutical arts, for example, dry or wet granulation, extrusion- spheronization, see also , Remington, J. P.; Beringer, P. Remington: The Science and Practice of Pharmacy; Lippincott Williams & Wilkins: Philadelphia, 2006, which is herein incorporated by reference in its entirety.
  • these drug-containing cores may be formed by compressing the PPI with one or more pharmaceutically acceptable excipients such as a filler (e.g. lactose), a binder (e.g., polyvinylpyrrolidone) and MgO.
  • a filler e.g. lactose
  • a binder e.g., polyvinylpyrrolidone
  • MgO polyvinylpyrrolidone
  • the active core may be prepared by mixing the PPI with one or more pharmaceutically acceptable excipients and MgO, and forming a plurality of cores (e.g., granules, spheroids etc.) through granulation, or extrusion-spheronization techniques.
  • the drug-containing particle is a granulated-extruded-spheronized pellet that contains PPI (such as esomeprazole), one or more polymeric binder, which impart resilient characteristics to dried granules, one or more hydrophilic fillers / diluents and optionally one or more flavors, sweeteners, and/or disintegrants.
  • PPI such as esomeprazole
  • polymeric binder which impart resilient characteristics to dried granules
  • hydrophilic fillers / diluents optionally one or more flavors, sweeteners, and/or disintegrants.
  • fillers / diluents typically used in the manufacture of drug-containing granules by high-shear granulation or pellets by granulation-extmsion-spheronization or minitablets by compression of high shear granules include lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • PPIs such as omeprazole and esomeprazole (and pharmaceutically acceptable salts thereof) degrade in the acidic environment of the stomach.
  • Enteric polymers which are insoluble in the acidic pH conditions of the stomach, but soluble in the higher pH conditions of the intestines, are used to protect PPI. While enteric coatings help protect the PPI from degradation in the acid environment, Applicant discovered that drug-containing particles coated with an enteric polymer alone (in the absence of MgO) still undergo degradation. It is the combination of the enteric polymer and MgO that significantly improves the stability of the PPI compared to existing formulations.
  • the DR particles disclosed herein comprise the drug-containing particles coated with a membrane (also referred to herein as a layer or coating) comprising an enteric polymer with a weight ranging from about 50% to about 80% based on the weight of the DR particle, e.g., about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80%, including all values and subranges in between these values.
  • enteric polymer is present at about 55% to about 75% based on the weight of the coated particle. In embodiments, enteric polymer is present at 70% based on the weight of the coated particle. In embodiments, enteric polymer is present at 60% based on the weight of the coated particle.
  • Non-limiting examples of enteric polymers include cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS LG, MG or HG dissolving above a pH of 5.0, 5.5 or 6.5, respectively), polyvinyl acetate phthalate, pH-sensitive acrylate copolymers, such as methacrylic acid/methylmethacrylate copolymers (e.g., EUDRAGIT ® L, L-55, L100, L30D, S, S100 and FS polymers from Eastman Chemical Co.), shellac, AQUATERIC® (cellulose acetate phthalate aqueous dispersion) from FMC Corp., and AQOAT® (hydroxypropyl methylcellulose acetate succinate aqueous dispersion) from Shin Etsu K.K., and mixtures thereof.
  • enteric polymers include cellulose acetate phthalate, hydroxypropyl methylcellulose phthal
  • a functional coating may be disposed over the enteric coating.
  • functional coatings are polymeric coating that are soluble in gastric conditions up to pH 5.0 and swellable and permeable above pH 5.0.
  • the functional coating is an aminomethacrylate copolymer. These copolymers are commercially available from Evonik, and are sold as EUDRAGIT® E polymers, such as EUDRAGIT® E-PO.
  • the functional coating may be applied at a weight gain ranging from about 1% to about 30%, e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% w/w, inclusive of all values and ranges between these values.
  • the enteric membrane of the DR particle or bead may also comprise additional ingredients such as plasticizers and antisticking agents.
  • the amount of plasticizer required in the coating depends upon the nature of the plasticizer, the properties of the polymer, and the ultimate desired properties of the coating.
  • the plasticizer may constitute from about 2% to about 40% (e.g. about 5% to about 30%) by weight of the polymer(s) in the DR coating, including, for example, about 2%, about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, and about 40%, inclusive of all ranges and sub-ranges there between.
  • Non-limiting examples of plasticizers include glycerin, triacetin, citrate esters, triethyl citrate, acetyltri ethyl citrate, tributyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, substituted triglycerides and glycerides, monoacetylated and diacetylated glycerides (e.g., Myvacet® 9-45), glyceryl monostearate, glycerol tributyrate, polysorbate 80, polyethylene glycol, propylene glycol, oils (e.g. castor oil, hydrogenated castor oil, sesame oil, olive oil, etc.), fatty acids, and mixtures thereof.
  • oils e.g. castor oil, hydrogenated castor oil, sesame oil, olive oil, etc.
  • Non-limiting examples of suitable anti-tacking agents include colloidal silicon dioxide, magnesium stearate, talc, glyceryl monostearate, and mixtures thereof.
  • the ratio of the functional polymer plus plasticizer to anti-tacking agent ranges from about 9: 1 to about 3 :2 by weight. In another embodiment, the ratio of the functional polymer plus plasticizer to anti-tacking agent ranges from about 4:1 to about 7:3 by weight.
  • the DR particles have a diameter ranging from about 100 microns to about 1000 microns, e.g., about 100 microns, about 125 microns, about 150 microns, about 175 microns, about 200 microns, about 225 microns, about 250 microns, about 275 microns, about 300 microns, about 325 microns, about 350 microns, about 375 microns, about 400 microns, about 425 microns, about 450 microns, about 475 microns, about 500 microns, about 525 microns, about 550 microns, about 575 microns, about 600 microns, about 625 microns, about 650 microns, about 675 microns, about 700 microns, about 725 microns, about 750 microns, about 775 microns, about 800 microns, about 825 microns, about 850 microns, about 875 microns, about 900 micron
  • the DR particles of the disclosure are significantly smaller than any DR beads of esomeprazole on the market currently (e.g., Dexcel). Smaller particles advantageously improve the compression properties of the particles, for example when the particles are compressed into tablets. In embodiments, the disclosed particles have improved hardness and/or decreased bead breakage compared to the particles in the product on the market.
  • Enteric coating level (% w/w) is important to acid resistance and taste-masking.
  • the particle has about 65-75% w/w (e.g., about 70% w/w) of coating level.
  • the enteric coating produces a DR particle having a diameter of at least 300 microns. In such embodiments, the perception of the drug taste is minimal and the particle displays acid resistance as measured in the examples described herein.
  • the PPI-containing DR particles comprises a compressible coating disposed over the enteric coating. This coating maintains enteric protection after compression and allows for rapid release of the PPI once the composition enters the intestine (i.e., after the composition passes through the acidic environment of the stomach).
  • compression coatings are described in U.S. Pat. Pub. 2011/0129530.
  • the compressible coating comprises a polymer that swells or forms pores in an aqueous medium. Swelling or pore formulation may be pH-independent.
  • the polymer is a neutral copolymer of ethyl acrylate and methyl methacrylate, such as Eudragit® NE30D.
  • the compressible coating comprises a reverse enteric polymer.
  • reverse enteric polymer refers to pH sensitive polymers, which are insoluble at pH values greater than those found in the stomach i.e. at pH values greater than 5.0 while being soluble at acidic pH values. Suitable reverse enteric polymers are thus insoluble in the oral cavity and soluble in the stomach.
  • the reverse enteric polymer is a copolymer of hydrophobic monomers and/or basic monomers; non-limiting examples of such reverse enteric polymers are described in U.S. Patent Application No. 2006/0134054.
  • the monomer is an acrylic or a methacrylic acid ester comprising, but not limited to, methyl (meth)acrylate, benzyl (meth)acrylate, dodecyl (meth)acrylate, octyl (meth)acrylate, cyclohexyl (meth)acrylate, phenyl (meth)acrylate, tertiary butyl (meth)acrylate, butyl (meth)acrylate, ethyl hexyl (meth)acrylate, propyl (meth)acrylate, or combinations thereof.
  • the monomer is a substituted acrylic or a methacrylic acid ester comprising, but not limited to, dimethyl amino ethyl (meth)acrylate, diethyl amino ethyl (meth)acrylate, piperidine ethyl (meth)acrylate, tertbutyl amino ethyl (meth)acrylate, or combinations thereof.
  • Examples of reverse enteric polymers in a compressible coating are provided in U.S. Pat. No. 10,076,494, which is herein incorporated by reference in its entirety.
  • the compressible coating ranges from about 10% to about 40% by weight of the coating particle, e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%, inclusive of all values and ranges between these values.
  • the compressible coating ranges from about 20% to about 30% by weight of the DR particle, e.g., about 20%, or about 25% or about 30%.
  • This compressible coated beads have dissolution at pH 6.8 which is rapid releasing prototype.
  • the amount of PPI (e.g., esomeprazole magnesium) in the DR particle will depend on the desired dose. In embodiments, the amount of PPI (e.g., esomeprazole magnesium) in the DR particle ranges from about 5% to about 30% weight of the DR particle, e.g.
  • the drug is present in an amount ranging from 10% to about 20%.
  • the DR particles comprises a binder.
  • binders include povidone (PVP: polyvinyl pyrrolidone), copovidone, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxy methyl cellulose (CMC), hydroxyethylcellulose, gelatin, polyethylene oxide, poly ethylene glycol (PEG), poly vinyl alcohol (PVA), acacia, dextrin, magnesium aluminum silicate, starch, aqueous acrylic system (such as AcrylEze), and polymethacrylates or a mixture or combination thereof.
  • the binder is present in an amount of from about 5-30% by weight, e.g.
  • the binder is present at about 5-15% by weight, (e.g., 8% by weight) based on the total weight of the active particle (DR bead).
  • the DR particle comprises the following components in the recited amounts:
  • the disclosure provides for a disintegrating stable composition comprising the DR particles containing the PPI.
  • the disintegrating composition includes one or more pharmaceutically acceptable excipients which swell, dissolve or otherwise facilitate disintegration. Disintegration may occur in the oral cavity of the patient or in a suitable liquid that is orally administered after the tablet disintegrates.
  • the one or more pharmaceutically acceptable excipient which swell, dissolve or otherwise facilitate disintegration of the composition may be a disintegrant, or it may be gas generating system (e.g., an effervescent system).
  • Non-limiting examples of disintegrants include crospovidone, croscarmellose sodium, a cellulose derivative, cross-linked derivatives of starch, sodium starch glycolate, pregelatinized starch, crosslinked carboxymethyl cellulose, crosslinked sodium carboxymethylcellulose, low substituted hydroxypropylcellulose or a mixture or combination thereof.
  • the disintegrant may also be a gas generating system which is comprised of a weak acid or a salt of a weak acid.
  • the salt of a weak acid produces the free weak acid.
  • the acid may be tartaric acid, acetic acid, lactic acid, or citric acid, or a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable salts include, but are not limited to sodium, magnesium, or calcium salts.
  • the other component of the gas generating system is comprised of a salt of an acid that releases a gas (e.g., CO2) in the presence of the weak acid (or salt thereof) described above.
  • gas-releasing acid may be a salt of carbonic acid.
  • These may be carbonates or hydrogen carbonates, such as for example sodium or potassium carbonate to sodium or potassium hydrogen carbonate or calcium carbonates, as well mixtures of these salts.
  • the gas is released by the interaction of the gas generating components with the saliva or the aqueous solution.
  • An example of such a formulation is described in U.S. Pat. No. 9,867,780, which is herein incorporated by reference in its entirety.
  • the composition is an orally disintegrating or dispersing tablet (ODT).
  • ODT orally disintegrating or dispersing tablet
  • the ODT composition comprises DR particles which comprise at least one PPI and rapidly-dispersing granules. Non-limiting examples of these ODTs comprising rapidly dispersing granules are described in U.S. Pat. App. Pub. 2012/0282335 and U.S. Pat. No. 8,771,729, each of which are herein incorporated by reference in their entireties.
  • the ODT comprises:
  • DR particles comprising a PPI (such as esomeprazole magnesium);
  • rapidly-dispersing granules also called microgranules
  • the rapidly-dispersing granules have an average particle size of not more than about 300 pm (e.g., about 300 pm, about 275 pm, about 250 pm, about 225 pm, about 200 pm, about 175 pm, about 150 pm, about 125 pm, about 100 pm, or less ), or in some embodiments not more than 200 pm;
  • excipients such as flavors, sweeteners, coloring agents, and disintegrants.
  • the rapidly-dispersing granules comprise (a) a disintegrant and b) a sugar alcohol or a saccharide, or combination thereof, wherein each of the disintegrant and sugar alcohol/saccharide have an average diameter of not more than about 30 pm (e.g., 30 pm,
  • the ratio sugar alcohol: disintegrant is 95:5.
  • the amount of sugar alcohol and/or saccharide in the rapidly dispersing granules ranges from about 99%- 90%, or about 95%- 90% of the total weight of the disintegrant-containing granules, including all ranges and sub-ranges there between.
  • the average particle size of a sugar alcohol and/or saccharide is about 30 pm or less, for example about 1 -
  • the rapidly-dispersing granules and DR particles may be present in the ratio of about 6/1 to about 1/2, more particularly from about 2/1 to about 1/1.
  • compositions disclosed herein are in the form of an orally disintegrating or dispersible tablet that has the total weight of the dosage form in the range of from 300 to 900 mg and includes rapidly dispersing granules comprising at least one sugar alcohol and /or a saccharide in combination with at least one disintegrant.
  • the stable composition is in the form of orally disintegrating tablet (ODT) and it comprises delayed release particles and rapidly dispersing granules, wherein the delayed release particles comprise esomeprazole or a pharmaceutically acceptable salt thereof, magnesium oxide and the particles are coated with an enteric polymer (which is disposed over the drug-containing layer), and wherein the ratio of esomeprazole, or its pharmaceutically acceptable salt, to magnesium oxide is in the range of from about 2:1 to about 10:1.
  • ODT orally disintegrating tablet
  • the magnesium oxide is present in the delayed release particles in an amount range from about 2- 15 w/w% based on the weight of the delayed release particle, e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11, about 12%, about 13%, about 14%, or about 15%. In some embodiments, about 9% weight by weight of the delayed release particle.
  • the stable composition is in the form of orally disintegrating tablet (ODT) and it comprises delayed release particles and rapidly dispersing granules, wherein the delayed release particles comprise esomeprazole or a pharmaceutically acceptable salt thereof, magnesium oxide and a binder and the particles are coated with a an enteric polymer, and wherein the ratio of esomeprazole, or its a pharmaceutically acceptable salt, to magnesium oxide is in the range from about 5 : 1 to about 7: 1 , the binder is hydroxypropyl cellulose and the enteric polymer is a pH-sensitive acrylate copolymer.
  • ODT orally disintegrating tablet
  • the magnesium oxide is present in the delayed release particles in an amount range from about 2-15 w/w% based on the weight of the delayed release particle, e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11, about 12%, about 13%, about 14%, or about 15%. In some embodiments, about 9% weight by weight of the delayed release particle.
  • the pharmaceutical composition is in the form of orally disintegrating tablet (ODT) and it comprises delayed release particles, which comprise a) a core comprising esomeprazole or a pharmaceutically acceptable salt thereof and magnesium oxide and b) a delayed release coating disposed over the core, and wherein the ratio of esomeprazole to magnesium oxide is in the range of from about 2:1 to about 10:1.
  • ODT orally disintegrating tablet
  • the magnesium oxide is present in the delayed release particles in an amount range from about 2-15 w/w% based on the weight of the delayed release particle, e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11, about 12%, about 13%, about 14%, or about 15%. In some embodiments, about 9% weight by weight of the delayed release particle.
  • the pharmaceutical composition is in the form of orally disintegrating tablet (ODT) and it comprises delayed release particles, which comprise a) a core comprising esomeprazole or a pharmaceutically acceptable salt thereof and magnesium oxide, b) a seal coating, and c) a delayed release coating disposed over the core, and wherein the ratio of esomeprazole, or its pharmaceutically acceptable salt, to magnesium oxide is in the range of from about 2:1 to about 10:1.
  • ODT orally disintegrating tablet
  • the magnesium oxide is present in the delayed release particles in an amount range from about 2-15 w/w% based on the weight of the delayed release particle, e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11, about 12%, about 13%, about 14%, or about 15%. In some embodiments, about 9% weight by weight of the delayed release particle.
  • the pharmaceutical composition is in the form of orally disintegrating tablet (ODT) and it comprises delayed release particles, which comprise a) a core comprising esomeprazole or one of its pharmaceutically acceptable salts and magnesium oxide, b) a seal coating, and c) a delayed release coating disposed over the core, and wherein the ratio of esomeprazole, or its pharmaceutically acceptable salt, to magnesium oxide is in the range of from about 5 : 1 and magnesium oxide is present in amount of 9% weight by weight of the delayed release particle.
  • the seal coat is disposed over the core and beneath the delayed release coating.
  • the pharmaceutical composition is in the form of orally disintegrating tablet (ODT) and it comprises delayed release particles, which comprise a) a core comprising esomeprazole or one of its pharmaceutically acceptable salts and magnesium oxide, b) a seal coating of hydroxypropyl cellulose disposed over the core and a c) delayed release coating comprising a pH-sensitive acrylate copolymer disposed over the seal coating, and wherein the ratio of esomeprazole, or one of its pharmaceutically acceptable salts, to magnesium oxide is in the range of from about 2:1 to about 10:1.
  • ODT orally disintegrating tablet
  • the magnesium oxide is present in the delayed release particles in an amount range from about 2- 15 w/w% based on the weight of the delayed release particle, e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11, about 12%, about 13%, about 14%, or about 15%. In some embodiments, about 9% weight by weight of the delayed release particle.
  • the pharmaceutical composition is in the form of orally disintegrating tablet (ODT) and it comprises delayed release particles, which comprise a) a core comprising esomeprazole or one of its pharmaceutically acceptable salts and magnesium oxide, b) a seal coating of hydroxypropyl cellulose disposed over the core, and a c) delayed release coating comprising a pH-sensitive acrylate copolymer disposed over the seal coating, and wherein the ratio of esomeprazole, or one of its pharmaceutically acceptable salts, to magnesium oxide is in the range of from about 5:1 to about 7:1.
  • ODT orally disintegrating tablet
  • the magnesium oxide is present in the delayed release particles in an amount range from about 2- 15 w/w% based on the weight of the delayed release particle, e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11, about 12%, about 13%, about 14%, or about 15%. In some embodiments, about 9% weight by weight of the delayed release particle.
  • the pharmaceutical composition is in the form of orally disintegrating tablet (ODT) and it comprises delayed release particles, which comprise a) a core comprising esomeprazole or one of its pharmaceutically acceptable salts and magnesium oxide, b) a seal coating of hydroxypropyl cellulose disposed over the core, and c) a delayed release coating comprising a pH-sensitive acrylate copolymer disposed over the seal coating, and wherein the ratio of esomeprazole, or one of its pharmaceutically acceptable salts, to magnesium oxide is about 5:1.
  • ODT orally disintegrating tablet
  • the pharmaceutical composition is in the form of orally disintegrating tablet (ODT) and it comprises delayed release particles, which comprise a) a core comprising esomeprazole or one of its pharmaceutically salts and magnesium oxide, b) a seal coating of hydroxypropyl cellulose disposed over the core, and c) a delayed release coating comprising a pH-sensitive acrylate copolymer disposed over the seal coating, and wherein the ratio of esomeprazole, or one of its pharmaceutically acceptable salts, to magnesium oxide is about 5:1 and magnesium oxide is about 9% weight by weight of the delayed release particle.
  • ODT orally disintegrating tablet
  • the ODT exhibits acceptable rate of disintegration when placed in the oral cavity or when dissolved in a solution (such as water).
  • the rate of disintegration of the compositions of the present disclosure in the oral cavity of an individual can be on the order of about 60 seconds or less, about 50 seconds or less, about 40 seconds or less, about 30 seconds or less, about 20 seconds or less, or about 10 seconds or less.
  • the rate of disintegration of the solid pharmaceutical compositions of the present disclosure measured using the USP ⁇ 701> Disintegration Test is about 60 seconds or less, about 45 seconds or less, about 30 seconds or less, about 20 seconds or less, or about 10 seconds or less.
  • compositions described herein provides delayed release.
  • Drug release may be measured using USP Test-1: Paddle, 100RPM, Stage-1: 300 mL 0. IN HC1 (2h); Stage-2: Add 700 mL of 0.086M dibasic sodium phosphate to make pH 6.8 (30 minute).
  • drug release may be measured using USP Test-3: Paddle, 100RPM, Stage-1 : 300 mL 0. IN HC1 (2h); Stage-2: transfer the beads to a 1000 mL VF and Assay.
  • about 80-100% (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, including all values and ranges between these values) of the dose is released within 30 minutes after the buffer stage-2 when tested for dissolution with USP Test-1.
  • about 90-111% e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, or 111%, including all values and ranges between these values
  • the ODT according to the disclosure exhibits the following properties:
  • the PPI (such as esomeprazole) containing ODT according to the present disclosure has the following specifications: round or oval shape; disintegration time: within about 30 sec in USP701 method; tablet hardness: suitable for packaging processes, the same as conventional tablets (bottles and blisters).
  • Each of the active ingredient coating, enteric coating functional coating, and/or compressible coating layers, and the compressed pharmaceutically composition, described herein may additionally include a pharmaceutically acceptable excipient(s), such as, but not limited to, 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.
  • a pharmaceutically acceptable excipient(s) such as, but not limited to, 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
  • Non-limiting examples of binders include povidone (PVP: polyvinyl pyrrolidone), copovidone, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxy methyl cellulose (CMC), hydroxyethylcellulose, gelatin, polyethylene oxide, poly ethylene glycol (PEG), poly vinyl alcohol (PVA), acacia, dextrin, magnesium aluminum silicate, starch, and polymethacrylates or a mixture or combination thereof.
  • PVP polyvinyl pyrrolidone
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • CMC carboxy methyl cellulose
  • gelatin polyethylene oxide
  • PEG poly ethylene glycol
  • PVA poly vinyl alcohol
  • acacia dextrin
  • magnesium aluminum silicate magnesium aluminum silicate
  • starch and polymethacrylates or a mixture or combination thereof.
  • Non-limiting examples of fillers include lactose, glucose, fructose, sucrose, dicalcium phosphate, sugar alcohols also known as “sugar polyol” such as sorbitol, mannitol, maltitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates (a blend of several sugar alcohols), corn starch, potato starch, sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, or a mixture or combination thereof.
  • sugar alcohols also known as “sugar polyol” such as sorbitol, mannitol, maltitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates (a blend of several sugar alcohols), corn starch, potato starch, sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, or a mixture
  • Non-limiting examples of diluents include dicalcium phosphate dihydrate, sugars, lactose, calcium phosphate, cellulose, kaolin, mannitol, sodium chloride, and dry starch or a mixture or combination thereof.
  • Non-limiting examples of surfactants include non-ionic, zwitterionic, anionic or cationic compounds. Generally, surfactants have a lipophilic and a hydrophilic moiety within the molecule. The surfactant may optionally comprise one or more of soaps, detergents, emulsifiers, and dispersing agents.
  • Suitable surfactants include, but are not limited to, glyceryl monostearate, lanolin alcohols, lecithin, mono- and di-glycerides, monoethanolamine, oleic acid, oleyl alcohol, poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, trolamine, and emulsifying wax or a mixture or combination thereof.
  • Non-limiting examples of glidant includes silicon dioxide.
  • Non-limiting examples of lubricants include sodium stearyl fumarate, stearic acid, polyethylene glycol or stearates, such as magnesium stearate or a mixture or combination thereof.
  • Non-limiting examples of plasticizers include cetyl alcohol, dibutyl sebacate, polyethylene glycol, polypropylene glycol, dibutyl phthalate, diethyl phthalate, triethyl citrate, tributyl citrate, acetylated monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters of fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol and sorbitol or a mixture or combination thereof.
  • Non-limiting examples of anti-tacking agents include magnesium stearate, calcium stearate, stearic acid, talc, colloidal silicon or a mixture or combination thereof.
  • Non-limiting examples of alkaline substances include organic and inorganic alkaline substances.
  • Suitable organic alkaline substances include, but are not limited to, basic amino acids such as arginine and lysine, amine derivatives and salts, amino sugars such as meglumine, salts of stearic acid such as sodium stearate and the like, with each possibility representing a separate embodiment.
  • Suitable inorganic alkaline agents include, but are not limited to, hydroxides such as sodium or potassium hydroxide, carbonates such as calcium, magnesium or zinc carbonate and the like.
  • Non-limiting examples of tonicity enhancing agents include ionic and non-ionic agents.
  • ionic compounds include, but are not limited to, alkali metal or alkaline earth metal halides, such as, for example, CaCk KBr, KC1, LiCl, Nal, NaBr or NaCl, and boric acid or a mixture or combination thereof. Each possibility represents a separate embodiment.
  • Non ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, and dextrose or a mixture or combination thereof.
  • Non-limiting examples of wetting agents include glycerin, starches or a mixture or combination thereof.
  • Non-limiting examples of buffering substances include acidic buffering agents such as short chain fatty acids, citric acid, acetic acid, hydrochloric acid, sulfuric acid and fumaric acid; and basic buffering agents such as tris, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and magnesium hydroxide or a mixture or combination thereof.
  • acidic buffering agents such as short chain fatty acids, citric acid, acetic acid, hydrochloric acid, sulfuric acid and fumaric acid
  • basic buffering agents such as tris, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and magnesium hydroxide or a mixture or combination thereof.
  • Non-limiting examples of flavoring agents include, but are not limited to, sweeteners such as sucralose, and synthetic flavor oils and flavoring aromatics, natural oils, extracts from plants, leaves, flowers, and fruits, or a mixture or combinations thereof.
  • sweeteners such as sucralose
  • synthetic flavor oils and flavoring aromatics natural oils, extracts from plants, leaves, flowers, and fruits, or a mixture or combinations thereof.
  • Exemplary flavoring agents include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus , vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, and fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot or a mixture or combination thereof.
  • Non-limiting examples of opacifiers include titanium dioxide.
  • Non-limiting examples of colorants include alumina (dried aluminum hydroxide), annatto extract, calcium carbonate, canthaxanthin, caramel, b-carotene, cochineal extract, carmine, potassium sodium copper chlorophyllin (chlorophyllin-copper complex), dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ferric ammonium ferrocyanide, ferric ferrocyanide, chromium hydroxide green, chromium oxide greens, guanine, mica-based pearlescent pigments, pyrophyllite, mica, dentifrices, talc, titanium dioxide, aluminum powder, bronze powder, copper powder, and zinc oxide or a mixture or combination thereof.
  • alumina dried aluminum hydroxide
  • annatto extract calcium carbonate
  • canthaxanthin caramel
  • b-carotene cochineal extract
  • carmine potassium sodium copper chlorophyllin (chlorophyllin-copper complex)
  • Non-limiting examples of anti-oxidants include tocopherols (e.g., alpha-tocopherol, beta-tocopherol, gamma-tocopherol, or delta-tocopherol), butylated hydroxytoluene (BEIT), butylated hydroxyanisole (BHA), citric acid, ascorbic acid, phenolic diterpenes (e.g., camosic acid, carnosol, rosmanol, epirosmanol, isorosmanol, or methyl carnosate), rosmarinic acid, eugenol, eugenyl acetate, clove bud extract, methanolic extract, tea catechins (e.g., epigallocatechin gallate, epicatechin gallate, epigallocatechin, or epicatechin), or a mixture or combination thereof.
  • tocopherols e.g., alpha-tocopherol, beta-tocopherol, gamma-tocopherol
  • the formulations of the disclosure may be manufactured by combining the delayed DR component with pharmaceutically acceptable excipients.
  • excipients enable the PPI (e.g., esomeprazole magnesium) to be formulated as tablets, pills, dragees, capsules, sachets, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject.
  • Pharmaceutical compositions for oral use may be obtained as solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable adjuvants, if desired, to obtain tablets or dragee cores.
  • Such oral pharmaceutical compositions may also be prepared by milling or melt extrusion.
  • Suitable excipients may be any of those disclosed herein and, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose formulation such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP) formulation.
  • disintegrating agents may be employed, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Wetting agents, such as sodium dodecyl sulfate and the like, may be added.
  • Coatings described above may be applied by spraying a solution containing the component (e.g., dispersing or solution containing the drug or enteric polymer) using e.g., a fluid bed coater.
  • a solution containing the component e.g., dispersing or solution containing the drug or enteric polymer
  • a fluid bed coater e.g., a fluid bed coater
  • the method of preparation the DR-particles(mean particle size of about 100-400 pm comprises the steps:
  • step (1) coating the active particles of step (1) with a seal coating comprising one or more hydrophilic polymer in an amount ranging from about 1% to about 10% w/w based on total weight of coated particle thus obtaining DL particles; and
  • step 2) coating the DL particles of step 2) with one or more enteric polymers in an amount of from about 15% to about 70% w/w, based on total weight of coated particle thus obtaining the DR particles.
  • the inter particle may be selected from spheres consisting of sugar, microcrystalline cellulose (MCC), polyol, camauba wax, silica, lactose-starch, and lactose- cellulose (preferred Celphere® inert core).
  • the binder may be selected among: hydrophilic hydroxypropylcellulose such as Klucel® in ethanol, or Eudragit® LI 00-55 in water/ ethanol, or with HPMCAS in water/acetone, or with aqueous acrylic system (AcrylEze®).
  • the layering can be obtained by an aqueous based suspension of esomeprazole (or a pharmaceutically acceptable salt thereof) with binder (hydrophilic hydroxypropylcellulose such as Klucel®), simethicone and polysorbate 80.
  • the seal coating may be 4.4% w/w of HPMC (hypromellose such as Opadry®)
  • the enteric polyme is Eudragit® L100-55 that can be mixed with a plasticizer (such Dibutyl sebacate).
  • the composition is a disintegrating composition.
  • the process for preparing disintegrating pharmaceutical compositions comprises:
  • a method of manufacturing the orally disintegrating pharmaceutical composition comprises the steps of:
  • a disintegrant e.g. crospovidone
  • step 4 blending the DR particles of step 2) with the rapidly disintegrating granules of step 3) and optionally with other pharmaceutically acceptable ingredients (such as flavoring agent, coloring agent, sweetener and additional disintegrant);
  • the compression is carried out in the following way: the DR particles are blended with rapidly dispersing microgranules (95:5 mannitol: crospovidone), silicified microcrystalline cellulose, crospovidone, citric acid, malic acid, sucralose and sodium stearyl fumarate.
  • microgranules 95:5 mannitol: crospovidone
  • silicified microcrystalline cellulose crospovidone
  • citric acid malic acid
  • sucralose sucralose
  • sodium stearyl fumarate sodium stearyl fumarate
  • the formulation does not contains lubricant used to aid in tableting.
  • the lubricant may be applied on the punch faces, as external lubricant instead.
  • esomeprazole S-and R-isomers of omeprazole are metabolized differently by the liver, resulting in higher plasma levels of the S-isomer (esomeprazole) than of the R-isomer.
  • the plasma elimination half-life of esomeprazole is approximately 1-1.5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces. Approximately 80% of the administered dose of esomeprazole is excreted as metabolites in urine and the remaining 20% is excreted in feces.
  • Esomeprazole when administered as a delayed-release capsule (e.g., as an enteric- coated particles formulation, such as Nexium®) produces peak plasma levels occurring at approximately 1.5 hours.
  • the systemic bioavailability is approximately 90% after repeated daily administration.
  • the AUC after administration of a single 40 mg dose of esomeprazole is decreased by 43-53% after food intake compared to fasting conditions.
  • Esomeprazole is 97% bound to plasma proteins.
  • Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system and the metabolites lack antisecretory activity.
  • CYP cytochrome P450
  • the patient after administering between about 10 mg and about 80 mg (e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg) of esomeprazole (or a pharmaceutically acceptable salt thereof), the patient has a maximum observed plasma drug concentration (Cmax) between about 0.5 pmol/L and about 10 pmol/L, including all values and ranges in between.
  • Cmax maximum observed plasma drug concentration
  • the Cmax is about 0.5 mihoI/L, 1 mihoI/L, about 2 mihoI/L, about 3 mihoI/L, about 4 mihoI/L, about 5 mihoI/L, about 6 mihoI/L, about 7 mmol/L, about 8 mihoI/L, about 9 mmol/L, or about 10 mihoI/L. In some embodiments, the Cmax is between 80 % and 125 % of any of the aforementioned values or ranges between the aforementioned values.
  • the Cmax is reported as geometric mean with a coefficient of variation (% CV).
  • the patient has a Cmax ranging from 80 % to about 125 % of 4.7 pmol/L (37 %) after administration of 40 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient has a Cmax ranging from 80 % to about 125 % of 2.1 pmol/L (45 %) after administration of 20 mg of esomeprazole.
  • the patient that is less than one year old has a Cmax ranging from 80 % to about 125 % of 0.87 pmol/L after administration of 1 mg/kg of esomeprazole (or a pharmaceutically acceptable salt thereof). In some embodiments, the patient that is between about 1 year old and about 5 years old has a Cmax ranging from 80 % to about 125 % of 2.98 pmol/L after administration of 10 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient that is between about 6 years old and about 11 years old has a Cmax ranging from 80 % to about 125 % of 1.77 pmol/L after administration of 10 mg of esomeprazole (or a pharmaceutically acceptable salt thereof). In some embodiments, the patient that is between about 6 years old and about 11 years old has a Cmax ranging from 80 % to about 125 % of 3.73 pmol/L after administration of 20 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient after administering between about 10 mg and about 80 mg (e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg) of esomeprazole (or a pharmaceutically acceptable salt thereof), the patient has an area under the concentration time curve (AUC) between about 1 pmol*h/L and about 20 pmol*h/L, including all values and ranges in between.
  • AUC concentration time curve
  • the AUC is about 0.5 pmol*h/L, about 1 pmol*h/L, about 2 pmol*h/L, about 3 pmol*h/L, about 4 pmol*h/L, about 5 pmol*h/L, about 6 pmol*h/L, about 7 pmol*h/L, about 8 pmol*h/L, about 9 pmol*h/L, about 10 pmol*h/L, about 11 pmol*h/L, about 12 pmol*h/L, about 13 pmol*h/L, about 14 pmol*h/L, about 15 pmol*h/L, about 16 pmol*h/L, about 17 pmol*h/L, about 18 pmol*h/L, about 19 pmol*h/L, or about20 pmol*h/L, including all values and ranges in between.
  • the AUC is between 80 % and 125 % of any of the aforementioned values or ranges between the aforementioned values. [0170] In some embodiments, the AUC is reported as geometric mean with a coefficient of variation (% CV). In some embodiments, the patient has a AUC ranging from 80 % to about 125 % of 12.6 pmoPh/L (42 %) after administration of 40 mg of esomeprazole (or a pharmaceutically acceptable salt thereof). In some embodiments, the patient has a AUC ranging from 80 % to about 125 % of 4.2 p oUh/L (59 %) after administration of 20 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient that is less than one year old has a AUC ranging from 80 % to about 125 % of 3.51 pmoUh/L after administration of 1 mg/kg of esomeprazole. In some embodiments, the patient that is between about 1 year old and about 5 years old has a AUC ranging from 80 % to about 125 % of 4.83 pmoUh/L after administration of 10 mg of esomeprazole (or a pharmaceutically acceptable salt thereof). In some embodiments, the patient that is between about 6 years old and about 11 years old has a AUC ranging from 80 % to about 125 % of 3.7 p oUh/L after administration of 10 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient that is between about 6 years old and about 11 years old has a AUC ranging from 80 % to about 125 % of 6.28 pmoUh/L after administration of 20 mg of esomeprazole (or a pharmaceutically acceptable salt thereof). In some embodiments, the patient that is between about 12 years old and about 17 years old has a AUC ranging from 80 % to about 125 % of 3.65 pmoUh/L after administration of 20 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient that is between about 12 years old and about 17 years old has a AUC ranging from 80 % to about 125 % of 13.86 pmoUh/L after administration of 40 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient after administering between about 10 mg and about 80 mg (e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg) of esomeprazole (or a pharmaceutically acceptable salt thereof), the patient has a time to reach Cmax (tmax) between about 0.1 hours (h) and about 4 h, including all values and ranges in between. The tmax is reported as a geometric mean.
  • the tmax is about 0.1 h, about 0.2 h, about 0.3 h, about 0.4 h, about 0.5 h, about 0.6 h, about 0.7 h, about 0.8 h, about 0.9 h, about 1 h, about 1.1 h, about 1.2 h, about 1.3 h, about 1.4 h, about 1.5 h, about 1.6 h, about 1.7 h, about 1.8 h, about 1.9 h, about 2 h, about 2.1 h, about 2.2 h, about 2.3 h, about 2.4 h, about 2.5 h, about 2.6 h, about 2.7 h, about 2.8 h, about 2.9 h, about 3 h, about 3.1 h, about 3.2 h, about 3.3 h, about 3.4 h, about 3.5 h, about 3.6 h, about 3.7 h, about 3.8 h, about 3.9 h, or about 4.0 h, including all values and range
  • the tmax is reported as geometric mean.
  • the patient has a tmax ranging from 80 % to about 125 % of 1.6 h after administration of 40 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient has a tmax ranging from 80 % to about 125 % of 1.6 h after administration of 20 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient that is less than one year old has a tmax ranging from 80 % to about 125 % of 3 h after administration of 1 mg/kg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient that is between about 1 year old and about 5 years old has a tmax ranging from 80 % to about 125 % of 1.44 h after administration of 10 mg of esomeprazole (or a pharmaceutically acceptable salt thereof). In some embodiments, the patient that is between about 6 years old and about 11 years old has a tmax ranging from 80 % to about 125 % of 1.79 h after administration of 10 mg of esomeprazole (or a pharmaceutically acceptable salt thereof). In some embodiments, the patient that is between about 6 years old and about 11 years old has a tmax ranging from 80 % to about 125 % of 1.75 h after administration of 20 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the patient that is between about 12 years old and about 17 years old has a tmax ranging from 80 % to about 125 % of 2 h after administration of 20 mg of esomeprazole (or a pharmaceutically acceptable salt thereof). In some embodiments, the patient that is between about 12 years old and about 17 years old has a tmax ranging from 80 % to about 125 % of 1.75 h after administration of 40 mg of esomeprazole (or a pharmaceutically acceptable salt thereof).
  • the half-life of esomeprazole is between about 0.1 hours (h) and about 3 h, including all values and ranges in between.
  • the ti/2 is reported as a geometric mean.
  • the ti/2 is about 0.1 h, about 0.2 h, about 0.3 h, about 0.4 h, about 0.5 h, about 0.6 h, about 0.7 h, about 0.8 h, about 0.9 h, about 1 h, about 1.1 h, about 1.2 h, about 1.3 h, about 1.4 h, about 1.5 h, about 1.6 h, about 1.7 h, about 1.8 h, about 1.9 h, about 2 h, about 2.1 h, about 2.2 h, about 2.3 h, about 2.4 h, about 2.5 h, about 2.6 h, about 2.7 h, about 2.8 h, about 2.9 h, or about 3 h, including all values and ranges in between.
  • the ti/2 is between 80 % and 125 % of any of the aforementioned values or ranges between the aforementioned values.
  • the ti/2 is reported as geometric mean. In some embodiments, the ti/2 ranges from 80 % to about 125 % of 1.5 h after administration of 40 mg of esomeprazole. In some embodiments, the ti/2 ranges from 80 % to about 125 % of 1.2 h after administration of 20 mg of esomeprazole. In some embodiments, the ti/2 in a patient that is less than one year old ranges from 80 % to about 125 % of 0.93 h after administration of 1 mg/kg of esomeprazole.
  • the ti/2 in a patient that is between about 1 year old and about 5 years old ranges from 80 % to about 125 % of 0.74 h after administration of 10 mg of esomeprazole. In some embodiments, the ti/2 in a patient that is between about 6 years old and about 11 years old ranges from 80 % to about 125 % of 0.88 h after administration of 10 mg of esomeprazole. In some embodiments, the ti/2 in a patient that is between about 6 years old and about 11 years old ranges from 80 % to about 125 % of 0.73 h after administration of 20 mg of esomeprazole.
  • the ti/2 in a patient that is between about 12 years old and about 17 years old ranges from 80 % to about 125 % of 0.82 h after administration of 20 mg of esomeprazole. In some embodiments, the ti/2 in a patient that is between about 12 years old and about 17 years old ranges from 80 % to about 125 % of 1.22 h after administration of 40 mg of esomeprazole.
  • the disclosure provides a method of treating a subject with a disease or condition that is responsive to a PPI.
  • the method comprise administering to a patient a solid disintegrating pharmaceutical composition comprising at least one PPI or a salt thereof in effective amount.
  • the PPI is esomeprazole or a pharmaceutically acceptable salt thereof, e.g., magnesium.
  • the solid disintegrating pharmaceutical composition is an ODT that contains esomeprazole magnesium.
  • the composition may be administered at any suitable regimen which treats the disease or condition.
  • the pharmaceutical composition is administered to a patient from one to five times a day.
  • the pharmaceutical composition is administered to a patient at least once a day, at least twice a day, at least three times a day, at least 4 times a day, or at least five times a day.
  • the pharmaceutical composition is administered to a patient at least one to five times a day for one week to 10 years or more.
  • the pharmaceutical composition is administered to a patient at least once a day, at least twice a day, at least three times a day, at least 4 times a day, or at least five times a day for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least ten weeks, at least fifteen weeks, at least twenty weeks, at least thirty weeks, at least forty weeks, at least fifty weeks, at least fifty-two weeks, at least sixty weeks, at least seventy weeks, at least eighty weeks, at least ninety weeks, or at least one hundred weeks or more.
  • the pharmaceutical composition is administered to a patient indefinitely.
  • the pharmaceutical composition is administered twice a day for at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, or at least about 12 weeks. In some embodiments, the pharmaceutical composition is administered twice a day during the induction and/or maintenance phase. In some embodiments, the pharmaceutical composition is administered twice a day for at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, or at least about 12 weeks during the induction phase.
  • the method comprises administering a pharmaceutical composition described herein (e.g., ODT), wherein the amount of the PPI (esomeprazole base) is 2.5 mg, 5 mg, 10 mg, 20mg, 30 mg, 40 mg, 45 mg or 60 mg per dose unit.
  • a pharmaceutical composition described herein e.g., ODT
  • the disease or condition is eosinophilic esophagitis (EoE), inflammatory EoE, EoE in early inflammatory stages of the disease, variant of EoE, or allergic variant of EoE.
  • EoE eosinophilic esophagitis
  • the patient with EoE that is treated according to the claimed method is a patient that does not respond or is not likely to respond to steroid treatment.
  • Steroid treatment includes treatment with a corticosteroid, such as fluticasone or budesonide propionate.
  • the corticosteroid is selected from the group consisting of budesonide, fluticasone, flunisolide, ciclesonide, mometasone, beclomethasone, tixocortol and salts, or esters and mixtures thereof.
  • the treatment of gastrointestinal inflammation may be measured by any means known in the art.
  • tests used to evaluate patients with this disease include, but are not limited to, biopsies, evaluation of symptoms (e.g. through patient reported outcome (PRO) or physician questionnaire), quality of life measurements, determination of Dysphagia-Free-Days in a patient, endoscopy (e.g. EREFS), esophageal compliance and/or improvement in esophageal remodeling (e.g.
  • EndoFLIP available from Crospon Inc.
  • EEsAI Strong Dysphagia Index
  • MDQ-30 decrease in food impaction
  • EoE-QOL-A decrease in food impaction
  • VDQ Vehicle Dysphagia Questionnaire
  • Avoidance Modification and Slow Eating (AMS) scores and/or histology.
  • patient response to treatment of EoE is determined by measuring changes in one or more questionnaire scores with a biological response such as histology score (e.g. eosinophil count).
  • histology score e.g. eosinophil count
  • Reliance on patient reported symptoms may yield false positive results as patients may modify their behavior to reduce incidents of dysphagia (e.g. avoiding problematic foods or other behavior modifications such as increased chewing or liquid consumption) which can alter questionnaire score regardless of whether biological symptoms have improved.
  • the response of patients with EoE is evaluated by assessing histology scores in a patient.
  • the histology score is assessed by one or more different histologic features, including but not limited to, eosinophil inflammation, basal zone hyperplasia, dilated intercellular spaces, lamina intestinal fibrosis, eosinophil abscess, surface layering, surface epithelial alteration, and dyskeratotic epithelial cells.
  • administration of the oral corticosteroid according to the methods disclosed herein for EoE treatment reduces a histology score in a treated patient compared to an untreated patient or the same patient before treatment.
  • the histology score is measured in a treated patient between week 1 and year 10.
  • administration of the pharmaceutical compositions disclosed herein reduces a histology score at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3 compared with the histology score in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces a histology score for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years, or more compared with the histology score in an untreated patient or the same patient before treatment.
  • the above described histology score is reduced by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with the histology score in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces the histology score by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3 compared with the histology score in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces the histology score by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more compared with the histology score in an untreated patient or the same patient before treatment.
  • administration of a PPI for EoE treatment reduces peak eosinophil (per high power field (HPF), in at least one biopsy in a treated patient compared to peak eosinophil per HPF in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein eeduces peak eosinophil in at least one biopsy to less than 15/HPF.
  • administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in at least one biopsy in a treated patient to less than about 14/HPF, less than about 13/HPF, less than about 12/HPF, less than about 11/HPF, less than about 10/HPF, less than about 9/HPF, less than about 8/HPF, less than about 7/HPF, less than about 6/HPF, less than about 5/HPF, less than about 4/HPF, less than about 3/HPF, less than about 2/HPF, less than about 1/HPF, or less (e.g. 0) in the patient.
  • administration of the pharmaceutical compositions disclosed herein reduce peak eosinophil in at least one biopsy to less than 1 HPF in the patient.
  • the reduction of peak eosinophil in at least one biopsy in a treated patient is measured between about week 1 and about year 10.
  • the reduction of peak eosinophil is measured at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in at least one biopsy to less than about 14/HPF, less than about 13/HPF, less than about 12/HPF, less than about 11/HPF, less than about 10/HPF, less than about 9/HPF, less than about 8/HPF, less than about 7/HPF, less than about 6/HPF, less than about 5/HPF, less than about 4/HPF, less than about 3/HPF, less than about 2/HPF, less than about 1/HPF or less (e.g.
  • administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in at least one biopsy to less than about 14/HPF, less than about 13/HPF, less than about 12/HPF, less than about 11/HPF, less than about 10/HPF, less than about 9/HPF, less than about 8/HPF, less than about 7/HPF, less than about 6/HPF, less than about 5/HPF, less than about 4/HPF, less than about 3/HPF, less than about 2/HPF, less than about 1/HPF or less (e.g. 0) in the patient for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years, or more
  • administration of the PPI according to the methods disclosed herein reduces peak eosinophil (per high power field (HPF) in at least one biopsy in a treated patient compared to peak eosinophil per HPF in an untreated patient or the same patient before treatment by at least about 10%, e.g., about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, inclusive of all values and subranges therebetween.
  • HPF peak eosinophil
  • the peak eosinophil count is reduced by an amount in the range of about 50% to about 99%, e.g., about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, inclusive of all values and subranges therebetween.
  • administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in at least one biopsy from a treated patient at week 12, week 26, or week 52. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in at least one biopsy from a treated patient to less than about 6/ HPF at week 12, week 26, or week 52. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in all tested biopsies from a treated patient at week 12, week 26, or week 52. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces peak eosinophil in all tested biopsies from a treated patient to less than about 6/HPF at week 12, week 26, or week 52.
  • administration of the pharmaceutical compositions disclosed herein reduce mean score in a patient questionnaire completed by the patient or a physician.
  • the questionnaire is Eosinophilic Esophagitis Activity Index (EEsAI), which can use either a 7-day recall period or a daily recall period to monitor the severity and frequency of dysphagia and any dietary modifications.
  • the questionnaire is Dysphagia Symptom Questionnaire (DSQ), which is a daily symptom diary used to monitor dysphagia frequency.
  • the questionnaire is a customized patient-reported outcome assessment which includes the assessment of dysphagia-free days.
  • the total score of a questionnaire such as the EEsAI or PROSE are used in combination with other patient assessments to measure patient response to treatment.
  • the correlation of questionnaire score with improvement in histological measurements indicates patient response to treatment.
  • the mean questionnaire score is measured in a treated patient with EoE between week 1 and year 10.
  • administration of the pharmaceutical compositions disclosed herein reduces the mean questionnaire score at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3 compared with the mean questionnaire score in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces the mean questionnaire score for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more compared with the mean questionnaire score in an untreated patient or the same patient before treatment.
  • the mean questionnaire score is reduced by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with the mean questionnaire score in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces the mean questionnaire score by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3 compared with the mean questionnaire score in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces the mean questionnaire score by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more compared with the mean questionnaire score in an untreated patient or the same patient before treatment.
  • the patient questionnaire is EEsAI.
  • administration of the pharmaceutical compositions disclosed herein reduces mean EEsAI score to less than 20.
  • administration of the pharmaceutical compositions disclosed herein reduces mean EEsAI score of a treated patient to less than about 19, less than about 18, less than about 17, less than about 16, less than about 15 less than about 14, less than about 13, less than about 12, less than about 11, less than about 10, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2, less than about 1, or about 0.
  • the reduction of mean EEsAI score in a treated patient is measured between about week 1 and about year 10.
  • the reduction of mean EEsAI score is measured at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • administration of the pharmaceutical compositions disclosed herein reduces mean EEsAI score to less than about 20, less than about 19, less than about 18, less than about 17, less than about 16, less than about 15, less than about
  • administration of the pharmaceutical compositions disclosed herein reduces mean EEsAI score to less than about 20, less than about 19, less than about 18, less than about 17, less than about 16, less than about 15, less than about
  • administration of the pharmaceutical compositions disclosed herein reduces mean EEsAI score in a treated patient at week 12, week 26, or week 52. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces mean EEsAI score in a treated patient to less than about 20 at week 12, week 26, or week 52. [0196] In some embodiments, administration of the pharmaceutical compositions disclosed herein reduce mean EoE Endoscopic Reference Score (EREFS) in a treated patient, which measures edema (e.g. decreased vascularity or pallot), rings present, exudates (e.g. white plaques), furrows, and/or stricture in the esophagus according to Table A. In some embodiments, the EREFS score in a patient correlates with histologic response (e.g. eosinophil count) and EREFS score can be used in conjunction with histologic response to measure patient response to treatment.
  • EREFS EoE Endoscopic Reference Score
  • the PPI compositions and methods for EoE traatment reduce the EREFS score for edema to 1 or 0.
  • the compositions and methods disclosed herein reduce the EREFS score for rings to 2, 1, or 0.
  • the compositions and methods disclosed herein reduce the EREFS score for exudates to 1, or 0.
  • the compositions and methods disclosed herein reduce the EREFS score for exudates to 1, or 0.
  • the compositions and methods disclosed herein reduce the EREFS score for furrows to 1, or 0.
  • the compositions and methods disclosed herein substantially remove strictures.
  • administration of the pharmaceutical compositions disclosed herein reduces the mean EREFS score to less than about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about 1, or about zero in a treated patient.
  • the mean EREFS score is measured in a treated patient between week 1 and year 10.
  • administration of the pharmaceutical compositions disclosed herein reduces the EREFS score at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • administration of the pharmaceutical compositions disclosed herein reduces the mean EREFS score for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more in a treated patient.
  • administration of the pharmaceutical compositions disclosed herein reduces the mean EREFS score to less than about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about 1, or about zero at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • administration of the pharmaceutical compositions disclosed herein reduces the mean EREFS score to less than about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about 1, or about zero for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more in a treated patient.
  • administration of the pharmaceutical compositions disclosed herein reduces mean EREFS score in a treated patient at about week 12, about week 26, or about week 52.
  • administration of the pharmaceutical compositions disclosed herein reduces episodes of dysphagia in a treated patient.
  • reduction of episodes of dysphagia in a treated patient is measured by determining Dysphagia-Free-Days in the patient.
  • improvement in Dysphagia-Free-Days in a patient is measured in conjunction with other patient measurements such as improved histologic scores (e.g. eosinophil counts) to measure patient response to treatment.
  • administration of the pharmaceutical compositions disclosed herein reduce dysphagia in a treated patient compared with episodes of dysphagia in an untreated subject or in the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduce episodes of dysphagia to fewer than about 6 per week. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces episodes of dysphagia to fewer than 6 per week over a time period of two weeks. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces episodes of dysphagia to fewer than about 6 per week, about 5 per week, about 4 per week, about 3 per week, about 2 per week, about one per week, or none per week.
  • administration of the pharmaceutical compositions disclosed herein reduces episodes of dysphagia to fewer than about 6 per week, about 5 per week, about 4 per week, about 3 per week, about 2 per week, about one per week, or none per week over a time period of two weeks.
  • episodes of dysphagia are reduced by up to about 100%. In some embodiments, episodes of dysphagia are reduced by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes of dysphagia in an untreated patient or the same patient before treatment. In some embodiments, dysphagia is eliminated. In some embodiments, dysphagia is assessed in a treated patient between week 1 and year 10.
  • administration of the pharmaceutical compositions disclosed herein reduces episodes of dysphagia at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • administration of the pharmaceutical compositions disclosed herein reduces dysphagia for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more compared with the number of episodes of dysphagia in an untreated patient or the patient before treatment.
  • episodes of dysphagia are reduced by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes of dysphagia in an untreated patient or the same patient before treatment at about week 1, week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • episodes of dysphagia are reduced by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes of dysphagia in an untreated patient or the same patient before treatment for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more compared with the number of episodes of dysphagia in an untreated patient or the patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces episodes of dysphagia in a treated patient at week 12, week 26, or week 52 compared with episodes of dysphagia in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces food impaction in a treated patient compared with episodes of food impaction in an untreated patient or in the same patient before treatment. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces episodes of food impaction to fewer than 4 per week. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces episodes of food impaction to fewer than 4 per week over a time period of two weeks. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces episodes of food impaction to fewer than about 4 per week, about 3 per week, about 2 per week, about one per week, or none per week.
  • administration of the pharmaceutical compositions disclosed herein reduces episodes of food impaction to fewer than about 4 per week, about 3 per week, about 2 per week, about one per week, or none per week over a time period of two weeks.
  • episodes of food impaction are reduced by up to about 100%.
  • episodes of food impaction are reduced by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes of food impaction in an untreated patient or the same patient before treatment.
  • food impaction is eliminated.
  • episodes of food impaction are assessed in a treated patient between week 1 and year 10.
  • administration of the pharmaceutical compositions disclosed herein reduces episodes of food impaction at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • administration of the pharmaceutical compositions disclosed herein reduces episodes of food impaction for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more compared with the number of episodes of food impaction in an untreated patient or the same patient before treatment.
  • episodes of food impaction are reduced by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes of food impaction in an untreated patient or the same patient before treatment at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • episodes of food impaction are reduced by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with episodes of food impaction in an untreated patient or the same patient before treatment for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more compared with the number of episodes of food impaction in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces episodes of food impaction in a treated patient at week 12, week 26, or week 52 compared with food impaction in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces Global EoE score in a treated patient compared with Global EoE score in an untreated patient or in the same patient before treatment.
  • the reduction of Global EoE score in a treated patient is measured between about week 1 and about year 10.
  • administration of the pharmaceutical compositions disclosed herein reduces Global EoE score at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3 compared with an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein reduces Global EoE score for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years compared with the Global EoE score in an untreated patient or the patient before treatment.
  • Global EoE score is reduced by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with Global EoE score in an untreated patient or the same patient before treatment commenced.
  • administration of the pharmaceutical compositions disclosed herein reduces Global EoE score by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with Global EoE score in an untreated patient or the same patient before treatment at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • administration of the pharmaceutical compositions disclosed herein reduces Global EoE score by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with Global EoE score in an untreated patient or the same patient before treatment for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years, or more.
  • Global EoE is scored on a scale of 0 to 10, with 0 representing no EoE symptoms, and 10 representing most severe EoE symptoms.
  • administration of the pharmaceutical compositions disclosed herein reduces Global EoE score in a treated subject to less than about 5. In some embodiments, administration of the pharmaceutical compositions disclosed herein reduces Global EoE score to less than about 10, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2, less than about 1, or about 0.
  • administration of the pharmaceutical compositions disclosed herein reduces Global EoE score in a treated subject to less than about 10, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2, less than about 1, or about 0 at about week 1, week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • administration of the pharmaceutical compositions disclosed herein reduces Global EoE score in a treated subject to less than about 10, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2, less than about 1, or about 0 for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years, or more.
  • administration of reduces Global EoE score in a treated patient at about week 12, about week 26, or about week 52 compared with Global EoE score in an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein improves characteristics as measured by endoscopy (e.g. EndoFlip) in a treated patient compared with an untreated patient or the same patient before treatment commenced.
  • characteristics include, but are not limited to esophagus diameter, esophageal compliance, focal narrowing of the esophagus, esophageal body distensibility, esophageal body cross-sectional areas (CSA), and intra-luminal diameter.
  • the characteristics as measured by endoscopy are assessed in a treated patient between week 1 and year 10.
  • administration of the pharmaceutical compositions disclosed herein improves characteristics as measured by endoscopy at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3 compared with an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein improves characteristics as measured by endoscopy for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more compared with an untreated patient or the same patient before treatment.
  • characteristics as measured by endoscopy are improved by up to about 100%.
  • characteristics as measured by endoscopy are improved by up to about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed herein improves characteristics as measured by endoscopy by up by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with an untreated patient or the same patient before treatment at about week 1, about week 2, about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 20, about week 30, about week 40, about week 50, about week 60, about week 70, about week 80, about week 90, about week 100, about year 1, about year 2, or about year 3.
  • administration of the pharmaceutical compositions disclosed herein improves characteristics as measured by endoscopy by up by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% compared with EndoFlip score in an untreated patient or the same patient before treatment for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 1 year, about 2 years, about 5 years, or about 10 years or more.
  • administration of the pharmaceutical compositions disclosed herein improves characteristics as measured by endoscopy in a treated patient at week 12, week 26, or week 52 compared with an untreated patient or the same patient before treatment.
  • administration of the pharmaceutical compositions disclosed reduces the number of episodes associated with EoE experienced by a patient over a period of time. Non-limiting examples of such episodes include difficulty swallowing a pill or food. The occurrence of such episodes may be reported by the patient as a feeling of discomfort after swallowing a pill or food, and may be measured after each instance of swallowing a pill or food or over a 24 hour period or more. Any method can be used to assess or report patient discomfort, including PROSE.
  • the number of episodes occurring over said period of time is reduced by at least 1 episode, at least 2 episodes, at least 3 episodes, at least 4 episodes, at least 5 episodes, at least 6 episodes, at least 7 episodes, at least 8 episodes, at least 9 episodes, at least 10 episodes, at least 11 episodes, at least 12 episodes, at least 13 episodes, at least 14 episodes, at least 15 episodes, at least 16 episodes, at least 17 episodes, at least 18 episodes, at least 19 episodes, or at least 20 episodes, least 21 episodes, at least 22 episodes, at least 23 episodes, at least 24 episodes, at least 25 episodes, at least 26 episodes, at least 27 episodes, at least 28 episodes, at least 29 episodes, or at least 30 episodes, least 31 episodes, at least 32 episodes, at least 33 episodes, at least 34 episodes, at least 35 episodes, at least 36 episodes, at least 37 episodes, at least 38 episodes, at least 39 episodes, or at least 40 episodes, least 41 episodes, at least 42 episodes, at least 43 episodes, at least 44 episodes, at least 45 episodes, at least 46 episodes, at least 47
  • the time period is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9, weeks about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 1 year, about 2 years, or about 3 years.
  • Esomeprazole rapidly disintegrating composition of the disclosure and the orally disintegrating tablet exhibiting extended release of the PPI.
  • EXAMPLE 1 20 mg Esomeprazole OPT without Magnesium Oxide
  • a secondary seal coating solution was prepared by adding Opadry Clear (76.5 g) to a solution of ethanol (1051.5g) and purified water (262.9 g) in a stainless steel container and mixed using a low shear agitator for NLT 45 minutes.
  • the microcrystalline cellulose (MCC) Celphere (CP-102: 651.8 g) was loaded into the pre-heated fluid-bed coater, Glatt GPCG-3 and airflow was adjusted to achieve adequate fluidization (see preheating parameters below, Table 1).
  • the drug layered coating suspension was sprayed while adjusting inlet temperature and airflow to achieve target bed temperature (see coating parameters below, Table 1). After 30-40 min, the spray rate was gradually increased while adjusting flow parameters to maintain the target bed temperature.
  • the seal coating solution was sprayed on to the drug layered beads and the seal coated beads were dried for 5 minutes (see coating parameters, Table 1). Then, the drug layered beads were discharged and sieved through US 50- 120 mesh sieves.
  • Table 1 Set-up of Fluid-bed Coater (Glatt GPCG 3 with Accessories and Process Parameters).
  • Machine Glatt GPCG-3 6” diameter Wurster, 18 mm partition, 16 mm tubing, 200 mesh screen; Atomization Air Pressure (bar): 1.3; Distribution Plate: C; Nozzle Height: Flush with air cap; Nozzle Tip Size: 1.2 mm Filter Shake Interval/Duration: 30sec/5sec. .2 Esomeprazole Magnesium Delayed Release (DR) Beads (70% Enteric Coated ) in Glatt GPCG3
  • Delayed Release Suspension A was prepared by adding purified water (692.3 g) and ethanol (5436.9g) to a suitable stainless steel container while mixing with a low shear agitator. Eudragit L100-55 (394.7g) was added and mixed using a low shear agitator (until visually dissolved). Dibutyl sebacate (38.7g) was added to the solution and mixed using a low shear agitator for NLT 20 minutes. Talc (100. Og) was added and the suspension is then continuously agitated using a low shear agitator. Delayed Release Suspension B is prepared as described for Suspension A above.
  • Delayed Release Suspension C was prepared by adding purified water (483.0 g) and ethanol (1932. Og) to a suitable stainless steel container while mixing with a low shear agitator.
  • Eudragit L100-55 (155.7g) was added and mixed using a low shear agitator (until visually dissolved).
  • Dibutyl sebacate (15.2g) was added to the solution and mixed using a low shear agitator for NLT 20 minutes.
  • Talc 39. lg was added and the suspension is then continuously agitated using a low shear agitator.
  • Suspension C was sprayed while adjusting inlet temperature and airflow to achieve target bed temperature using the same coating processing parameters as utilized for application of the Suspensions A and B.
  • Suspension C was sprayed in its entirety to produce 70% w/w enteric DR coated beads.
  • the esomeprazole DR beads were discharged and sieved through US 40-120 mesh sieves.
  • the DR beads obtained had an average particle size in the range of approximately 340 pm.
  • Table 2 Set-up of Fluid-bed Coater DR Coated Beads (Glatt GPCG 3 with Accessories and Process Parameters).
  • Machine Glatt GPCG-3 7” diameter Wurster, 18 mm partition, 14 mm tubing, 200 mesh screen; Atomization Air Pressure (bar): 1.5; Distribution Plate: C; Nozzle Height: Flush with air cap; Nozzle Tip Size: 1.0 mm; Filter Shake Interval/Duration: 30sec/5sec
  • the rapidly-dispersible microgranules comprising a sugar alcohol such as mannitol and a disintegrant such as crospovidone were manufactured following the procedures disclosed in U.S. patent No. 8,077,288 and 8,545,881, both of which were herein incorporated in their entirety for all purposes.
  • D-mannitol 152 kg
  • a disintegrant such as crospovidone
  • GMX 600 high shear granulator
  • the high shear granulation was passed through a Comil from Quadro, dried in a fluid-bed dryer, and again passed through the Comil to mill oversized granules.
  • the rapidly-dispersible microgranules thus obtained typically had an average particle size in the range of approximately 125-200 pm.
  • Blend A (Table 3) was prepared by adding to a 4 L bin blender half of the rapidly dispersing granules (739.5 g), followed by the DR Beads (367.1 g) described above, PRSOLV® SMCC 90, silicified microcrystalline cellulose NF (300.0 g), crospovidone (75.0 g), sucralose (3.0 g) and the remaining rapidly dispersing granules to the bin blender and blended for 25 minutes at 15 rpm. sodium stearyl fumarate (15.0 g) was then added and blended an additional 5 minutes at 15 rpm.
  • Blend B (Table 3) was prepared with the inclusion of malic acid.
  • Blend B was prepared by adding to the bin blender half of the rapidly dispersing granules (732.0 g) to a 4 L bin blender, followed by the DR Beads (367.1 g), PRSOLV® SMCC 90, silicified microcrystalline cellulose NF (300.0 g), crospovidone (75.0 g), malic acid (7.5 g), sucralose (3.0 g) and the remaining rapidly dispersing granules and blended for 25 minutes at 15 rpm. sodium stearyl fumarate (15.0 g) was then added and blended an additional 5 minutes at 15 rpm. Composition of the two blends is provided in Table 3.
  • Blend A (Table 4) and Blend B (Table 5) were tested for stability at stability conditions (45 °C, 75% RH, 3 months (40/75)). After 1 month, Blend A had 0.22% impurities, and Blend B had 0.27% impurities.
  • magnesium oxide as a pH modifying, alkaline agent
  • adding magnesium oxide (MgO) with esomeprazole in the drug coating layer significantly improved the stability of esomeprazole and the acid resistance of the formulation.
  • Formulations containing MgO are described below.
  • EXAMPLE 2 20 mg Esomeprazole ODT with Magnesium Oxide (Lead Batch)
  • Drug layered beads were prepared using the same process as described above, except that MgO was mixed with esomeprazole magnesium and applied as a part of the drug layer.
  • Purified water 5632 g was added to a suitable stainless steel container and 2.2 g of a 30% simethicone emulsion was added while mixing with a low shear agitator.
  • Hydroxypropyl cellulose KLUCELTM EF: 216g was added and mixed using a low shear agitator for not less than (NLT) 20 minutes until a clear solution is obtained.
  • esomeprazole magnesium and MgO are then added to the solution and mixed using a homogenizer for NLT 15 min.
  • the drug layered coating suspension is then continuously agitated using a low shear agitator.
  • a secondary seal coating solution was prepared by adding Opadry Clear (110 g) to a solution of ethanol (1512g) and purified water (378 g) in a stainless steel container and mixed using a low shear agitator for NLT 45 minutes.
  • the microcrystalline cellulose (MCC) Celphere (CP-203: 682 g) was loaded into the preheated fluid-bed coater, Glatt GPCG-3 and airflow was adjusted to achieve adequate fluidization (see preheating parameters below, Table 6).
  • the drug layer coating suspension was sprayed while adjusting inlet temperature and airflow to achieve target bed temperature (see coating parameters below, Table 6). After 30-40 min, the spray rate was gradually increased while adjusting flow parameters to maintain the target bed temperature. After the entire drug layer coating suspension was sprayed, the seal coating solution was sprayed on to the drug layered beads and the seal coated beads were dried for 5 minutes (see coating parameters, Table 5). Then the drug layered beads were discharged and sieved through US 40-120 mesh sieves. Table 7 shows the composition of Esomeprazole layered beads
  • Machine Glatt GPCG-3 6” diameter Wurster, 18 mm partition, 16 mm tubing, 200 mesh screen; Atomization Air Pressure (bar): 1.3 ; Distribution Plate: C; Nozzle Height: Flush with air cap; Nozzle Tip Size: 1.2 mm; Filter Shake Interval/Duration: 30sec/5sec
  • Table 7 Composition of Esomeprazole layered beads in Lead Batch .2 Esomeyr azole Magnesium Delayed Release (DR) Beads (60% Enteric Coated )
  • DR beads were prepared using the same produced as described above in Example 1.2
  • Delayed Release Suspension A was prepared by adding purified water (1380 g) and acetone (7820g) to a suitable stainless steel container while mixing with a low shear agitator.
  • Eudragit L100-55 (592g) was added and mixed using a low shear agitator (until visually dissolved).
  • Dibutyl sebacate (59.2g) was added to the solution and mixed using a low shear agitator for NLT 20 minutes.
  • Talc 148.6g was added and the suspension was continuously agitated using a low shear agitator.
  • Delayed Release Suspension B was prepared by adding purified water (327 g) and acetone (1855.3g) to a suitable stainless steel container while mixing with a low shear agitator.
  • Eudragit L100-55 140.5g was added and mixed using a low shear agitator (until visually dissolved).
  • Dibutyl sebacate 14g was added to the solution and mixed using a low shear agitator for NLT 20 minutes.
  • Talc (35.3 lg) was added and the suspension is then continuously agitated using a low shear agitator.
  • Table 8 Set-up of Fluid-bed Coater DR Coated Beads (Glatt GPCG 3 with Accessories and Process Parameters)
  • Table 9 Composition of Esomeprazole DR beads .3 Manufacture of Rapidly-Dispersing Microgranules
  • a blend of DR Beads and rapidly dispersing microgranules was prepared by adding half of the rapidly dispersing granules (739.5 g) to a 4 L bin blender, followed by the esomeprazole DR Beads (367.1 g) described above, PROSOLV® SMCC 90, silicified microcrystalline cellulose NF (300.0 g), crospovidone (75.0 g), sucralose (3.0 g) and the remaining rapidly dispersing granules to the bin blender and blended for 25 minutes at 15 rpm. Sodium stearyl fumarate (15.0 g) was then added and blended an additional 5 minutes at 15 rpm.
  • the composition of the ODT is shown in Table 10.
  • the blend was compressed on a Fette 52i rotary press, set up for 4 Station operation (1/4 tooled) utilizing a power feed frame, 1” mono cams and a 10 mm fill cam
  • the fill depth was adjusted to achieve a target tablet weight of 675 mg to produce tablets containing 20 mg of esomeprazole (22.3 mg esomeprazole magnesium). Both pre-compression and main compression forces were adjusted to achieve tablets with an average crushing strength of 38 N.
  • EXAMPLE 3 Comparative Esomeprazole ODT with Functional Layer Over Enteric Layer [0245] A comparative ODT was prepared following the protocol described above in Example 2. This comparative ODT contained an additional functional layer over the enteric layer.
  • the esomeprazole layered beads in the comparative ODT contained 45.0% esomeprazole magnesium and 9% magnesium oxide.
  • esomeprazole layered beads were then coated with 37% Eudragit® L100-55, 9.3% Talc, 3.7% dibutyl sebacate to form DR beads.
  • a functional coating of 15.0% of polyethylene glycol 6000 was applied over the DR beads.
  • the ODT was prepared using 21.48% w/w DR beads, 51.22% rapidly dispersing microgranules, 20% PROSOLV® SMCC 90, 5% crospovidone, 1% malic acid, 0.3% sucralose, and 1% sodium stearyl fumarate.
  • EXAMPLE 4 Various testing on ODT of the described herein (Lead Batch), Comparative ODT, marketed Dexcel Omeprazole ODT, marketed DR capsule by Nexium
  • Table 12a Impurity Results for Esomeprazole ODT with Magnesium Oxide- Lead Batch; conditions: 75% relative humidity, 60°C for 72hrs
  • Dissolution testing was carried out according to USP Esomeprazole DR Capsule Monograph Dissolution Test 1. ODTs were placed in 300 mL 0. IN HC1 for 2 hours followed by the addition of 700 mL of 6.8 buffer for 30 minutes. Two dissolution tests were run (Assay 1 and Assay 2).
  • EXAMPLE 5 Sensory testing of 20 mg Esomeprazole Strawberry ODT (contains malic acid), 20 mg Esomeprazole Peppermint ODT (does not contain malic acid) and 20 mg Omeprazole GoodSense Delayed Release ODT Strawberry
  • Esomeprazole Peppermint ODT tested here was prepared as described above, it contained the following ingredients: Esomeprazole Mg trihydrate, methacrylic acid copolymer, hydroxypropyl cellulose, mannitol, silicon dioxide, crospovidone, microcrystalline cellulose, Opdry, Polysorbate 80, dibutyl sebacate, sucralose, MgOxide, talc, sodium stearyl fumarate, nature peppermint flavor.
  • Esomeprazole Strawberry ODT tested here was prepared as described above, it contained the following ingredients: Esomeprazole Mg trihydrate, methacrylic acid copolymer, hydroxypropyl cellulose, mannitol, silicon dioxide, crospovidone, microcrystalline cellulose, Opdry, Polysorbate 80, dibutyl sebacate, sucralose, MgOxide, talc, sodium stearyl fumarate, malic acid, nature/ artificial strawberry flavor.
  • the sensory panelists evaluated all samples using the Flavor Profile Methods of Descriptive Sensory Analysis (Keane, P. The Flavor Profile Method. In C. Hootman (Ed.), Manual on Descriptive Analysis Testing for Sensory Evaluation ASTM Manual Series: MNL 13. Baltimore, MD. (1992)).
  • the Flavor profile is used to identify, characterize and quantify the sensory attributes of products, e.g. basic tastes, texture, mouthfeel.
  • Amplitude initial overall perception of the balance and fullness of a flavored product, considering the appropriateness of aromas and flavor notes present, their blend and intensity and existence of off-notes. Scale: 0: none, 1: low, 2: moderate, 3: strong. Amplitude is an overall measure of the quality of the initial flavor and has been shown to correlate with patient palatability and acceptance. An amplitude of 1 1 ⁇ 2 is appropriate for most drug products [0264] Character notes: aromatics, basic tastes and feeling factors (listed in order of appearance along with a measurement of strength) intensity scale: 0: none, 1: slight, 2: moderate, 3: strong. [0265] After Taste: measurement of all sensation remaining at selected time intervals [0266] The Flavor Leadership Criteria (L.B.
  • the Taste Profiling Procedure comprises the following steps: 1) The panelists cleansed their palates with spring water and unsalted crackers. 2) One ODT was dispensed to each panelist. 3) Starting at the same time, panelists placed the tablet on top of tongue and rolled in the mouth until the point at which the panelist normally would have swallowed. The material left in the mouth was then expectorated and the disintegration time was recorded. 4) The panelists then independently evaluated and recorded the initial and aftertaste characteristics at periodic intervals up to 30 minutes as flavor persisted. 5) The panelists recited their individual results and a preliminary Flavor Profile was generated for the sample. 6) Steps 1 through 4 were repeated for a second sample using the preliminary Flavor Profile from Step 5 as a guide, with the anelists making any necessary modifications. 7) The panelists recited their individual results and a final Flavor
  • the three ODTs had noticeable particles upon disintegration, resulting in a gritty texture.
  • GoodSense ODT was considerably rougher and had larger particles, of similar size to sand.
  • a delayed release solid disintegrating pharmaceutical composition comprising at least one Proton Pump Inhibitor (PPI) or a pharmaceutically acceptable salt thereof, and magnesium oxide.
  • PPI Proton Pump Inhibitor
  • a delayed release solid orally disintegrating pharmaceutical composition comprising at least one Proton Pump Inhibitor (PPI) or a pharmaceutically acceptable salt thereof, and magnesium oxide.
  • PPI Proton Pump Inhibitor
  • composition of embodiment 1, comprising Delayed Release (DR) particles which comprise at least one PPI, and magnesium oxide.
  • DR Delayed Release
  • composition of embodiment 1, wherein the PPI is esomeprazole, omeprazole, lansoprazole, pantoprazole, or rabeprazole, or any pharmaceutically acceptable salts thereof.
  • composition of embodiment 1, wherein the PPI is esomeprazole magnesium.
  • composition of embodiment 3, where the DR particles comprise at least one PPI and magnesium oxide and has at least one coating layer comprising an enteric polymer.
  • composition of embodiment 3, wherein the DR particles comprise an inert core, a layer of PPI and magnesium oxide disposed on the core and at least one coating layer comprising an enteric polymer over the PPI layer.
  • composition of embodiment 2 which is in the form of orally disintegrating tablet (ODT).
  • composition of embodiment 3, wherein the DR particles comprise an inert core, a layer of PPI and magnesium oxide together with binder disposed on the core and at least one coating layer comprising an enteric polymer over the PPI- binder layer.
  • composition of embodiment 9 wherein the binder is selected from the group of hydrophilic hydroxypropylcellulose such as Klucel LF, Klucel EF, Eudragit L100-55, HPMCAS, or an aqueous acrylic system (such as AcrylEze).
  • hydrophilic hydroxypropylcellulose such as Klucel LF, Klucel EF, Eudragit L100-55, HPMCAS, or an aqueous acrylic system (such as AcrylEze).
  • composition of embodiment 3, wherein the DR particles comprise an inert core, a layer of PPI and magnesium oxide together with binder disposed on the core, a seal layer polymer disposed over the PPI layer, and at least one coating layer comprising an enteric polymer over the seal layer polymer.
  • composition of embodiment 11, wherein the seal layer polymer may be selected form the group of hydroxypropylcellulose (e.g., KLUCEL ® LF), hydroxypropyl methylcellulose or hypromellose (e.g., OP ADR Y ® CLEAR or PHARMACO ATTM 603), low- viscosity ethylcellulose, or mixtures thereof.
  • hydroxypropylcellulose e.g., KLUCEL ® LF
  • hydroxypropyl methylcellulose or hypromellose e.g., OP ADR Y ® CLEAR or PHARMACO ATTM 603
  • low- viscosity ethylcellulose e.g., OP ADR Y ® CLEAR or PHARMACO ATTM 603
  • composition of embodiment 3, wherein the DR particle is a granulated-extruded- spheronized particle that comprises at least one PPI, one or more polymeric binder and one coating layer comprising an enteric polymer.
  • compositions of embodiment 6, wherein the enteric polymer is selected from the group of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS LG, MG or HG), polyvinyl acetate phthalate, pH- sensitive methacrylic acid/methylmethacrylate copolymers, shellac, and mixtures thereof.
  • composition of embodiment 3, wherein the DR particle comprises about 10 to 20% by weight, preferably about 15% of esomeprazole or a salt thereof based on the total weight of the DR particle.
  • composition of embodiment 3 comprising Delayed Release (DR) particles which comprise at least one PPI and at least one additional pharmaceutically acceptable excipient which swell, dissolve or otherwise facilitate disintegration of the composition.
  • DR Delayed Release
  • composition of embodiment 16 comprising Delayed Release (DR) particles which comprise at least one PPI and rapidly-dispersing granules.
  • DR Delayed Release
  • composition of embodiment 18, wherein the rapidly-dispersing granules comprise at least one disintegrant and a sugar alcohol or a saccharide and the ratio of sugar alcohol and / or saccharide to disintegrant is varying from about 90/10 to about 99/1, preferably ratio sugar alcohol: disintegrant is 95:5.
  • composition of embodiment 17, wherein the DR particles and the rapidly-dispersing granules are in the ratio of about 6/1 to about 1/2, more preferably from about 2/1 to about 1/1.
  • composition of embodiment 16 wherein the additional pharmaceutically acceptable excipient which swell, dissolve or otherwise facilitate disintegration of the composition is a disintegrant. 22. The composition of embodiment 16, wherein the additional pharmaceutically acceptable excipient which swell, dissolve or otherwise facilitate disintegration of the composition is a gas generating system.
  • PPI esomeprazole base
  • composition of embodiment 23 in the form of an orally disintegrating tablet for a twice- a-day administration is provided.
  • composition of embodiment 2 which disintegrates in the oral cavity of an individual in less than about 60 seconds or less, or preferably less than about 20 seconds or it disintegrate in less than about 60 second, preferably less than 20 seconds as measured using the USP ⁇ 701> Disintegration Test.
  • composition of embodiment 2 which releases not less than 80%(84-96) of the dose in 20 minutes when tested for dissolution using USP Test-1 Paddle, 100RPM, Stage-1 : 300 mL 0. IN HC1 (2h)Stage-2: Add 700 mL of 0.086M dibasic sodium phosphate to make pH 6.8 (30 minute); of USP Test-2 :Paddle, 100RPM, Stage-1: 300 mL 0.1N HC1 (2h), Stage-2: transfer the beads to a 1000 mL VF and Assay.
  • a process for preparing delayed release solid disintegrating pharmaceutical compositions comprising at least one Proton Pump Inhibitor (PPI) or a salt thereof comprising: a) preparing the delayed release particles comprising: inert core, Esomeprazole disposed over the core, optional seal coating, and enteric coating disposed over the esomeprazole layer; b) blending the particles of step a) with excipient and/ or rapidly dispersing granules; c) compressing into tablets the mixture of step b).
  • PPI Proton Pump Inhibitor
  • a method of treating a subject with illnesses comprising administering a solid orally disintegrating pharmaceutical composition comprising at least one Proton Pump Inhibitor (PPI) or a salt thereof in effective amount.
  • PPI Proton Pump Inhibitor

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Abstract

La divulgation concerne des compositions pharmaceutiques à libération retardée comprenant au moins un inhibiteur de pompe à protons (PPI), ou un de ses sels pharmaceutiquement acceptables, de l'oxyde de magnésium et un ou plusieurs polymères entériques. Selon certains modes de réalisation, le PPI, ou son sel pharmaceutiquement acceptable, et l'oxyde de magnésium sont présents sous la forme d'un mélange, et la quantité de PPI, ou de son sel pharmaceutiquement acceptable dans le mélange est supérieure ou égale à la quantité d'oxyde de magnésium (MgO) dans le mélange.
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Cited By (1)

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US11684571B2 (en) 2016-08-18 2023-06-27 Ellodi Pharmaceuticals, L.P. Methods of treating eosinophilic esophagitis

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US20120128764A1 (en) * 2009-02-23 2012-05-24 Aptalis Pharmatech, Inc. Controlled-release compositions comprising a proton pump inhibitor
US20140328861A1 (en) * 2011-12-16 2014-11-06 Atopix Therapeutics Limited Combination of CRTH2 Antagonist and a Proton Pump Inhibitor for the Treatment of Eosinophilic Esophagitis
US8932596B2 (en) * 2009-09-07 2015-01-13 Dbv Technologies Method of treating eosinophilic esophagitis
US20150209432A1 (en) * 2012-07-26 2015-07-30 Lupin Limited Pharmaceutical compositions of proton pump inhibitor

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US20120128764A1 (en) * 2009-02-23 2012-05-24 Aptalis Pharmatech, Inc. Controlled-release compositions comprising a proton pump inhibitor
US8932596B2 (en) * 2009-09-07 2015-01-13 Dbv Technologies Method of treating eosinophilic esophagitis
US20140328861A1 (en) * 2011-12-16 2014-11-06 Atopix Therapeutics Limited Combination of CRTH2 Antagonist and a Proton Pump Inhibitor for the Treatment of Eosinophilic Esophagitis
US20150209432A1 (en) * 2012-07-26 2015-07-30 Lupin Limited Pharmaceutical compositions of proton pump inhibitor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11684571B2 (en) 2016-08-18 2023-06-27 Ellodi Pharmaceuticals, L.P. Methods of treating eosinophilic esophagitis
US11896710B2 (en) 2016-08-18 2024-02-13 Ellodi Pharmaceuticals, L.P. Methods of treating eosinophilic esophagitis

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