CLIAMS:We Claim:
1. A delayed release pharmaceutical formulation comprising omeprazole or its pharmaceutically acceptable salt in multi-particulate form and inactive particulates.
2. The delayed release pharmaceutical formulation according to claim 1, wherein the delayed release pharmaceutical formulation is in the form of sachet.
3. The delayed release pharmaceutical formulation according to claim 1 wherein the particulate comprises powder, granules or pellets.
4. The delayed release pharmaceutical formulation according to claim 1 wherein multi-particulates are in enteric coated pellets; wherein enteric coated pellets comprises
a) inert pellets
b) at least one seal coating layer of hydrophilic or hydrophobic materials
c) omeprazole or its pharmaceutically acceptable salt layer
d) at least one subcoating of hydrophilic or hydrophobic materials
e) at least one enteric coating
5. The delayed release pharmaceutical formulation according to claim 4 wherein hydrophobic materials for coating are ethyl celluloses, low substituted hydroxylpropyl celluloses, cellulose acetates, cellulose propionates, cellulose acetate propionates, cellulose acetate butyrates, cellulose acetate phthalates, polyalkyl methacrylates, polyalkyl acrylates, crosslinked vinylpyrrolidone polymers, and hydrogenated castor oil.
6. The delayed release pharmaceutical formulation according to claim 4 wherein hydrophilic materials for coating are copolymers of N-vinylpyrrolidone, hydroxypropyl methylcellulose, vinyl and acrylic polymers, and polyacrylic acid.
7. The delayed release pharmaceutical formulation according to claim 4 wherein enteric coating materials are methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, and shellac.
8. A process of preparing a delayed release pharmaceutical formulation comprising the steps of:
a) Seal coating the inert pellets with a solution or suspension comprising at least one pharmaceutical acceptable excipient and water;
b). Applying coating on the seal coat with a solution or suspension comprising omeprazole or its pharmaceutically acceptable salts, at least one pharmaceutical acceptable excipient and water;
c). Sub coating the drug loaded pellets with a solution or suspension comprising at least one pharmaceutical acceptable excipient and water;
d). Enteric coating the sub coated pellets with a solution or suspension comprising at least one enteric coating material, at least one pharmaceutical acceptable excipient and water;
e). Optionally lubricating the pellets;
f). Mixing the pellets with inactive particulate and filling in the sachets.
9. A delayed release pharmaceutical formulation and process for the preparing pharmaceutical formulation substantially as herein described and illustrated by examples herein.
,TagSPECI:Aspects of the present application relate to delayed release pharmaceutical formulations comprising omeprazole or its pharmaceutically acceptable salts, esters, hydrates, solvates, derivatives, or single enantiomers thereof, processes of preparation, and methods of using such compositions for the treatment of diseases and disorders. In particular aspects, the present application relates to multi-particulate systems comprising omeprazole magnesium comprised in a sachet, and processes for preparing the same.
The drug compound having the adopted name “omeprazole magnesium” has a chemical name 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt (2:1).
Omeprazole is categorized as a proton pump inhibitor and is indicated for the treatment of duodenal ulcer and gastric ulcer in adults and for treatment of gastroesophageal reflux disease (GERD) in adults and children, and maintenance of healing of erosive esophagitis.
Omeprazole magnesium is the active ingredient in commercial products, including those sold as Prilosec® for Delayed-Release Oral Suspension.
Indian Patent No. 2959/DEL/1997 of Astra Aktiebolag discloses a stable oral enteric coated composition containing a core material comprising the magnesium salt of omeprazole.
Indian Patent No. 182618 of Astra discloses a process for preparation of enteric coated pharmaceutical formulation containing magnesium salt of omeprazole.
Indian Patent No. 4584/DELNP/2007 of AstraZeneca AB discloses an oral pharmaceutical dosage form; suitable for making a suspension comprising an acid sensitive proton pump inhibitor as the active ingredient distributed in a multitude of enteric coated pellets and a granulate comprising a diluent, gelling agent, binder and disintegrant.
International Patent Application Publication No. WO 95/01977 of Astra Aktiebolag discloses magnesium omeprazole, characterized in having a degree of crystallinity which is higher than 70% as determined by X-ray powder diffraction.
International Patent Application Publication No. WO 2005/007117 of Santarus, Inc. discloses a pharmaceutical formulation in the form of a powder for suspension, comprising an acid-labile proton pump inhibitor in micronized form, an antacid, and a suspending agent.
International Patent Application Publication No. WO 2006/031256 A1 of Santarus, Inc discloses a method of treating or preventing nocturnal GERD symptoms in a patient in need thereof, by administering a pharmaceutical composition comprising a proton pump inhibitor and a buffering agent.
India Patent 1354/DEL/1998 of AstraZeneca AB discloses an enteric coated oral pharmaceutical formulation, wherein the active ingredient is present in a core and on the said core material a separating layer and a drug release modifying layer is present, wherein HPMC is used as a binding agent and/or a constituent of the separating layer.
International Patent Application Publication No. WO 1996/001623 A1 of Astra discloses the use of HPMC as a binder in omeprazole compositions.
Oral liquid dosage forms have long been recognized as an alternative to orally administrable solid dosage forms that pose difficulties in swallowing, especially in children and elderly patients.
Proton pump inhibitors are, however, susceptible to degradation and/or transformation in acidic and neutral media. The degradation is catalyzed by acidic compounds and is stabilized in mixtures with alkaline compounds.
There remains a need for preparing stable pharmaceutical formulations comprising omeprazole magnesium which are easy to prepare, and which are devoid of the swallowing difficulties associated with orally administrable solid dosage forms.

SUMMARY
In aspects, the present application relates to pharmaceutical formulations comprising omeprazole or its pharmaceutically acceptable salts, esters, hydrates, solvates, derivatives, or single enantiomers thereof. In embodiments, pharmaceutical formulations of the present application comprise omeprazole magnesium in delayed release form.
In embodiments, delayed release omeprazole magnesium may be formulated in the form of multi-particulates to be filled in sachets.
In embodiments, the invention relates to preparation of dosage forms prior to administration. The contents of sachets are emptied into a predefined volume of aqueous vehicle to form a suspension.
In embodiments, the present invention provides a delayed release pharmaceutical formulation comprising Omeprazole or its pharmaceutically acceptable salts wherein Omeprazole or its pharmaceutically acceptable salts is present in the form of multi-particulates; and inactive particulates, wherein the inactive particulates are devoid of a binder; and wherein the composition is filled in sachets.
Aspect of the invention provides pharmaceutical formulation comprising enteric coated pellets comprising omeprazole, inactive particulate comprising a diluent, a thickening agent and other pharmaceutically acceptable excipients and wherein the inactive particulate is devoid of a binder.
In aspects, the pharmaceutical formulation containing omeprazole pellets and inactive particulate are constituted with water to form a suspension and are given by oral, nasogastric or direct gastric administration.
Embodiments of the present invention provide pharmaceutical formulations comprising enteric coated pellets, wherein the enteric coated pellets comprise cores having a seal coating comprising a cellulose derivative; omeprazole magnesium layer optionally comprising an alkalizer over the seal coating; one or more subcoating comprising hydrophilic or hydrophobic materials over the drug layer followed by a coating comprising a drug release modifying polymer and optionally, a seal coating layer covering the release modifying layer.
In embodiments, a seal coating that is provided between omeprazole magnesium and a core comprises hydrophilic or hydrophobic materials, or combinations thereof.
In embodiments, one or more sub-coatings that prevent direct contact between omeprazole magnesium and the drug release modifying layer comprises hydrophilic or hydrophobic materials, or combinations thereof.
In embodiments, a seal coating may be present in amounts of about 1% to about 15% by weight of a pellet.
In embodiments, one or more sub-coatings may be present in amounts of about 5% to about 30% by weight of a pellet.
In embodiments, the present invention relate to pharmaceutical formulations comprising inactive particulate that comprises a diluent, a thickening agent, a pH modifier, a disintegrant and optionally a colorant and a flavor, and wherein the inactive particulate is devoid of a binder.
In embodiments, omeprazole magnesium delayed release pellets and inactive particulate are filled together into sachet.
In embodiments, the present application provides processes for preparing omeprazole magnesium delayed release pellets and inactive particulate compositions.
In embodiments, the present application provides processes for preparing pharmaceutical formulations comprising omeprazole magnesium delayed release pellets and inactive particulate compositions, optionally alongwith one or more pharmaceutically acceptable excipients.
In embodiments, pharmaceutical formulations comprise delayed release compositions containing omeprazole magnesium, wherein not more than about 20% of labeled amount of omeprazole magnesium is released in 0.1N HCL in 2 hours in Acid stage and not less than about 50% of labeled amount of omeprazole magnesium is released in pH 6.8 phosphate buffer in 45 minutes in Buffer stage, when subjected to in vitro dissolution study.
In embodiments, omeprazole magnesium formulations of the present application are used for treatment of duodenal ulcer and gastric ulcer in adults and for treatment of gastroesophageal reflux disease (GERD) in adults and children and maintenance of healing of erosive esophagitis.
In embodiments, omeprazole magnesium formulations of the present application are bioequivalent to Prilosec® Delayed-Release Oral Suspension packets.
DETAILED DESCRIPTION
In aspects, the present invention relates to pharmaceutical formulations comprising omeprazole or its pharmaceutically acceptable salts, esters, hydrates, solvates, derivatives, or single enantiomers thereof. In embodiments the pharmaceutical formulations of the present application comprise omeprazole magnesium in delayed release form.
The term “omeprazole” as used herein this application refers to any of omeprazole, and its pharmaceutically acceptable salts, esters, hydrates, solvates, derivatives, or single enantiomers thereof.
Delayed release omeprazole magnesium may be formulated in the form of multi-particulates to be filled in sachets. In various embodiments, multi-particulates according to the present application may be in the form of granules, pellets, spheroids, extrudates, mini-tablets, and the like.
In embodiments, the present invention provides a delayed release pharmaceutical formulation comprising Omeprazole or its pharmaceutically acceptable salts wherein Omeprazole or its pharmaceutically acceptable salts is present in the form of multi-particulates; and inactive particulates wherein, the inactive particulates are devoid of a binder; and wherein the composition is filled in sachets.
The term “inactive particulates” according to the present invention refer to a composition comprising one or more pharmacologically inactive pharmaceutically acceptable excipients, but not the active agent. The “inactive particulates” are in the form of multi-particulates such as pellets, granules or powder.
Embodiments of the present application relate to pharmaceutical formulations containing omeprazole magnesium, which comprise a core having a seal coating, an omeprazole magnesium-containing layer thereupon, covered with a subcoating layer, followed by a coating comprising an enteric polymer and, optionally, an outermost seal coating layer. In one aspect of the same embodiment, the omeprazole magnesium-containing layer includes an alkalizer.
In aspects, the application relates to pharmaceutical formulations in the form of sachets. In embodiments, the application relates to preparation of a dosage form prior to administration. The contents of the sachets can be emptied into a predefined volume of an aqueous vehicle to form a suspension.
Aspects of the application provide pharmaceutical formulations comprising enteric coated pellets comprising omeprazole, further comprising a diluent, a thickening agent, and other pharmaceutically acceptable excipients.
In embodiments, when a dosage form of the invention in the form of sachet is to be administered to the patient, the contents of the sachet are suspended in an aqueous vehicle. The contents get quickly dispersed in the vehicle and provide a homogeneous suspension in a reproducible manner with regard to the distribution of the solid particles containing the pharmacologically active ingredient in the aqueous vehicle. This ensures that a uniform dose of the active agent is provided to a subject every single time upon administration.
In the context of the present application, the term “core” refers to pharmacologically inert particles that may be in the form of multi-particulates such as beads, spheroids, granules, pellets, powder, mini-tablets and the like.
In the context of the present application, the terms “layer,” or “coating,” or “deposit”, unless otherwise stated, are used synonymously.
Embodiments of the present application relate to pharmaceutical formulations, comprising: cores having a seal coating comprising a cellulose derivative; an omeprazole magnesium-containing layer optionally comprising an alkalizer over the seal coating; one or more sub-coatings comprising hydrophilic or hydrophobic materials over the drug layer; an outer coating comprising a drug release modifying substance; and optionally, a seal coating layer covering the drug release modifying coating.
In embodiments, a seal coating that prevents direct contact between omeprazole magnesium and a core comprises a cellulose derivative, optionally with other hydrophilic or hydrophobic materials, or combinations thereof. A seal coating can be formed as one or more layers of pharmaceutically acceptable excipients.
In embodiments, a core is coated with a seal coating and then layered with an omeprazole magnesium coating. In embodiments, more than one seal coating between the core and the omeprazole magnesium layer are also contemplated as being within the scope of the present application.
Aspect of the present application provides delayed release pharmaceutical formulation, wherein multi-particulates are in enteric coated pellets; wherein enteric coated pellets comprises
a) inert pellets b) at least one seal coating layer of hydrophilic or hydrophobic materials c) omeprazole or its pharmaceutically acceptable salt layer d) at least one subcoating of hydrophilic or hydrophobic materials e) at least one enteric coating.
An aspect of the present application provides processes for preparing pharmaceutical formulations of the application, embodiments comprising:
a) providing an intermediate layer coating over cores, optionally with other pharmaceutically acceptable excipients, using techniques such as powder coating, spray coating, dip coating, fluidized bed coating, and the like;
b) providing omeprazole magnesium coating, optionally with an alkalizer and other pharmaceutically acceptable excipients, over the intermediate layer;
c) providing subcoating layer, optionally with other pharmaceutically
acceptable excipients, over the drug layer;
d) providing a coating of a drug release modifying substance, such as a cellulose polymer, cellulose phthalate polymer or a derivative thereof, methacrylic acid alkyl ester or a copolymer thereof, and the like, including any mixtures thereof;
e) optionally, providing a seal coating of one or more of hydrophilic or hydrophobic polymers;
f) optionally, lubricating the pellets; and;
g) mixing the pellets with pharmacologically inactive particulates wherein the inactive particulates are devoid of a binder, and filling into a sachet, optionally with other pharmaceutically acceptable excipients.
Aspect of the present application provides process of preparing a delayed release pharmaceutical formulation comprising the steps of:
a) Seal coating the inert pellets with a solution or suspension comprising at least one pharmaceutical acceptable excipient and water;
b). Applying coating on the seal coat with a solution or suspension comprising omeprazole or its pharmaceutically acceptable salts, at least one pharmaceutical acceptable excipient and water;
c). Sub coating the drug loaded pellets with a solution or suspension comprising at least one pharmaceutical acceptable excipient and water;
d). Enteric coating the sub coated pellets with a solution or suspension comprising at least one enteric coating material, at least one pharmaceutical acceptable excipient and water;
e). Optionally lubricating the pellets;
f). Mixing the pellets with inactive particulate and filling in the sachets.
In embodiments of the present application, seal coated cores can be layered or coated with omeprazole magnesium by layering omeprazole magnesium as a powder, suspension, or solution, with or without a binder, such as by using a fluid bed processor.
"Pharmaceutically acceptable salt," or "salt," includes, for example, a salt of omeprazole prepared with formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, or 2-hydroxyethanesulfonic acids.
Acid addition salts can be prepared from the free base using conventional methodology involving reacting the free base with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Acid addition salts of omeprazole can be halide salts, which are prepared using hydrochloric or hydrobromic acids.
Omeprazole basic salts include alkali metal salts, alkaline earth metal salts, and transition metal salts. Salt forms of omeprazole include, e.g., omeprazole sodium and omeprazole magnesium.
Cores that are useful in the context of present application include, but are not limited to: water-soluble cores such as sugar spheres, lactose, starch, organic acids such as tartaric acid, citric acid, ascorbic acid, malic acid, succinic acid, and the like; and water-insoluble cores such as microcrystalline cellulose, silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, and the like. Mixtures of any two or more compounds thereof are also contemplated.
Various materials that may be used for seal coating include, but are not limited to: hydrophilic materials such as homopolymers or copolymers of N-vinylpyrrolidone, cellulose derivatives such as hydroxypropyl methylcelluloses, vinyl and acrylic polymers, polyacrylic acid, and the like; hydrophobic substances such as cellulose derivatives like ethyl celluloses, low substituted hydroxylpropyl celluloses (L-HPC), cellulose acetates, cellulose propionates (lower, medium, or higher molecular weight), cellulose acetate propionates, cellulose acetate butyrates, cellulose acetate phthalates; polyalkyl methacrylates; polyalkyl acrylates; crosslinked vinylpyrrolidone polymers; hydrogenated castor oil; and the like. Other classes of coating substances, and their mixtures in various ratios, are also within the purview of this application without limitation.
The seal coating layer may be coated over the cores using techniques such as powder coating, spray coating, dip coating, fluidized bed coating, and the like, or a combination of such techniques.
In embodiments of the present application, a seal coating comprises one or more layers of different hydrophilic or hydrophobic materials, or combinations thereof.
In embodiments the omeprazole magnesium coating comprises an alkalizer such as calcium carbonate, calcium acetate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, sodium bicarbonate, sodium borate, sodium carbonate, ammonium carbonate, diethanolamine, monoethanolamine, sodium phosphate dibasic, trolamine, magnesium carbonate, magnesium oxide and the likes, or mixtures thereof. The alkalizer further helps to improve the stability of the pharmaceutical formulation by preventing omeprazole magnesium from reacting with the enteric polymer.
In embodiments one or more “separating or subcoating layers” can be applied to the core material by coating or layering procedures in suitable equipment such as coating pans, coating granulators, and fluidized bed apparatus, using water and/or organic solvents for the coating process. As an alternative, the separating layer or layers can be applied to a core material using powder coating techniques. The materials for separating layers are pharmaceutically acceptable compounds such as, for instance, sugar, polyethylene glycol, polyvinylpyrrolidones, polyvinyl alcohols, polyvinyl acetates, hydroxypropyl celluloses, methyl-celluloses, ethylcelluloses, hydroxypropyl methylcelluloses, carboxymethylcellulose sodium, and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, fumed silica, talc, and other additives may also be included in a separating layer.
In embodiments, a drug release modifying layer is applied onto the core material covered with a separating layer, using a suitable coating technique. A drug release modifying polymer may be dispersed or dissolved in water or in a suitable organic solvent. As drug release modifying polymers, one or more, separately or in combination, of the following can be used: solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac, and other suitable drug release modifying layer polymers.
Various pharmaceutically acceptable excipients that may be used as drug release modifying substances include, but are not limited to, cellulosic polymers such as hydroxypropylmethyl cellulose phthalates, hydroxypropylcellulose phthalates, hydroxypropyl methylcellulose hexahydrophthalates, cellulose acetate phthalates, cellulose ester-ether phthalates, alkali salts of cellulose acetate phthalates, alkaline earth salts of cellulose acetate phthalates, cellulose acetate hexahydrophthalates, acrylic acid polymers and copolymers, such as methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl esters; copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate with a terpolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride, such as Eudragit? RS, Eudragit? S100, Eudragit? L100, etc., vinyl polymers and copolymers such as polyvinyl acetates, polyvinyl acetate phthalates, vinyl acetate crotonic acid copolymers and ethylene-vinyl acetate copolymers, shellac, ammoniated shellac, shellac-acetyl alcohol and shellac n-butyl stearate and the like, and any mixtures thereof. Other classes of polymers, copolymers of these polymers, and their mixtures in various ratios as desired are within the scope of this application without limitation.
Many of the drug release modifying substances are generally insoluble in acidic environments such as gastric fluids, but are soluble in higher-pH environments such as the duodenum and lower areas of the gastrointestinal tract. These enteric polymers thus delay release of the drug substance contained inside a dosage form, by preventing contact of the drug-containing compositions and fluids until higher-pH conditions are encountered. By selecting appropriate polymers, drug release from a dosage form can be obtained in a desired portion of the digestive system.
The drug release modifying layers can contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers include, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, triethyl citrate, cetyl alcohol, polyethylene glycols, polysorbates, and other plasticizers.
In embodiments, a pharmacologically inactive particulate comprises a diluent, a thickening agent, a pH modifier, a disintegrant, and optionally, a colorant and/or a flavor. In embodiments, the inactive particulate is devoid of a binder.
According to embodiments, an inactive particulate is manufactured by a process in which a diluent, a thickening agent, a pH modifier, a disintegrant are mixed and granulated together, and thereafter dried and wherein the inactive particulate contains a binder.
In embodiments, the moisture content of the formulation comprising pellets of omeprazole magnesium and inactive particulate, measured as loss on drying, is about 0.1-5% (w/w), or 0.5-3% (w/w).
In embodiments when the contents of the formulation in the form of a sachet are suspended in water, a stable and substantially lump-free homogenous suspension is obtained.
In embodiments, a preparation process for inactive particulate includes mixing a diluent, a disintegrant, and a thickening agent; granulating the mixture using a solvent, drying the granules, and sifting through a sieve.
In embodiments of the present application, a delayed release omeprazole magnesium composition and an inactive particulate composition are filled into a sachet.
"Suspending agents" or "thickening agents" include compounds such as: polyvinylpyrrolidones, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, and polyvinylpyrrolidone K30; polyethylene glycols, e.g., a polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400; sodium carboxymethylcellulose; methylcelluloses; hydroxypropyl methylcelluloses; polysorbate-80; hydroxyethylcelluloses; sodium alginate, polypropylene glycols; alginates, such as sodium alginate; gums, such as gum tragacanth, gum acacia, and guar gum; xanthans, including xanthan gum (Xanutral™ in various grades); sugars; cellulosics, such as, e.g., methylcelluloses, sodium carboxymethylcellulose (e.g., BlanoseTM in various grades), hydroxypropyl methylcelluloses, and hydroxyethylcelluloses; polysorbate 80; polyethoxylated sorbitan monolaurates; and the like.
The term "excipient" or "pharmaceutically acceptable excipient" includes any one or more of fillers, diluents, lubricants, carriers, disintegrants, thickening agents, effervescents, sweetners, flavorants, colorants, etc. The foregoing lists of excipients are representative of the substances that can be used, and are not exhaustive. Those skilled in the art will be aware of other useful substances, and their uses in the present application are also contemplated.
Pharmaceutical formulations of the present application can optionally contain coloring agents such as iron oxides, acceptable natural or synthetic coloring agents, etc. which can be added during a granulation step or at any other point in a process.
The flavoring agents that can be used include natural and artificial flavors. These flavors may be one or more of synthetic flavor oils and flavoring aromatics, and/or oils, oleo resins and extracts derived from plants, leaves, flowers, fruits, etc., and combinations thereof. Representative flavor oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds. Also useful are artificial, natural or synthetic fruit flavors such as vanilla, chocolate, coffee, cocoa and citrus oil, including lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. These flavorings can be used individually or in admixture. Commonly used flavors also include mints such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavors, whether employed individually or in admixture.
In the context of the present application, during the preparation of the pharmaceutical compositions and finished dosage forms, one or more pharmaceutically acceptable excipients may optionally be used, including, but not limited to: diluents such as microcrystalline cellulose (MCC) (e.g., AVICEL® in various grades), silicified MCC (e.g., Prosolv™ HD 90), microfine cellulose, lactose, starches, pregelatinized starches, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, and the like; binders such as acacia, guar gum, alginic acid, dextrin, maltodextrin, methyl celluloses, ethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses (e.g., KLUCEL® various grades), hydroxypropyl methylcelluloses (e.g., METHOCEL® various grades), carboxymethyl cellulose sodium, povidones (e.g., various grades of KOLLIDON® and PLASDONE®), starches, and the like; disintegrants such as carboxymethyl cellulose sodium (e.g. Ac-Di-Sol®and Primellose® various grades), crospovidones (e.g. Kollidon®, Polyplasdone®), povidone K-30, polacrilin potassium, starches, pregelatinized starches, sodium starch glycolate (e.g. Explotab®) and the like; surfactants including anionic surfactants such as chenodeoxycholic acid, 1-octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxycholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium cholate hydrate, sodium dodecyl sulfate (SDS or SLS), cationic surfactants such as cetylpyridinium chloride monohydrate and hexadecyl- trimethylammonium bromide, nonionic surfactants such as N-decanoyl-N-methylglucamine, octyl a-D-glucopyranoside, n-Dodecyl b-D-maltoside (DDM), sorbitan esters, polyoxyethylene sorbitan esters like polysorbates, and the like; pH modifying agent like citric acid; plasticizers such as acetyl tributyl citrate, phosphate esters, phthalate esters, amides, mineral oils, fatty acids and esters, glycerin, triacetin or sugars, fatty alcohols, polyethylene glycol, ethers of polyethylene glycol, fatty alcohols such as cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol and the like.
Solvents that may be used in processing steps such as granulation, layering, and coating include, without limitation, water, alcohols like ethanol, isopropanol, mixtures of water with an alcohol in any ratios, and organic solvents like acetone, methanol, methylene chloride, and the like.
The different physicochemical properties of the active ingredient, and as well of excipients, are to be considered, as these properties affect the processing and formulation properties of the compound. Various important physicochemical properties include, but are not limited to, particle sizes, densities (bulk density and tapped density), compressibility index, Hausner’s ratio, angle of repose, etc.
Particle sizes of active pharmaceutical ingredient can affect a solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by drug particle sizes and size distributions. This can be critical for low-dose drugs, and satisfactory dosage units of low doses are difficult to manufacture from a drug that does not meet certain particle size and size distribution requirements. Also, particle sizes can play an important role in the dissolution of active ingredient from the final dosage form for certain drugs, because of their poor solubility. Hence, these physicochemical properties not only affect the processes of preparing the pharmaceutical compositions, but also affect the performance of pharmaceutical products, both in vitro and in vivo.
The selection of appropriate particles sizes of omeprazole magnesium and inactive granules, as well as of excipients, is within the scope of the application. The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 is a size for which at least 90 volume percent of the particles have sizes smaller than the said value. Likewise, D10 refers to 10 volume percent of the particles having sizes smaller than the given value. D50 refers to at least 50 volume percent of the particles having sizes smaller than the given value, and D [4,3] refers to the mean particle size. Methods for determining D10, D50, D90, and D [4,3] include laser diffraction techniques, such as using equipment sold by Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom, or by Horiba.
In embodiments, the formulations of the present application comprise omeprazole magnesium, or a pharmaceutically acceptable form of omeprazole magnesium, having a particle size distribution such that: D90 is less than about 250 µm, or less than about 100 µm; and D50 is less than about 120 µm, or less than about 50 µm.
Flowability of materials is measured and represented using the Carr Index. The Carr Index is the percentage ratio of the difference between tapped density and bulk density to tapped density, calculated as:
Carr Index = [(Tapped density-Bulk density) ÷ Tapped density] × 100.
Carr Index values below about 15% represent materials with very good flow properties and values above about 40% represent materials with very poor flow properties.
In embodiments, pellets containing omeprazole magnesium and inactive particulate have Carr Index values substantially lower than the 40% described for products with poor flow properties. Values of Carr Index for omeprazole magnesium pellets of the present application are generally less than about 40%, or less than about 30%. This indicates superior handling capabilities during processing into pharmaceutical dosage forms.
Values of Carr Index for inactive particulate of the present application are generally less than about 40%, or less than about 30%. This indicates superior handling capabilities during processing into pharmaceutical dosage forms.
The densities can be determined using standard test method 616 “Bulk Density and Tapped Density” from United States Pharmacopeia 32, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2009.
The dosage forms of the present application can be subjected to in vitro dissolution testing, such as according to Test 711 “Dissolution” in United States Pharmacopeia 32, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2009 (“USP”), to determine the rate at which the active substance is released from the dosage forms, and the content of drug substances can be determined in dissolution media using techniques such as high performance liquid chromatography (HPLC).
An environment that a dosage form is likely to encounter when administered to a human (in vivo) can be correlated to in vitro dissolution studies conducted using various dissolution media, such as, but not limited to, simulated gastric fluid (SGF) with or without pepsin, simulated intestinal fluid (SIF) with or without pancreatin, 0.01N hydrochloric acid, pH 1.2, 4.5, 5.5, 6.0, 6.8, 7.2, and 7.4 buffers, pH 2.1 SGF, pH 5.0 and 4.5 acetate buffers, pH 4.5 ammonium acetate buffer, pH 5.0 fed state simulated intestinal fluid (FeSSIF), pH 6.5 fasted state simulated intestinal fluid (FaSSIF), pH 6.8 phosphate buffer, with or without sodium lauryl sulphate (SLS), pH 1.5 HCl buffer, and the like.
In embodiments, pharmaceutical products comprise delayed release formulations of omeprazole magnesium, wherein in an in vitro USP dissolution test not more than about 20% of the label amount of omeprazole magnesium is released into 0.1N HCl within 2 hours, and at least about 50% of the label amount of omeprazole magnesium is released in a pH 6.8 phosphate buffer within 45 minutes.
Among the omeprazole magnesium-related degradants and impurities that may be present in omeprazole magnesium-containing formulations are those identified as the compounds having Formulas I-VIII.
Formula I: 2-Mercapto-5-methoxy benzimidazole
Formula II: N-Oxide impurity
Formula III: 5-Methoxy-2-[[(3, 5-dimethyl-2-pyridine-2 yl) methyl] sulfonyl]-1H benzimidazole)]]
Formula IV: 5-methoxy-2--[[(4-methoxy-3, 5-dimethylpyridin-2-yl) methyl] sulfonyl]-1H benzimidazole)]]
Formula V: 5-methoxy-2--[[(4-methoxy-3, 5-dimethylpyridin-2-yl) methyl] sulfanyl]-1H benzimidazole)]]
Formula VI: 2-((5-methoxy-1H-benzo[d] imidazole-2-ylthio) methyl)-3,5-dimethylpyridine-4-ol
Formula VII: 2-((5-methoxy-1H-benzo[d] imidazole-2-yl)-3,5-dimethyl-4-oxo-1,4-dihydropyridine-2carboxylic acid
Formula VIII: 6-methoxy-2-(-4methoxy-3,5-dimethyl-pyridine-2ylmethanesulfinyl)-1-methyl-1H-benzimidazole
Omeprazole magnesium and its impurities can be analyzed using high performance liquid chromatography (HPLC) analytical procedures, such as the procedure described below.
Mobile phase A: Weigh and transfer about 24 g of glycine into a 2000 mL beaker and dissolve in 1500 mL of water. Adjust the pH of the solution to 9±0.1 with 50% sodium hydroxide solution, dilute to 2000 mL with water and mix well. Filter through a 0.45µm Nylon 66 membrane filter. Degas in a sonicator for about 10 minutes.
Mobile phase B: Mix acetonitrile and methanol in the volume ratio of 85:15, respectively. Degas in a sonicator for about 10 minutes.
Gradient program:
Time (minutes) Flow A (vol. %) B (vol. %)
0 1 90 10
10 1 88 12
22 1 80 20
27 1 65 35
38 1 50 50
38 1 90 10
45 1 90 10
Detector wavelength: 305 nm.
Column: 100×4.6 mm, 3.0 µm, Hypersil BDS C-18.
Column temperature: 25°C; Flow rate: 1.0 mL/minute.
Injection volume: 10 µL; Run time: 45 minutes.
Diluent: Dissolve 4 g of sodium hydroxide in 1000 mL of methanol.
Impurity stock solution: Transfer an accurately weighed amount of 2 mg of desmethoxy impurity into a 20 mL volumetric flask, dissolve and dilute to volume with diluent, and mix well.
System suitability solution: Transfer an accurately weighed amount of 20 mg of omeprazole USP reference standard or working standard into a 25 mL volumetric flask, add 1 mL of impurity stock solution and 25 mL of diluent, sonicate to dissolve the material completely, dilute to volume with diluent, and mix well.
Standard stock solution: Transfer an accurately weighed amount of about 65 mg of omeprazole USP Reference standard or working standard into a 100 mL volumetric flask, add 30 mL of diluent, sonicate to dissolve, dilute to volume with diluent, and mix well. Maintain the temperature of water in the sonicator bath between 15°C and 20°C.
Pipette 3 mL of the above solution into a 50 mL volumetric flask, dilute to volume with diluent, and mix well.
Standard preparation: Pipette 4 mL of the above solution into a 100 mL volumetric flask, dilute to volume with diluent, and mix well.
Test preparation: Empty the contents of 8 sachets carefully without losing pellets. Transfer an accurately weighed amount equivalent to 80 mg of omeprazole into a 100 mL volumetric flask. Add 70 mL of diluent, shake the flask to disperse the contents uniformly and sonicate for 30 minutes with intermediate shaking, make up to volume with diluent, and mix well.
Typical relative retention times observed for impurities I-VIII and omeprazole magnesium are 0.33, 0.74, 0.97, 0.86, 1.18, 0.80, 0.19, 1.80, and 1.0 respectively.
Typical relative response factor values observed for impurities I-VIII and omeprazole magnesium are 3.0, 0.78, 1.08, 0.87, 1.02, 0.77, 1.28, 0.79, and 1.0 respectively.
In embodiments, a pharmaceutical composition comprising omeprazole magnesium has one or more of certain impurities mentioned hereinbefore, a highest unidentified individual impurity present in amounts less than about 2%, and total impurities present in amounts less than about 5%. Impurity concentrations are expressed herein as a percentage of the labeled omeprazole magnesium content.
In embodiments, the application includes the use of formulation packaging materials, such as triple laminate pouches made of a polyethylene terephthalate (PET) layer, an aluminum foil layer, and a polyethylene (PE) layer to pack the formulations of the present invention.
In embodiments, the application provides packages suitable for commercial sale, which provide formulation stability during storage, transportation, and use.
In embodiments, pharmaceutical formulations of the present application are useful for treatment of duodenal ulcer and gastric ulcer in adults and for treatment of gastroesophageal reflux disease (GERD) in adults and children and maintenance of healing of erosive esophagitis.
The following examples are provided to further illustrate certain specific aspects and embodiments of the application in greater detail, and should not be regarded as limiting the scope of the application in any manner. In the examples, “#70/#80 mesh” wherever it appears means particles that pass through a #70 mesh sieve and are retained on a #80 mesh sieve. The same system is used for describing other sieve size pairs.

EXAMPLES
EXAMPLE 1: Sachet formulations containing omeprazole magnesium 10 mg delayed release multi-particulates and 3 g inactive particulates.
Part 1: Omeprazole Magnesium Delayed-Release Pellets
Ingredient mg/Sachet
1A 1B 1C 1D 1E
Sugar spheres #70/#80 mesh 28.5 4.5 4.5 4 6
Seal Coating
Hydroxypropyl methylcellulose 1.5 0.2 0.2 0.2 0.3
Water* q.s. q.s. q.s. q.s. q.s.
Drug Loading
Omeprazole magnesium (crystalline) 10.3 10.3 10.3 10.3 10.35
Hydroxypropyl methylcellulose 10.8 3.4 3.7 6.6 3.933
Magnesium oxide (heavy) 0.2 0.2 0.2 0.3 0.259
Methanol* q.s. q.s. q.s. q.s. -
Methylene chloride* q.s. q.s. q.s. q.s. -
Water* - - - - q.s.
Subcoating
Hydroxypropyl methylcellulose 5.9 2.5 2.5 2.8 2.501
Talc 9.3 4 4 4.2 3.001
Magnesium stearate 0.8 0.4 0.4 0.3 0.375
Silicon dioxide 0.8 0.4 0.4 0.3 0.375
Methanol* q.s. q.s. q.s. q.s. -
Methylene chloride* q.s. q.s. q.s. q.s. -
Water* - - - - q.s.
Enteric Coating
Methacrylic acid copolymer (Eudragit® L 30D 55) 54.8 23.3 20.5 19.8 24.631
Triethyl citrate 6.8 2.9 2.6 2 2.463
Talc 7.2 4.6 5.3 4 4.926
Titanium dioxide 1.4 0.6 0.5 0.5 0.493
Water* q.s. q.s. q.s. q.s. q.s.
Lubrication
Talc - 0.3 0.6 0.3 0.596
Total 138.4 57.6 55.7 55.6 60.203
* Evaporates during processing.

Part 2: Inactive Particulates
Ingredient mg/Sachet
1A 1B 1C 1D 1E
Dextrose anhydrous 2813.3 2813.3 2813.3 2788.3 2793.28
Crospovidone 75 75 75 75 75
Xanthan gum (Xanthural® 11 K) 75 -- -- 70 65
Microcrystalline cellulose (Avicel™ CL611) -- 75 -- -- --
Polypropylene glycol alginate -- -- 75 -- --
Citric acid anhydrous 4.9 4.9 4.9 4.9 4.92
Iron oxide yellow 1.8 1.8 1.8 1.8 1.8
Hydroxypropyl cellulose (Klucel® JF) 30 30 30 -- --
Strawberry flavor -- -- -- 60 60
Isopropyl alcohol* q.s. q.s. q.s. q.s. q.s.
Total 3000 3000 3000 3000 3000
* Evaporates during processing.
Manufacturing procedure for formulas 1A, 1B, 1C, and 1D:
PART A: Omeprazole magnesium delayed release pellets
Seal coating
1. Dissolve hydroxypropyl methylcellulose (HPMC) in water with stirring, to form a clear solution. Spray this solution onto pre-warmed sugar spheres in a fluid bed processor (FBP). Dry the seal coated pellets in the FBP for 1 hour and use a #60/#80 mesh fraction for further processing.
Drug loading
2. Dissolve HPMC in a mixture of methanol and methylene chloride (75:25 by volume) /water with stirring to form a clear solution. Add magnesium oxide with stirring and continue stirring to form a smooth dispersion. Add omeprazole magnesium with stirring and stir.
3. Spray the dispersion of step 2 onto pre-warmed, seal coated pellets from step 1, in a FBP. Dry the drug loaded pellets in the FBP for 1 hour and use a #40/#60 mesh fraction for further processing.
Subcoating:
4. Dissolve HPMC in a mixture of methanol and methylene chloride (75:25 by volume) /water with stirring to form a clear solution. Sequentially add talc, magnesium stearate, and silicon dioxide to the mixture, stirring for 15 minutes after each addition. Filter the dispersion through a #200 mesh sieve.
5. Spray the dispersion of step 4 onto pre-warmed drug loaded pellets of step 3 in a FBP. Dry the subcoated pellets in the FBP for 1 hour and use a #40/#60 mesh fraction for further processing.
Enteric coating:
6. Disperse talc and titanium dioxide in water and pass the dispersion through a colloid mill for about 1 hour. Mix Eudragit L-30D 55 and triethyl citrate and add the talc and titanium dioxide dispersion with stirring. Add water to obtain the desired consistency with stirring. Filter the dispersion through a #200 mesh sieve.
7. Spray the dispersion of step 6 onto pre-warmed sub coated pellets of step 5 in a FBP. Dry the coated pellets in the FBP for 1 hour and use a #30/#40 mesh fraction for further processing.
8. Sift lubrication talc through a #60 mesh sieve and blend with the enteric coated pellets of step 7.
PART B: Inactive particulates
1. Sift dextrose anhydrous, crospovidone, xanthan gum (in 1A and 1D), microcrystalline cellulose (in 1B), polypropylene glycol alginate (in 1C), and iron oxide yellow through a #30 mesh sieve.
2. Prepare a granulating solution by dissolving citric acid in isopropyl alcohol and use to granulate the sifted materials of step 1 in a rapid mixer granulator.
3. Dry the granules of step 2 in a fluid bed dryer until the loss on drying (LOD) is =2%.
4. Sift the dried granules of step 3 through a #20 mesh sieve and sift strawberry flavor through a #60 mesh sieve, and blend.

Packaging
1. Fill the Part A pellets and Part B particulates into sachets.

An in vitro dissolution study is performed using sachets prepared as described for Examples 1C and 1D with the following testing conditions, and the averages of results for six sachets are shown in Table 1.
Media: 300 mL of 0.1 N HCl for the first two hours, then 700 mL of degassed pH 6.8 phosphate buffer.
Apparatus: USP type 2; Rotation speed: 100 rpm; Temperature: 37±0.5°C.
Table 1
Minutes Cumulative % of Drug Released Into pH 6.8 Buffer
1C 1D
30 97 101
45 94 99

An in vitro dissolution study is performed using sachets prepared as described for Example 1D and the commercial PRILOSEC sachets with the following testing conditions, and the averages of results for six sachets are shown in Table 2.
Media: 500 mL of 0.1N HCl for the first two hours, then 500 mL of pH 6.5 FaSSIF.
Apparatus: USP type 2.
Rotation speed: 100 rpm in acid medium, then 50 rpm.
Temperature: 37±0.5°C.
Table 2
Minutes Cumulative % of Drug Released Into FaSSIF
PRILOSEC 1D
5 7 1
10 31 27
15 54 57
20 72 79
30 93 93
45 97 94

Prepared sachets of Example 1D are stored under the accelerated stability testing conditions of 40°C and 75% relative humidity (RH) for 3 months. The samples are analyzed for drug content and the impurities of Formula I-VIII before, during, and after the storage, and results are shown in the tables below, where values are percentages of the label drug content. Analyses for 1 month (1M), 2 months (2M) and 3 months (3M) of storage are reported in Table 3.
Table 3
Time Impurities Relating to Omeprazole Magnesium
Highest Individual
Impurity Total Impurities
Initial 0.10 0.12
1M 0.09 0.28
2M 0.13 0.31
3M 0.08 0.33

EXAMPLE 2: Sachet formulations containing omeprazole magnesium 10 mg delayed release multi-particulates and 3 g inactive particulates.
Part 1: Omeprazole Magnesium Delayed-Release Pellets
Ingredient mg/Sachet
2A 2B
Sugar spheres #70/#80 mesh 4 4.5
Seal Coating
Hydroxypropyl methylcellulose 0.2 0.2
Water* q.s. q.s.
Drug Loading
Omeprazole magnesium (crystalline) 10.4 10.4
Hydroxypropyl methylcellulose 6.6 3.6
Magnesium oxide (heavy) 0.3 0.2
Methanol* q.s. q.s.
Methylene chloride* q.s. q.s.
Subcoating
Hydroxypropyl methylcellulose 2.8 2.5
Talc 4.1 3.5
Magnesium stearate 0.3 0.3
Silicon dioxide 0.4 0.4
Methanol* q.s. q.s.
Methylene chloride* q.s. q.s.
Enteric Coating
Methacrylic acid copolymer (Eudragit® L 30D 55) 17.2 20.5
Triethyl citrate 1.7 2.5
Talc 6.9 5
Titanium dioxide 0.4 0.5
Water* q.s. q.s.
Lubrication
Talc 0.3 --
Total 55.6 54.1
* Evaporates during processing.
Part 2: Inactive Particulates
Ingredient mg/Sachet
2A 2B
Dextrose anhydrous 2813.3 2723.3
Crospovidone 75 75
Xanthan gum (Xantural® 180) 75 --
Sodium carboxymethylcellulose (BlanoseTM 9M31F-PH) -- 150
Citric acid anhydrous 4.9 4.9
Iron oxide yellow 1.8 1.8
Strawberry flavor 30 45
Isopropyl alcohol* q.s. q.s.
Total 3000 3000
* Evaporates during processing.
Manufacturing procedure for formulas 2A and 2B:
PART A: Omeprazole Magnesium delayed release pellets
Seal coating:
1. Dissolve HPMC in water with stirring. Spray the solution onto sugar spheres in a FBP. Dry the pellets in the FBP for 1 hour and use a #60/#80 mesh fraction for subsequent processing.
Drug loading:
2. Dissolve HPMC in a mixture of methanol and methylene chloride (50:50 by volume) with stirring. Add magnesium oxide and stir to form a smooth dispersion. Add omeprazole magnesium and stir.
3. Spray the dispersion of step 2 onto pre-warmed seal-coated pellets of step 1 in a FBP. Dry the drug-loaded pellets in the FBP for 1 hour and use a #40/#60 mesh fraction for subsequent processing.
Subcoating:
4. Dissolve HPMC in a mixture of methanol and methylene chloride (75:25 by volume) with stirring. Sequentially add talc, magnesium stearate, and silicon dioxide, stirring for 15 minutes after each addition. Filter the dispersion through a #100 mesh sieve.
5. Spray the dispersion of step 4 onto pre-warmed drug-loaded pellets of step 3 in a FBP. Dry subcoated pellets in the FBP for 3 hours and use a #35/#60 mesh fraction for further processing.
Enteric coating:
6. Disperse talc and titanium dioxide in water and pass the dispersion through a colloid mill for about 1 hour. Prepare a mixture of Eudragit® L-30D 55 and triethyl citrate. Add the talc and titanium dioxide dispersion to the Eudragit mixture with stirring. Add additional water with stirring, to obtain the desired consistency. Filter the dispersion through a #100 mesh sieve.
7. Spray the dispersion of step 6 onto pre-warmed subcoated pellets of step 5 in a FBP. Dry the enteric coated pellets in the FBP for 1 hour and use a #30/#40 mesh fraction for subsequent processing.
8. Sift lubrication talc through a #60 mesh sieve and blend with enteric-coated pellets of step 7.
PART B: Inactive Particulates
1. Sift dextrose and crospovidone through a #20 mesh sieve. Sift xanthan gum (in 2A), BlanoseTM 9M31F-PH (in 2B), and iron oxide yellow through a #30 mesh sieve.
2. Dissolve citric acid in isopropyl alcohol and granulate the combined sifted materials of step 1 in a rapid mixer granulator.
3. Dry the granules of step 2 in a fluid bed dryer until the LOD is =2%.
4. Sift the dried granules of step 3 through a #20 mesh sieve and sift strawberry flavor through a #60 mesh sieve, then blend.
Packaging
1. Fill the part A pellets and Part B particulates into sachets.