EP2661260A2

EP2661260A2 - Modified release benzimidazole formulations

Info

Publication number: EP2661260A2
Application number: EP11853533.5A
Authority: EP
Inventors: Lingam MEKA; Srinivasa Almareddy REDDY; Vagisha SINHA; Hitesh JOGIA; Srinivas Arutla; Raviraj PILLAI; Rahul Sudhakar Gawande; Prasad Vure; Venkateswarlu Vobalaboina
Original assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Current assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Priority date: 2010-12-29
Filing date: 2011-12-29
Publication date: 2013-11-13
Also published as: UA112855C2; NZ613090A; WO2012092486A3; EP2661260A4; EA201390979A1; AU2011352037A1; WO2012092486A2; CN103402501A

Abstract

A pharmaceutical formulation providing more than one release of a benzimidazole drug. In embodiments, drug-containing particles are coated with at least one polymer having solubility at pH values about 5 to about 7.5 and other drug-containing particles are coated with at least one polymer having solubility at pH values about 5 to about 6.

Description

MODIFIED RELEASE BENZI IMIDAZOLE FORMULATIONS

INTRODUCTION

Aspects of the present application relate to pharmaceutical formulations comprising a substituted benzimidazole drug, and processes for preparing the same. Particular aspects relate to formulations comprising omeprazole. Aspects further relate to therapeutic uses and methods of treatment employing

formulations comprising omeprazole, including methods of treating gastric acid secretion disorders.

Several substituted benzimidazole derivatives including rabeprazole, omeprazole, esomeprazole, lansoprazole, pantoprazole, and mixtures thereof, are known to be useful for inhibiting gastric acid secretion in mammals and man, by controlling gastric acid secretion at the final step of the acid secretory pathway. These active ingredients are acid-labile, creating several problems in formulating such acid-labile compounds into oral dosage forms because of the acidic environment of the stomach. In particular, the drugs will be rapidly decomposed and change color under moist conditions or in an acidic to neutral aqueous solution.

When these compounds are formulated into pharmaceutical preparations for oral administration, they require special techniques to avoid contact of drug with gastric acid of the stomach. One technique that is used is to coat the acid- labile compound, or granules or pellets containing it, with an enteric coating, which is insoluble in water under acidic conditions and soluble in water under neutral to alkaline conditions. However, the material used in enteric coatings itself is acidic, which can cause the decomposition of the acid-labile compound. Such

decomposition occurs even during the enteric coating process, which results in discoloration of the surface of drug-containing cores. In order to avoid such problems, an inert subcoating, which is not acidic, can be provided between a drug-containing core and an enteric coating.

For substances that are labile in acid media, but have better stability in neutral to alkaline media, it can be advantageous to add alkaline inactive excipients to increase the stability of the active compound during manufacturing and storage. In particular, substituted benzimidazole derivatives such as omeprazole, esomeprazole, etc. are not only unstable in acidic conditions but also are not stable in the neutral solid state. Thus, in order to enhance the storage stability, an alkaline base, such as sodjum bicarbonate or magnesium carbonate, can be added to the formulations, and/or the substituted benzimidazole derivatives can be converted to their alkaline base salts, which are usually more stable than the free species.

Among the active ingredients used herein is a substituted benzimidazole compound having a chemical name 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl]-1 /-/-benzimidazole and represented by structural Formula I, hereinafter referred to by its adopted name "omeprazole."

Formula I

Omeprazole is the active ingredient in products sold as PRILOSEC® delayed-release capsules, containing 10 mg, 20 mg, or 40 mg of omeprazole in the form of enteric-coated granules and marketed by Astra-Zeneca. PRILOSEC delayed-release capsules have following inactive ingredients: cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, hypromellose, lactose, mannitol, sodium lauryl sulfate, and other ingredients. The capsule shells have the following inactive ingredients: gelatin-NF, FD&C Blue #1 , FD&C Red #40, D&C Red #28, titanium dioxide, synthetic black iron oxide, isopropyl alcohol, butyl alcohol, FD&C Blue #2, D&C Red #7 Calcium Lake, and, in addition, the 10 mg and 40 mg capsule shells also contain D&C Yellow #10.

U.S. Patent No. 7,790,755 discloses a controlled release preparation, in particular a capsule comprising a tablet, granule, or fine granule, wherein the release of active ingredient is controlled, and a gel-forming polymer that delays the migration speed in the gastrointestinal tract. It provides a controlled release preparation wherein the release of active ingredient of drug is controlled, which releases an active ingredient for an extended period of time with staying or slowly migrating in the gastrointestinal tract. U.S. Patent No 5,175,003 discloses a dual mechanism of drug release using polymer mixture composed of pH-sensitive enteric materials and film- forming plasticizers capable of conferring permeability to the enteric material, for use in drug-delivery systems; a matrix pellet composed of a dual mechanism polymer mixture permeated with a drug and sometimes covering a

pharmaceutically neutral nucleus; a membrane-coated pellet comprising a matrix pellet coated with a dual mechanism polymer mixture envelope of the same or different composition; and a pharmaceutical dosage form containing matrix pellets. The matrix pellet releases acid-soluble drugs by diffusion in acid pH and by disintegration at pH levels of nominally about 5.0 or higher.

U.S. Patent No 7,635,490 discloses a dosage form comprising at least one active ingredient, and first core and second cores surrounded by and separated by a shell. The dosage form provides a delay of at least one hour between the initial release of active ingredient contained in said first core and the initial release of active ingredient contained in said second core after contacting of the dosage form with a liquid medium.

U.S. Patent Application Publication No. 2009/0214599 discloses a pharmaceutical formulation comprising at least one proton pump inhibitor structured and arranged to provide an initial pH-dependent delayed release, and a pH-dependent extended release of the at least one proton pump inhibitor. These delivery systems are constructed to provide unique PPI release rates, and particularly to formulations designed to treat gastric acid related conditions, especially to counteract nocturnal acid breakthrough. The formulations particularly contain proton pump inhibitor formulations that have a pH-dependent protective layer, and exhibit a pH-dependent extended release.

U.S. Patent Application Publication No. 2009/0028941 discloses dosage forms for delayed and pulsed release of therapeutic agents into the stomach. The dosage forms are gastric retentive dosage forms that achieve release of the therapeutic agent into the stomach and upper gastrointestinal tract subsequent to administration of the dosage form. The dosage forms find particular use in administration of acid-labile active agents such as proton pump inhibitors, and in treating gastric acid secretion such as gastro-esophageal reflux disease (GERD) and nocturnal acid breakthrough (NAB). U.S. Patent No. 6,013,281 , of which the entire content is incorporated by reference, discloses that a separating layer is formed in situ by direct application of an acidic enteric material onto an alkaline core containing benzimidazoles.

U.S. Patent Application Publication No. 2007/0141 137 describes a capsule preparation, which comprises a medicine unstable to moisture, is stable in a low moisture state, and has pH-independent disintegration properties.

There remains a need for providing pharmaceutical formulations comprising omeprazole or esomeprazole derivative thereof or a pharmaceutically acceptable salt for providing effective plasma concentrations of the active agent for extended durations of time.

SUMMARY

Aspects of the present disclosure relate to modified drug release formulations comprising at least one benzimidazole compound, such as omeprazole, for oral administration, together with one or more excipients.

In embodiments, the present disclosure provides dosage forms comprising a first portion of drug having delayed release from the dosage form after oral administration, and a second portion of drug having extended release from the dosage form after oral administration.

In embodiments, the present disclosure provides modified release omeprazole formulations, which are in the form of multi-particulates, or multiparticulates that are filled into capsules.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows a dissolution profile of a formulation as prepared in Example

3.

Fig. 2 shows a dissolution profile of a formulation as prepared in Example 13, using 0.1 N HCI for the first 2 hours then a pH 6.5 FaSSIF buffer, with 900 mL of media and a paddle apparatus stirred at 75 rpm.

DETAILED DESCRIPTION

Aspects of the present disclosure relate to modified drug release formulations comprising at least one benzimidazole drug, such as omeprazole, together with one or more excipients, for oral administration. In embodiments, the present disclosure provides dosage forms comprising a first portion of drug that has delayed released from the dosage form after oral administration, and a second portion of drug that has extended release from the dosage form after oral administration.

In embodiments, the present disclosure provides modified release formulations wherein a benzimidazole drug is a proton pump inhibitor, such as omeprazole, esomeprazole, lansoprazole, or dexlansoprazole.

In embodiments, the present disclosure provides stabilized modified drug release omeprazole formulations comprising at least two fractions of multiparticulates, wherein at least one fraction is in the form of immediate release, delayed release, extended release, sustained release, pulsatile release, or prolonged release.

In embodiments, the present disclosure provides modified drug release omeprazole formulations comprising at least two fractions, wherein weight ratios of first and second fractions of multi-particulates varies from about 1 :9 to about 9:1.

In embodiments, a delivery vehicle comprises a component that protects at least a portion of a dose from inactivation due to exposure to acidic conditions of the stomach.

In embodiments, the present disclosure relates to dual release formulations of omeprazole, comprising, in combination: (a) omeprazole; and (b) a polymeric excipient; wherein the polymeric excipient acts to provide an initial pH-dependent delayed release and a pH-dependent extended release of the drug.

In embodiments, a first portion of drug is released from a dosage form in less than about 60 minutes after ingestion of the dosage form. In embodiments, a second portion of drug is released from a dosage form in about 2 hours to about 6 hours after ingestion of the dosage form.

In embodiments, the present disclosure provides modified release formulations comprising omeprazole, esomeprazole, lansoprazole, or

dexlansoprazole. Omeprazole is used in the following discussion as a representative of the entire class of substituted benzimidazole drugs, but the present application is not limited to the use of this specific drug.

In embodiments, the application includes methods for preparing

omeprazole dosage forms, comprising:

a) applying a layer of a suspension, dispersion, or solution of omeprazole and at least one water-soluble excipient onto a particulate pharmacologically inert substance;

b) optionally, applying an intermediate coating;

c) applying an enteric coating surrounding the core of a) or intermediate layer of b);

d) optionally, applying a release-controlling coating layer over c), wherein the release-controlling coating layer is a diffusion-controlled layer, gel-forming polymer layer, pH-dependently soluble layer, extended-release coating layer, or any combinations thereof; and

e) combining the composition with at least one pharmaceutically acceptable excipient.

In embodiments, a drug stabilizer may be present in a subcoating.

In embodiments, the present application relates to stabilized modified release formulations containing omeprazole and a water-soluble excipient, such as a polyvinylpyrrolidone.

In embodiments, the disclosure provides methods for preparing

omeprazole compositions, comprising:

a) layering a suspension, dispersion, or solution of omeprazole, a water- soluble excipient, and a dissolution enhancer, together with one or more other pharmaceutically acceptable excipients, onto a particulate pharmacologically inert substance;

b) optionally, applying an intermediate coating and drying;

d) optionally, applying a release-controlled coating-layer over c), wherein the release-controlled coating-layer is a diffusion-controlled layer, gel-forming polymer layer, pH-dependently soluble layer, extended-release coating layer, or any combination thereof; and e) combining the formed composition with at least one pharmaceutically acceptable excipient.

Modified release formulations of the present application are intended to provide effective plasma concentrations of the contained active agent for an extended duration of time, following administration.

In embodiments, the omeprazole used to make the compositions, or contained in the compositions, is in an amorphous form, or one or more crystalline forms, or mixtures thereof. In embodiments, the omeprazole used as the active agent is in a substantially amorphous form, which form is substantially retained during the manufacturing of the composition and also during storage of a formulation for commercially relevant periods. In embodiments, the omeprazole used as the active agent is in a substantially crystalline form, which form is substantially retained during the manufacturing of the composition and also during storage of a formulation for commercially relevant periods.

In embodiments, the present disclosure provides modified release omeprazole formulations, which are in form of multi-particulates, or multiparticulates filled into capsules.

In embodiments, omeprazole formulations of the present application are in the form of pellets or mini-tablets, filled into capsules.

In embodiments, omeprazole formulations of the present application comprise a single fraction of multi-particulates, such as pellets or mini-tablets filled into capsules, wherein a multi-particulate fraction comprises cores containing the drug for extended release, having thereupon a layer of a drug-containing coating for immediate release. These can be further coated with an enteric polymer, wherein the multi-particulates are optionally coated to form a subcoating layer prior to enteric coating.

In embodiments, omeprazole formulations of the present application comprise at least two fractions of multi-particulates, such as mini-tablets or pellets filled into capsules, wherein one fraction of multi-particulates is coated with an enteric polymer that dissolves in a pH range between about 3 and 7 to release the active agent, and wherein another fraction of multi-particulates is coated with an enteric polymer that dissolves in a pH range between about 4 and 8 to release the active agent, and wherein the multi-particulates in each of the two fractions are optionally coated to form a subcoating layer, prior to enteric coating. In embodiments, compositions of the present application are prepared using omeprazole or a pharmaceutically acceptable form of omeprazole having particle size distributions such that: Dgo is about 1 pm to about 1000 pm, or about 1 pm to about 500 pm, or about 10 pm to about 250 pm; and Dso is from about 1 pm to about 500 pm, or about 1 pm to about 250 pm, or about 1 pm to 100 pm. A D_x value is the maximum dimension of particles comprising "x" percent of the particles in a sample.

In embodiments, the present application includes modified release formulations comprising omeprazole or pharmaceutically acceptable salts thereof, releasing less than about 10% of the contained active ingredient within about 120 minutes after immersion into 750 or 1000 ml_ of a 0.1 N hydrochloric acid (pH 1.2) dissolution medium, using test method 711 "Dissolution" in United States

Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP"), and type 2 apparatus. Further release of the drug occurs after a subsequent immersion into a neutral or alkaline pH aqueous medium, in the range of about 10% to about 45% of drug dissolving within about 90 minutes and about 50% to about 100% of the drug dissolving within about 300 minutes.

An environment that a dosage form is likely to encounter when

administered to humans (in vivo) can be correlated to in vitro dissolution studies conducted using various dissolution media such as simulated gastric fluid (SGF) with or without pepsin, simulated intestinal fluid (SIF) with or without pancreatin, 0.01 N hydrochloric acid (HCI) , pH 1.2, 4.5, 5.5, 6.0, 6.8, 7.0, 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 HCI buffer, and the like. Many useful dissolution media are described in the USP.

In embodiments, the present application relates to modified release formulations of omeprazole, comprising, in combination: (a) omeprazole or a pharmaceutically acceptable salt thereof; and (b) a water-soluble excipient.

In embodiments, the present application relates to modified release formulations of omeprazole, comprising, in combination: (a) omeprazole or a pharmaceutically acceptable salt thereof; and (b) a water-soluble excipient;

wherein the water-soluble excipient acts as a stabilizer for the drug. In embodiments, the application relates to modified release formulations of omeprazole, having concentrations of a dissolution enhancer in the range of about 0.1% to 5% by weight of the total composition.

Various basic inorganic salts that are useful in the formulations include, but are not limited to, basic inorganic salts of sodium, potassium, magnesium and calcium. Examples of basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like. Examples of basic inorganic salts of magnesium are magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg₆AI₂(OH)i₆ C0₃-4H₂0], aluminum hydroxide-magnesium [2.5MgO Al₂0₃-xH₂0], and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, and the like.

Organic bases that may be used in the present application include pharmaceutically acceptable organic bases, including, for example, meglumine, lysine, Ν,Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and mixtures of any two or more thereof.

In embodiments, the disclosure relates to modified release formulations of omeprazole, wherein concentrations of alkaline compounds are in the range of about 0.1% to 10% by weight of the total composition.

In embodiments, the disclosure relates to modified release formulations of omeprazole, wherein weight ratios of omeprazole to alkaline compound are in the range of about 1 :0.01 to 1 :5.

In embodiments, the disclosure relates to modified release formulations containing about 20-60 mg of omeprazole in a capsule.

In embodiments, the disclosure includes compositions and/or formulations where omeprazole retains its original physical form in the formulation during exposure to stability testing storage conditions, such as, but not limited to, 40°C and 75% relative humidity (RH) for about three months.

The compositions of the disclosure can be further processed into various pharmaceutical dosage forms as prepared, or can be combined with one or more pharmaceutically acceptable excipients. The different pharmaceutical dosage forms which comprise the pharmaceutical compositions of the present application include solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules. Modified release compositions may comprise hydrophilic, lipophilic, or hydrophobic release rate controlling substances, or their combinations to form matrix or reservoir, or combinations of matrix and reservoir systems. The compositions may be prepared using any techniques, such as direct blending, dry granulation, wet granulation (aqueous or non-aqueous, or partly aqueous and partly non-aqueous, or aqueous-alcoholic), or by extrusion and spheronization. Compositions may be presented as uncoated, film coated; sugar coated compression-coated, powder coated, and enteric coated or modified release coated forms.

In embodiments, the application includes oral pharmaceutical compositions in a solid dosage form, comprising: (a) a core containing omeprazole, a water- insoluble excipient, and optionally an alkaline compound; (b) a subcoating coated onto the core; and (c) an enteric coating coated onto the subcoating. In certain embodiments, the subcoating is chemically inert.

In embodiments, the disclosure includes oral pharmaceutical compositions in a solid dosage form, comprising: (a) a core containing omeprazole, a water- insoluble excipient, a dissolution enhancer, and optionally an alkaline compound; (b) optionally, a subcoating coated onto the core; and (c) an enteric coating. In embodiments, an enteric coating is coated directly onto the core. In embodiments, the oral pharmaceutical compositions further include a subcoating coated onto the core, with the enteric coating being coated onto the subcoating.

The cores may include pharmaceutically acceptable excipients such as any one or more of diluents or bulking agents, surfactants, disintegrants, stabilizers, pH dependent or pH independent polymers, binders, and others. Cores of the present application may be prepared by homogenously mixing omeprazole and one or more pharmaceutically acceptable excipients, such as any of those mentioned hereinabove. In embodiments, cores of the present application comprise inert particulate materials such as a diluent or sugar spheres, onto which a solution containing omeprazole is sprayed or layered. The mixture can then be formulated into small beads, pellets, granules, fine granules, or mini-tablets, and filled into hard gelatin or soft gelatin capsules using conventional procedures.

An inert subcoating can separate a core from an enteric coating polymer that contains free carboxyl groups, which may cause degradation and/or discoloration of the drug. The inert subcoating may also serve as a pH-buffering zone in which hydrogen ions diffusing from the outside toward the alkaline core can react with hydroxyl ions diffusing from the alkaline core toward the surface of the coated articles. A subcoating may comprise one or more layers.

An inert subcoating can be applied to core pellets or mini-tablets using any techniques, including conventional coating procedures in a suitable coating pan or in a fluidized bed apparatus, using water and/or organic solvents for the coating solutions or dispersions. Water soluble or insoluble polymers that can be used for an inert subcoating include, for example, sugars, zein, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, hydroxyethyl celluloses, polyvinyl alcohols, polyethylene glycols, poloxamers (e.g., Pluronic™ products), ethylcelluloses, gelatins, polyarginines, polyglycines, polyvinylpyrrolidones, vinyl acetate copolymers, and any mixtures thereof.

In the case of mini-tablets, a coating may also be applied using a dry coating technique. The inert sub-coating may also include pharmaceutically acceptable water-soluble or tablet excipients that rapidly disintegrate in water. Common plasticizers, pigments, titanium dioxide, talc, and other additives may also be included into an inert subcoating. In the case of gelatin capsules, the gelatin capsule itself serves as a subcoating. The quantity of inert subcoating of the present application may vary from about 0.1 % to 10%, or about 0.5 to 4%, of the total weight of a core.

Useful water soluble excipients include any pharmaceutically acceptable water soluble polymers such as, but not limited to, polyvinylpyrrolidones or povidones (such as grades K25, K29, K30, and K90), hydroxypropyl celluloses, hydroxyethyl celluloses, hydroxypropyl methylcelluloses, polyvinyl alcohols, carboxymethylcellulose sodium, and any mixtures thereof. Further water soluble excipients according to the present application include sugars and sugar alcohols, preferably having low hygroscopicity, and include, for example, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, and mixtures of any two or more thereof.

In embodiments, the application relates to modified release formulations of omeprazole, wherein concentrations of water-soluble excipient are in the range from about 0.001 % to about 10% by weight of the total composition. The multi-particulates may optionally include a dissolution enhancer.

Dissolution enhancers increase the rate of dissolution of the drug from the carrier. In general, dissolution enhancers are amphiphilic compounds and are generally more hydrophilic than the carrier. Exemplary dissolution enhancers include: salts such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, and potassium phosphate; alcohols such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; surfactants, such as poloxamers (such as poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), docusate salts, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbates, polyoxyethylene alkyl esters, sodium lauryl sulfate, and sorbitan monoesters; sugars such as glucose, sucrose, xylitol, sorbitol, and mannitol;

amino acids such as alanine and glycine; and any mixtures thereof. For example, the dissolution enhancer can be a salt, such as sodium chloride.

In embodiments, the application relates to modified release formulations of omeprazole, wherein concentrations of dissolution enhancer are in the range of about 0.1% to 5% by weight of the total composition.

An enteric coating is applied either directly onto cores, or onto subcoated cores, frequently using conventional coating techniques such as, for instance, pan coating or fluidized bed coating, with solutions of pH dependent polymers in water and/or suitable organic solvents, or by using suspensions of the polymers, to provide a modified release of the active agent. Enteric coating polymers that can be used, for example, include cellulose acetate phthalates (CAP), hydroxypropyl methylcellulose phthalates (HPMCP), polyvinyl acetate phthalates (PVAP), hydroxypropyl methylcellulose acetate succinates (HPMCAS), cellulose acetate trimellitates, hydroxypropyl methylcellulose succinates, cellulose acetate succinates, cellulose acetate hexahydrophthalates, cellulose propionate phthalates, copolymers of methylmethacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methylmethacrylate and methacrylic acid, copolymers of methylvinyl ether and maleic anhydride (e.g., Gantrez™ ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymers, natural resins such as zein, shellac and copal collophorium, carboxymethyl ethylcelluloses, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, materials known under the trade name Eudragir L12.5, L100, or Eudragit^® S12.5, S100, and several commercially available enteric dispersion systems (e.g., Eudragit^® L30D55, Eudragit^® FS30D, Eudragit^® L100-55, Eudragit^® S100 (all from Evonik Industries), Kollicoat^®

MAE30D and 30DP (from BASF), Estacryl^® 30D (from Eastman Chemical), Aquateric^® and Aquacoat^® CPD30 (from FMC), and any mixtures thereof.

The enteric coating layer can optionally contain a pharmaceutically acceptable plasticizer such as, for instance, cetanol, triacetin, citric acid esters such as, for instance, those known under the trade name Citroflex^® (Pfizer, New York), phthalic acid esters, dibutyl succinate, or similar plasticizers. The amount of plasticizer is usually optimized for each enteric coating polymer and is used in the range of about 1-40% of the enteric coating polymer. Dispersants such as talc, colorants and pigments may also be included into an enteric coating layer. The weight of enteric coating applied is about 0.5-20%, or about 2-10%, of the weight of core material or subcoated core material.

In embodiments, a coating is applied either directly onto cores or onto subcoated cores, using coating techniques such as, for instance, pan coating or fluidized bed coating, using pH independent polymers dissolved or dispersed in water and/or organic solvents, or by using suspensions of polymers, to provide a modified release of the active agent.

In embodiments, cores contain one or more release modifying polymers in admixture with omeprazole, to form a matrix. In embodiments, a modified release matrix is further coated with a pH dependent polymer or pH independent polymer, or combinations thereof.

One or more polymers that can be used in a release-controlled coating layer of the present disclosure for modified release include hydrophilic, hydrophobic, and lipophilic substances, and combinations thereof. Examples of polymers include, without limitation thereto, cellulose ethers, e.g., hydroxypropyl methylcelluloses (hypromellose or HPMC), hydroxypropylcelluloses (HPC), hydroxyethylcelluloses, ethylcelluloses, carboxymethylcellulose sodium, polyvinylpyrrolidones, including non-crosslinked polyvinylpyrrolidones,

carboxymethyl starches, polyethylene glycols, polyoxyethylenes, poloxamers (polyoxyethylene-polyoxypropylene copolymers), polyvinyl alcohols, glucanes (glucans), carrageenans, scleroglucanes (scleroglucans), mannans,

galactomannans, gellans, alginic acid and derivatives (e.g., sodium or calcium alginate, propylene glycol alginate), polyaminoacids (e.g. gelatin), methylvinyl ether/maleic anhydride copolymers, polysaccharides (e.g. carageenan, guar gum, xanthan gum, tragacanth and ceratonia), alpha-, beta- or gamma-cyclodextrins, dextrin derivatives (e.g. dextrin), hydroxypropyl methylcellulose phthalates, cellulose acetate phthalates, carboxymethylethyl celluloses, methyl methacrylate- methacrylic acid copolymers, methacrylic acid-ethyl acrylate copolymers, ethyl acrylate-methyl methacrylate-trimethyl ammonium ethyl methacrylate chloride copolymers, methyl methacrylate-ethyl acrylate copolymers, methacrylic acid- methyl acrylate-methyl methacrylate copolymers, hydroxypropyl cellulose acetate succinates, polyvinyl acetate phthalates, polymethacrylates (e.g. copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups), acrylic acid polymers (e.g., carbomers), shellac and derivatives thereof, cellulose acetates, cellulose butyrates, cellulose diacetates, cellulose triacetates, cellulose propionates, cellulose acetate butyrates, other acetylated cellulose derivatives, and the like, including any mixtures thereof.

Examples of lipophilic or hydrophobic substances that can be used in the present application include, without limitation thereto, waxes (e.g., carnauba wax , microcrystalline wax, beeswax, and polyethoxylated beeswax), natural fats (coconut, soya, and cocoa) including modified forms such as totally or partially hydrogenated, hydrogenated castor oil, hydrogenated vegetable oil, fatty acid derivatives such as mono-, bi- and tri-substituted glycerides, phospholipids, glycerophospholipids, glyceryl palmitostearate, glyceryl behenate, glyceryl monostearate, diethyleneglycol palmitostearate, polyethyleneglycol stearate, polyethyleneglycol palmitostearate, polyoxyethylene-glycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, fatty alcohols associated with polyethoxylate fatty alcohols, cetyl alcohol, stearic acid, saturated or unsaturated fatty acids and their hydrogenated derivatives, lecithin, cephalins, chitosan and derivatives thereof, sphingolipids, sterols such as cholesterol and its substituted derivatives, etc.

In embodiments, multi-particulates are coated with a gel forming polymer release-controlled coating layer, wherein the gel forming polymer release- controlled coating layer is a layer containing one or more kinds of substances such as polyethylene oxides (PEO), for example, Polyox® WSR 303, molecular weight: 7000000, Polyox® WSR Coagulant, molecular weight: 5000000, Polyox® WSR 301 , molecular weight: 4000000, Polyox® WSR N-60K, molecular weight: 2000000, and Polyox® WSR 205, molecular weight: 600000, manufactured by Dow Chemical Co., Ltd., hydroxypropyl methylcelluloses (HPMC), such as Metlose® 90SH 10000, Metlose® 90SH50000, and Metlose® 90SH30000, manufactured by Shin-Etsu Chemical Co., Ltd., carboxymethylcelluloses (CMC- Na), such as Sanlose F-1000MC, hydroxypropyl celluloses (HPC), for example, HPC-H, manufactured by Nippon Soda Co., Ltd., hydroxyethylcelluloses (HEC), carboxyvinyl polymer HIVISWAKO 103, 104 and 105 manufactured by Wako Pure Chemical Industries Ltd., carbomers such as CARBOPOL® 943 from The Lubrizol Corporation, chitosan, sodium alginate, pectin, and the like. These may be used alone or as any mixture of at least two by mixing in appropriate proportions.

In embodiments, multi-particulates are coated with a diffusion-controlled release coating layer, wherein the diffusion-controlled release coating layer is a layer containing one or more kinds of substances such as ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer (Eudragit® RS) (aminoalkylmethacrylate copolymer RS) or Eudragit® RL (aminoalkylmethacrylate copolymer RL), methyl methacrylate-ethyl acrylate copolymer (Eudragit® NE30D), ethylcelluloses, and the like. Further, these materials may be mixed in a desired ratio, and can be used by mixing with hydrophilic pore forming substances such as hydroxypropyl methylcelluloses (HPMC), hydroxypropyl celluloses (HPC), carboxyvinyl polymers, polyethylene glycols (e.g., PEG 6000), lactose, mannitol, and organic acids.

EUDRAGIT® polymers are products of Evonik Industries AG, Essen, Germany. Commercially available products include, but are not limited to, EUDRAGIT RL, EUDRAGIT RS, EUDRAGIT RL PO, EUDRAGIT RS PO, EUDRAGIT RD, EUDRAGIT L, EUDRAGIT S, EUDRAGIT L 100-5, EUDRAGIT NE 30D, and EUDRAGIT E 100.

Polymers sold as EUDRAGIT™ have the general repeating unit:

where R is COOH for the EUDRAGIT L products, R is COOCH₂N(CH₃)₂ for the EUDRAGIT E products, R is COOCH₃ for the EUDRAGIT NE 30 D product, and R is COOCH₂CH₂N⁺(CH3)₃Cr for the EUDRAGIT E and EUDRAGIT RS products. The alkyl groups vary between different products, and have 1-4 carbon atoms.

The United States Pharmacopoeia and National Formulary describes

"methacrylic acid copolymer" as a fully polymerized copolymer of methacrylic acid and an acrylic or methacrylic ester. Three types of copolymers, namely Type A, Type B, and Type C, are defined in the monograph. They vary in their methacrylic acid content and solution viscosity. Type C may contain suitable surface-active agents. The polymers, Type A (e.g., EUDRAGIT L) and Type B (e.g., EUDRAGIT S), can be referred to as "ammoniomethacrylate copolymers," consisting of fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

Similar polymers are available from other sources. Some of the products have multiple uses, such as for enteric coatings and/or intermediate coatings, for purposes of the present application.

In embodiments, the application includes modified release pharmaceutical compositions comprising omeprazole, optionally together with one or more pharmaceutically acceptable excipients, wherein said compositions are in multi- particulate form.

In embodiments, the application includes modified release pharmaceutical compositions comprising cores that comprise omeprazole, optionally together with one or more pharmaceutically acceptable excipients, and having a coating comprising one or more polymers, wherein the compositions are in multi- particulate form.

In embodiments, modified release multi-particulates of omeprazole comprise non-pareil cores such as sugar or similar substances, upon which omeprazole is coated, optionally together with one or more pharmaceutically acceptable excipients, using any of techniques such as powder layering, solution spraying, suspension spraying, and any other techniques known to those skilled in the art.

In embodiments, modified release compositions of the application comprise omeprazole-loaded non-pareil cores, having a coating comprising one or more pH independent polymers, pH dependent polymers, or combinations thereof. In embodiments, the disclosure includes pharmaceutical compositions comprising modified release multi-particulates comprising omeprazole-containing cores and a coating comprising one or more polymers, and optionally having one or more further coatings.

In embodiments, multi-particulates comprising omeprazole further contain one or more non-functional or functional coatings, to provide modified release of the active agent.

Multi-particulate formulations of the application can be prepared using the techniques described herein, as well as other methods known to those having skill in the art.

In embodiments, fractions of multi-particulates comprising omeprazole are coated with different concentrations of polymers, giving portions having different release profiles, and these can be combined to form a pharmaceutical

composition or dosage form to achieve desired modified release profiles.

In embodiments, fractions of multi-particulates comprising omeprazole are coated with different types of polymers, either enteric polymers (pH dependent polymers) or modified release polymers (pH independent polymers), giving different release profiles, and these can be combined to form a pharmaceutical composition or dosage form to achieve desired modified release profiles.

In embodiments, multi-particulates comprising omeprazole can be combined with pharmaceutically acceptable excipients and compounded to form a pharmaceutical composition, which can be compressed into tablets or placed into suitable capsule shells, using techniques known to those having skill in the art. In embodiments, compositions of the present application are filled into hard gelatin capsules, wherein empty hard gelatin capsule shells comprise one or more of hydroxymethyl celluloses, carrageenan, potassium chloride, vinyl polymers such as polyvinyl acetate and polyvinyl alcohol, and the like.

Pharmaceutically acceptable excipients according to the present application include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, anti-oxidants, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form

preparations.

Various useful fillers or diluents according to the present application include, but are not limited to, starches, lactose, mannitol (e.g., Pearlitol™ SD200), cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV) and others. Different starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (e.g., PCS PC10 from Signet Chemical Corporation), starch 1500, starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (e.g., National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include, but are not limited to, Ceolus™ KG801 , Avicel™ PH101 , PH 02, PH301 , PH302 and PH-F20, PH-112 microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include, but are not limited to, carmellose, sugar alcohols such as mannitol (e.g., Pearlitol™ SD200), sorbitol, and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful binders for use in the present application include, but are not limited to, hydroxypropylcelluloses, also called HPC (e.g., Klucel™ LF, Klucel™ EXF) and useful in various grades, hydroxypropyl methylcelluloses, also called hypromellose or HPMC (e.g., Methocel™ products) and useful in various grades, polyvinylpyrrolidones (PVP or povidone, such as grades K25, K29, K30, and K90), copovidones (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol® products), methylcelluloses, polymethacrylates, and starch.

Various useful disintegrants include, but are not limited to, carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di- sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, Kollidon™ CL (BASF, Germany), Polyplasdone™ XL, XI- 10, and INF-10 (ISP Inc., USA), and low-substituted hydroxypropylcellulose. Examples of low-substituted hydroxypropylcellulose include but are not limited to low-substituted hydroxypropylcellulose LH11 , LH21 , LH31 , LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.

Useful surface-active agents according to the present application include non-ionic, cationic, anionic, and zwitterionic surface-active agents. Useful non- ionic surface-active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (e.g., Span™ products) and polyhydroxyethylenically treated sorbitan esters (e.g., Tween™ products), aliphatic alcohols and poly(ethylene glycol) ethers, and phenol and PEG ethers. Useful cationic surface-active agents include quaternary ammonium salts (e.g. cetyltrimethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethanolamine stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate. Natural surface-active agents may also be used, such as for example phospholipids, e.g. diacylphosphatidyl glycerols, diaceylphosphatidyl cholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as, for example, soybean lecithin and egg yolk.

In embodiments, stabilized compositions of the present application contain at least one antioxidant. The antioxidant may be present either as a part of the composition or as a packaging component. Thus, in one particular embodiment of a process according to the present application, an antioxidant is introduced into the formulation during the drug loading stage over the inert cores. The

antioxidants are present in an amount effective to retard decomposition of omeprazole, as it is susceptible to oxidation.

In embodiments, the content of antioxidant in the formulation ranges from about 0.001 to 10 percent of the active agent content.

Among the antioxidants, non-limiting examples that may be used include ascorbic acid and its salts, tocopherols, sulfite salts such as sodium metabisulfite or sodium sulfite, sodium sulfide, dl-alpha-tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, and propyl gallate. Other suitable antioxidants will be readily recognized by those skilled in the art.

Useful lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and any combinations thereof.

One or more glidant materials, which improve the flow of powder blends, pellets, mini-tablets, etc., and minimize dosage form weight variations, can be used. Useful glidants include, but are not limited to, silicon dioxide, talc, and combinations thereof.

Coloring agents can be used to color code the compositions, for example, to indicate the type and dosage of the therapeutic agent therein. Coloring agents can also be used to differentiate the varied fractions of multi-particulates comprising a unit dosage form such as a capsule. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, and zinc oxide, combinations thereof, and the like.

Various solvents can be used in processes of preparation of

pharmaceutical compositions of the present application, including, but not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, Ν,Ν-dimethylformamide, tetrahydrofuran, and any mixtures thereof. In general, liquids that are used as solvents and vehicles for the various processing operations will not be present in a finished formulation, as they will be evaporated when they are no longer needed. For example, a liquid phase of a fluid coating composition will evaporate during drying, after the coating has been applied.

Useful pH independent polymers according to the present application include, but are not limited to, carbomers, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene

terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidones, polyvinyl acetates, polyvinyl alcohols,

polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters,

nitrocelluloses, methylcelluloses, ethylcelluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, hydroxybutyl methylcelluloses, natural polymers such as alginates and other polysaccharides that include, but are not limited to, arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans, xylans (such as, for example, inulin), levan, fucoidan, carrageenan, galatocarolose, pectic acid, pectin, amylose, pullulan, glycogen; amylopectin, dextran, pustulan, chitin, agarose, keratan, chondroitan, dermatan, hyaluronic acid, alginic acid, xanthan gum, starches and various other natural homopolymer or heteropolymers such as those containing one or more of aldoses, ketoses, acids or amines, erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, mannitol, sorbitol, lactose, sucrose, trehalose, maltose, cellobiose, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine, and neuraminic acid, and naturally occurring derivatives thereof, and including dextran and cellulose, collagen, chemical derivatives thereof (e.g., from substitutions and additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, synthetic polymers such as polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho esters), polyurethanes, poly(butyric acid), poly(valeric acid), poly(caprolactone), poly(hydroxybutyrate), poly(lactide-co-glycolide), poly(lactide-co-caprolactone) copolymers, and any mixtures thereof.

Various pH dependent polymers for use in the present application include, but are not limited to, Eudragit® 100, and Eudragit® ND 40, polymers and copolymers of acrylic and methacrylic acids, cellulose acetate butyrates, cellulose acetate phthalates, hydroxypropyl methylcellulose phthalates, poly(methyl methacrylate) polymers, poly(ethylmethacrylate) polymers,

poly(butylmethacrylate) polymers, poly(isobutylmethacrylate) polymers, poly(hexylmethacrylate) polymers, poly(isodecylmethacrylate) polymers, poly(lauryl methacrylate) polymers, poly(phenylmethacrylate) polymers, poly(methyl acrylate) polymers, poly(isopropyl acrylate) polymers, poly(isobutyl acrylate) polymers, poly(octadecyl acrylate) polymers, and any mixtures thereof. In embodiments, one or more pH independent or pH dependent polymers are used for coating the compositions of the present application, including but not limited to Eudragit® RS PO and RL PO.

Useful additives for coating include, but are not limited to, plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.

Various useful plasticizers include, but are not limited to, substances such as castor oil, diacetylated monoglycerides, dibutyl sebaciate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. An opacifier like titanium dioxide may also be present, in amounts ranging from about 0.5% to about 20%, based on the total weight of the coating.

Anti-adhesives are frequently used in film coating processes to avoid sticking effects during film formation and drying. An example of a useful anti- adhesive for this purpose is talc. The anti-adhesive is frequently present in the film coating in an amount of about 0.5% (w/w) to 15% (w/w) based upon the total weight of the coating.

The foregoing descriptions of excipients are not intended to be exhaustive. Those skilled in the art will be aware of many other substances that are useful in the practice of the application, and the use of such substances is specifically included in this application.

In an aspect, the disclosure includes methods of preparing pharmaceutical compositions of the present application.

In embodiments, the disclosure includes pharmaceutical compositions of omeprazole that may be prepared by spray drying a suspension or solution comprising omeprazole and a water soluble sugar derivative, with or without an organic base and optionally together with one or more pharmaceutically acceptable excipients. Alternatively, omeprazole compositions may be prepared using fluid bed granulation techniques, where a solution or suspension of omeprazole, with or without a stabilizer and optionally together with one or more pharmaceutically acceptable excipients, is sprayed onto pharmacologically inert particulates, or layered on the inert particulates. In specific embodiments, compositions of the present disclosure may be prepared by processes including: (a) dissolving omeprazole or a pharmaceutically acceptable salt thereof in an organic solvent; (b) adding a water-soluble excipient, which acts as stabilizer; (c) optionally, adding one or more pharmaceutically acceptable excipients such as an alkaline compound, a binder, polymer, and/or a disintegrant to the solution; (d) spraying the solution onto a substrate comprising at least one diluent, optionally together with a disintegrant, to obtain a granulated mass; (e) drying the mass; (f) optionally, milling the mass; (g) mixing one or more excipients such as diluent, disintegrant, lubricant and/or glidant with the dried mass of (e) or milled mass of (f); (h) compressing the material of (g) to form mini- tablets; (i) optionally subcoating the mini-tablets; (j) coating the mini-tablets of (h) or (i) with a pH dependent polymer or a pH independent polymer; and (k) filling the coated mini-tablets into a capsule. In variations, a capsule comprises at least two fractions of coated mini-tablets, wherein one fraction is coated with one or more pH independent polymers and the other fraction is coated with one or more pH dependent polymers. In other variations, the capsule comprises at least two different fractions of coated mini-tablets, wherein fractions are independently coated with one or more pH independent polymers or one or more pH dependent polymers.

In embodiments, compositions of the present disclosure may be prepared by processes including: (a) dissolving omeprazole or a pharmaceutically acceptable salt thereof in an organic solvent; (b) adding a water-soluble excipient, which acts as stabilizer; (c) adding a dissolution enhancer; (d) optionally, adding one or more pharmaceutically acceptable excipients such as an alkaline compound, a binder, a polymer, and/or a disintegrant to the solution; (e) spraying the solution onto a substrate comprising at least one diluent, optionally together with a disintegrant, to obtain a granulated mass; (f) drying the mass; (g) optionally, milling the mass; (h) mixing one or more excipients such as a diluent, disintegrant, lubricant, and/or glidant with the dried mass of (f) or milled mass of (g); (i) compressing the material of (h) to form mini-tablets; (j) optionally sub-coating the mini-tablets; (k) coating the mini-tablets of (i) or (j) with a pH dependent polymer or a pH independent polymer; and (I) filling the coated mini-tablets into capsules. In variations, the capsule comprises at least two fractions of coated mini-tablets, wherein one fraction is coated with one or more pH independent polymers and the other fraction is coated with one or more pH dependent polymers. In variations, a capsule comprises at least two different fractions of coated mini-tablets, the fractions being independently coated with one or more pH independent polymers or one or more pH dependent polymers.

In embodiments, compositions of the present disclosure may be prepared by processes including: (a) dissolving omeprazole or a pharmaceutically acceptable salt thereof in an organic solvent; (b) adding a water-soluble excipient, which acts as stabilizer; (c) adding a dissolution enhancer; (d) optionally, adding one or more pharmaceutically acceptable excipients such as a alkaline

compound, binder, polymer, and/or disintegrant to the solution; (e) coating sugar spheres with the drug solution; (f) drying the particles; (g) optionally subcoating the drug layered particles; (f) coating the particles of (f) or (g) with a pH dependent polymer or a pH independent polymer; and (h) filling the coated particles into capsules. In variations, a capsule contains at least two fractions of coated particles, wherein one fraction is coated with one or more pH independent polymers and the other fraction is coated with one or more pH dependent polymers. In variations, a capsule comprises at least two different fractions of coated particles, wherein the fractions are independently coated with one or more pH independent polymers or one or more pH dependent polymers.

In embodiments, omeprazole compositions may be prepared using powder layering techniques, wherein a powder comprising omeprazole, a stabilizer, and a dissolution enhancer, optionally, together with one or more other pharmaceutically acceptable excipients, is layered onto pharmacologically inert particles, while being sprayed with a binder solution. In specific embodiments, compositions of the present application may be prepared by processes including: (a) preparing a drug layering powder by mixing the drug with a water-soluble excipient, dissolution enhancer, and diluent, optionally together with one or more pharmaceutically acceptable excipients such as an alkaline compound and/or a disintegrant; (b) preparing a binder solution; (c) coating sugar spheres with drug layering powder, while spraying the binder solution to obtain drug layered pellets; (d) drying the pellets; (e) optionally, sub-coating the drug layered pellets; (f) coating the pellets of (d) or (e) with a pH dependent polymer or a pH independent polymer; and (g) filling the coated pellets into capsules. In variations, a capsule comprises at least two fractions of coated pellets, wherein one fraction is coated with one or more pH independent polymers and the other fraction is coated with one or more pH dependent polymers. In variations, a capsule comprises at least two different fractions of coated pellets, wherein the fractions are independently coated with one or more pH independent polymers or one or more pH dependent polymers.

Equipment suitable for processing the pharmaceutical compositions of the present application include any one or more of rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, blenders, roller compactors, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, multi-mills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like.

In embodiments, the disclosure includes forms of packaging for

omeprazole compositions, to provide stability during storage and transportation. Stabilization of the omeprazole compositions of the present application can be improved by using package forms such as packages inhibiting the permeation of oxygen and moisture, packages having an inert gas atmosphere (where air is replaced with gases not comprising oxygen), vacuum packages, and packages having an enclosed deoxidizer. The stabilization is improved by reducing oxygen amounts with which the solid preparations are directly brought into contact, using these package forms. When a deoxidizer is enclosed, the pharmaceutical solid preparation is packaged with an oxygen permeating material, and it may be contained within another package. Oxygen absorbents such as Stabilox® products are useful in minimizing the degradation of active agent due to oxidation.

In embodiments, compositions of the present disclosure include a desiccant and/or an oxygen absorbent as a component of packaging. A desiccant is a hygroscopic substance that induces or sustains a state of dryness

(desiccation) in its local vicinity in a well-sealed container. Commonly encountered pre-packaged desiccants are solids in pouches, and work through absorption or adsorption of water, or a combination of the two. Desiccants for specialized purposes may be in forms other than solid, and may work through other principles, such as chemical bonding of water molecules. Pre-packaged desiccants are most commonly used to remove excessive humidity that would normally degrade or even destroy products sensitive to moisture. Non-limiting examples of various desiccants are anhydrous calcium sulfate (e.g., Drierite®), silica gels, calcium chloride, montmorillonite clays, and molecular sieves.

In an aspect, the application provides methods of treating gastrointestinal inflammatory diseases and gastric acid-related diseases in mammals and man, including reflux esophagitis, gastritis, duodenitis, gastric ulcer, and duodenal ulcer, by administering the formulations and pharmaceutical compositions of the present application. The compounds and compositions of this application may be administered to a subject in a therapeutically effective amount.

The pharmaceutical dosage forms of the present application are intended for oral, buccal, or sublingual administration to a patient in need thereof.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. As used herein, the term "omeprazole" includes the compound omeprazole, pharmaceutically acceptable salts, esters, pro-drugs thereof, the active metabolites of omeprazole and the prodrugs thereof, and their polymorphs, solvates and hydrates.

The term "pharmaceutically acceptable salt" as used herein refers to salts which are known to be non-toxic and are commonly used in pharmaceutical practice. Such pharmaceutically acceptable salts include metal salts, salts with organic bases, salts with basic amino acids, etc. Metal salts include, for example, alkali metal salts, such as sodium and potassium salts, and alkaline earth metal salts, such as calcium, magnesium, and barium salts. Salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexyl amine, N,N- dibenzylethylenediamine, etc. Salts with basic amino acids include, for example, salts with arginine, lysine, etc. Acid addition salts such as hydrochloride salts and the like are also included.

In the present application, omeprazole and its salts can be used in any crystalline form, amorphous form, or combinations thereof.

The term "modified release" (MR) according to the present disclosure implies that the drug release can be delayed release (DR), extended release (ER), sustained release (SR), pulsatile release (PSR), or prolonged release (PR), or a combination of immediate release and one or more of delayed release, extended release, sustained release, pulsatile release, and prolonged release.

The term "delayed release" according to the present disclosure implies that the drug is not substantially released in the stomach region of the gastrointestinal tract (GIT); instead, drug release takes place substantially in the upper part of the intestine or a later part of the intestinal tract.

The term "sustained release" according to the present disclosure implies that the drug is released with varied quantities substantially throughout the GIT in a controlled manner.

The term "pulsatile release" according to the present disclosure implies that the drug is released as one or more pulses in any part of the GIT, immediately or in a delayed manner.

The term "extended release" according to the present disclosure implies that the drug is not substantially released in the stomach region of the GIT;

instead, drug release takes place substantially in the upper part of the intestine over an extended duration of time.

The term "prolonged release" according to the present disclosure implies that little drug is released immediately, i.e., the initial drug release starts after a lag time, followed by immediate release of the drug or in a portion of the GIT or varied quantities of drug release throughout the GIT thereafter.

The term "release-controlled coating-layer" according to the present disclosure implies a coating layer having a function of delaying or extending the release of active ingredient, such as a "pH-dependently soluble layer", or a "diffusion-controlled layer" or by an eroding or disintegrating mechanism.

The term "pH-dependently soluble release-controlled coating layer" according to the present disclosure implies a coating layer that does not dissolve or decompose in the acidic pH of the stomach, and dissolves or decomposes in the intestine.

The term "diffusion-controlled coating layer" according to the present disclosure implies a coating layer which itself is not dissolved and which releases an active ingredient through pores that are formed in the layer.

The term "gel-forming polymer coating layer" according to the present disclosure implies a coating layer that rapidly forms highly viscous gels upon contacting water, and prolongs the retention time in the digestive tract. The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, such as a filler, diluent, carrier, etc. The excipients that are useful in preparing a

pharmaceutical composition are generally safe, non- toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. An "excipient" or "pharmaceutically acceptable excipient" as used in the specification includes both one and more than one such excipient.

The term "acid-labile compound" means any compound, which is not stable in acidic conditions or which undergoes degradation or hydrolysis via acid or proton catalyzed reactions.

A polymeric substance that "dissolves" or is "soluble" in a particular aqueous environment to facilitate release of the drug from a formulation, whether at particular pH conditions or independently of pH, may not actually form a solution. It is considered to dissolve or be soluble if it swells sufficiently to have characteristics of a dissolved species, decomposes, or forms a solution.

Certain specific aspects and embodiments are more particularly described in the following examples, being provided solely for purposes of illustration, and the scope of the application is not to be limited thereto.

EXAMPLE 1 : Omeprazole-containing pellets.

Ingredient Grams

A. Seal Coating

Sugar spheres (25-30 mesh) 35

Hypromellose, 5 cps (Methocel E5 Premium) 1.75

Water* q.s.

B. Drug Coating

Omeprazole 20

Hypromellose, 5 cps (Methocel E5 Premium) 5

Meglumine 2.5

Poloxamer 407 (Pluronic F127) 2.5

Water* q.s.

C. Subcoating Hypromellose, 5 cps (Methocel E5 Premium) 8.6

Talc 1.3

Titanium dioxide 1.3

Water* q.s.

D. Enteric Coating

Eudragit L 100 55 30

Triethyl citrate^" 3

Talc 3

Isopropyl alcohol^* q.s.

E. Lubrication

Talc 0.05

* Evaporates during processing.

Manufacturing procedure:

A. Seal Coating

1. Hypromellose is dissolved in water and sprayed onto sugar spheres, using a fluid bed processor (FBP), to achieve a weight gain of 5% after drying, and the coated spheres are dried.

B. Drug Loading

1. Hypromellose, poloxamer 407, and meglumine are mixed with water.

2. Omeprazole is added to the material of step 1 with stirring for at least 15 minutes.

3. Seal coated pellets from step A1 are coated with the material of step 2 using a FBP.

C. Subcoating

1. Hydroxypropyl methylcellulose is dissolved in water.

2. Talc and titanium dioxide are homogenized in water.

3. The dispersion of step 2 is mixed with the polymer solution of 1 and stirred.

4. The dispersion is sprayed onto drug loaded pellets from step B3, using a FBP, to achieve a weight gain of 16% after drying.

D. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100 55 is added to the solution of step 1 , with stirring. 3. Talc is added to solution of step 2 and continuously stirred throughout the coating process.

4. The dispersion of step 3 is sprayed onto sub-coated pellets from step C4 to achieve a weight gain of 45±5% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

6. The cured pellets are sifted through a 16 mesh sieve, and then through a 24 mesh sieve, and particles retained on the 24 mesh sieve are used for further processing.

E. Lubrication

1. Blend the pellets of step D6 with talc.

EXAMPLE 2: Omeprazole-containing pellets.

Ingredient Grams

A. Seal Coating

Sugar spheres (25-30 mesh) 130

Hypromellose, 5 cps (Methocel E5 Premium) 6.5

Water* q.s.

B. Drug Coating

Omeprazole 20

Hypromellose, 5 cps (Methocel E5 Premium) 5

Meglumine 2.5

Poloxamer 407 (Pluronic F127) 2.5

Water* q.s.

C. Subcoating

Hypromellose, 5 cps (Methocel E5 Premium) 20.2

Talc 2.9

Titanium dioxide 2.9

Water* q.s

D. Enteric Coating

Eudragit L 100 55 30

Triethyl citrate 6

Talc 3

Isopropyl alcohol* q.s. E. Lubrication

Talc 0.5

^* Evaporates during processing.

Manufacturing procedure:

A. Seal Coating

1. Hypromellose is dissolved in water and sprayed onto sugar spheres, using a fluid bed processor (FBP), to achieve a weight gain of 5% after drying.

B. Drug Loading

1. Hypromellose, poloxamer 407, and meglumine are dissolved in water.

2. Omeprazole is added to the dispersion of step 1 , with stirring for at least 15 minutes.

3. Seal coated pellets from step A1 are coated with the dispersion of 2, using a FBP.

C. Subcoating

1. Hydroxypropyl methylcellulose is dissolved in water.

2. Talc and titanium dioxide are homogenized in water.

3. The dispersion of step 2 is mixed with the polymer solution of step 1 and stirred.

D. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100 55 is added to the solution of step 1 , with stirring.

3. Talc is added to the solution of step 2 and continuously stirred throughout the coating process.

4. The dispersion of 3 is sprayed onto sub-coated pellets from step C4 to achieve a weight gain of 20±5% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

6. The cured pellets are sifted through a 16 mesh sieve, then through a 24 mesh sieve, and particles retained on the 24 mesh sieve are used for further processing.

E. Lubrication 1. Blend the pellets of step D6 with talc.

EXAMPLE 3: Omeprazole capsule formulation.

* Evaporates during processing.

Manufacturing procedure:

A. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100 55 is added to the solution of step 1 , with stirring.

3. Talc is added to solution of step 2 and continuously stirred throughout the coating process.

4. The dispersion of step 3 is sprayed onto subcoated pellets to achieve target weight gain of 60±5% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

6. The dried pellets are sifted through a 16 mesh sieve, then through a 24 mesh sieve, and particles retained on the 24 mesh sieve are used for further processing.

B. Overcoating

1. Triethyl citrate is dissolved in methanol. 2. Eudragit L100 -55 and Eudragit RL PO is added to the solution of step 1 , with stirring.

4. The dispersion of 3 is sprayed onto enteric-coated pellets to achieve target weight gain of 15 ± 5% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

C. Lubrication and Encapsulation

1. Blend the pellets from step B6 with talc.

2. Fill 1 14 mg of pellets from Example 1 and 1 5 mg of pellets from step 1 into a capsule.

Capsules are tested for their dissolution characteristics using the USP method, by immersion of the capsules into a pH 6.5 buffer medium and periodically analyzing for the drug content in the medium. Fig. 3 shows the results, where the y-axis is the cumulative percentage of contained drug that dissolves and the x-axis is minutes.

EXAMPLE 4: Omeprazole capsule formulation.

Ingredient Grams

Subcoated pellets from Example 1 77.95

A. Enteric Coating

Eudragit L 100 55 40

Triethyl citrate 4

Talc 4

Isopropyl alcohol* q.s.

B. Overcoating

Eudragit RL PO 7.59

Eudragit L 100 55 7.59

Talc . 2.28

Triethyl citrate 1.52 Methanol^* q.s.

Lubrication

Talc 0.07

^* Evaporates during processing.

Manufacturing procedure:

A. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100 55 is added to the solution of step 1 , with stirring.

4. The dispersion of step 3 is sprayed onto subcoated pellets to achieve a weight gain of 60±5% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

6. The dried pellets are sifted through a 16 mesh sieve, and then through a 24 mesh sieve, and particles retained on the 24 mesh sieve are used for further processing.

B. Overcoating

1. Triethyl citrate is dissolved in methanol.

2. Eudragit^® L100 -55 and Eudragit RL PO are added to the solution of step 1 , with stirring.

4. The dispersion of step 3 is sprayed onto enteric coated pellets from step

A6 to achieve a weight gain of 15±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

6. The dried pellets are sifted through a 14 mesh sieve, then through a 24 mesh sieve, and particles retained on the 24 mesh sieve are used for further processing.

C. Lubrication and Encapsulation

1. Blend the pellets from step B6 with talc.

2. Fill 114 mg of pellets from Example 1 and 145 mg of pellets from step 1 into a capsule. EXAMPLE 5: Omeprazole capsule formulation.

* Evaporates during processing.

Manufacturing procedure:

A. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100- 55 is added to the solution of step 1 , with stirring.

5. The pellets are cured in the FBP for 2 hours at 40°C.

B. Overcoating

1. Triethyl citrate is dissolved in methanol.

2. Eudragit^® L100 -55 and Eudragit RL PO are added to the solution of step 1 , with stirring. 3. Talc is added to solution of step 2 and continuously stirred throughout the coating process.

4. The dispersion of step 3 is sprayed onto enteric coated pellets to achieve a weight gain of 15±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

C. Lubrication and Encapsulation

1. Blend the pellets from step B6 with talc.

2. Fill 114 mg of pellets from Example 1 and 145 mg of pellets from step 1 into a capsule.

EXAMPLE 6: Omeprazole capsule formulation.

* Evaporates during processing.

Manufacturing procedure:

A. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol. 2. Eudragit^® L 100 -55 is added to the solution of step 1 , with stirring.

5. The pellets are cured in the FBP for 2 hours at 40°C.

B. Overcoating

1. Triethyl citrate is dissolved in methanol.

4. The dispersion of step 3 is sprayed onto enteric coated pellets from step A6 to achieve a weight gain of 15±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

C. Lubrication and Encapsulation

1. Blend the pellets of step B6 with talc.

2. Fill 1 14 mg of pellets from Example 1 and 145 mg of pellets from step 1 into a capsule.

EXAMPLE 7: Omeprazole capsule formulation

Ingredient Grams

Subcoated pellets from Example 1 77.95

A. Enteric Coating

Eudragit L 100 55 45.56

Triethyl citrate 4.56

Talc 4.56 Isopropyl alcohol* q.s.

B. Overcoating

Eudragit RL PO 12.8

Eudragit L 100 55 3.2

Talc 2.4

Triethyl citrate 1.6

Methanol* q.s.

C. Final Coating

Eudragit L 100 55 10.47

Triethyl citrate 1.05

Talc 1.05

Isopropyl alcohol* q.s.

Lubrication

Talc 0.1

^* Evaporates during processing.

Manufacturing procedure:

A. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100 55 is added to the solution of step 1 , with stirring.

5. The pellets are cured in the FBP for 2 hours at 40°C.

B. Overcoating

1. Triethyl citrate is dissolved in methanol.

2. Eudragit^® L100 55 and Eudragit RL PO are added to the solution of step 1 , with stirring.

3. Talc is added to solution of step 2 and continuously stirred throughout the coating process. 4. The dispersion of step 3 is sprayed onto overcoated pellets from step A6 to achieve a weight gain of 15±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

C. Final Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100- 55 is added to the solution of step 1 , with stirring.

4. The dispersion of step 3 is sprayed onto overcoated pellets to achieve a weight gain of 10±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

D. Lubrication and Encapsulation

1. Blend the pellets from step C6 with talc.

2. Fill 1 14 mg of pellets from Example 1 and 165.3 mg of pellets from step 1 into a capsule.

EXAMPLE 8: Omeprazole capsule formulation.

Ingredient Grams

Subcoated pellets from Example 1 77.95

A. Enteric Coating

Eudragit L 100 55 45.56

Triethyl citrate 4.56

Talc 4.56

Isopropyl alcohol* q.s.

B. Overcoating

Eudragit RL PO 8.53

Eudragit L 100 55 2.13 Talc 1.6

Triethyl citrate 1.066

Methanol^* q.s

C. Lubrication

Talc 0.5

* Evaporates during processing.

Manufacturing procedure:

A. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit L 100 55 is added to the solution of step 1 , with stirring.

4. The dispersion of 3 is sprayed onto subcoated pellets to achieve a weight gain of 70±5% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

B. Overcoating

1. Triethyl citrate is dissolved in methanol.

4. The dispersion of step 3 is sprayed onto enteric coated pellets from step

A6 to achieve a weight gain of 10±2% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

C. Lubrication and Encapsulation

1. Blend the pellets from step B6 with talc. 2. Fill 1 14 mg of pellets from Example 1 and 146.5 mg of pellets from step 1 into a capsule.

EXAMPLE 9: Omeprazole capsule formulation.

* Evaporates during processing.

Manufacturing procedure:

A. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100 55 is added to the solution of step 1 , with stirring. 3. Talc is added to the solution of step 2 and continuously stirred throughout the coating process.

4. The dispersion of step 3 is sprayed onto subcoated pellets to achieve a weight gain of 70±5% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

B. Overcoating 1. Triethyl citrate is dissolved in methanol.

2. Eudragit® L100 -55 and Eudragit RL PO are added to the solution of 1 , with stirring.

3. Talc is added to solution of 2 and continuously stirred throughout the coating process.

4. The dispersion of 3 is sprayed onto enteric coated pellets from step A6 to achieve a weight gain of 15±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

C. Lubrication and Encapsulation

1. Blend the pellets from step B6 with talc.

2. Fill 1 14 mg of pellets from Example 1 and 152.7 mg of pellets from step 1 into a capsule.

EXAMPLE 10: Omeprazole capsule formulation.

* Evaporates during processing. Manufacturing procedure:

A. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit® L 100 55 is added to the solution of stepl , with stirring.

4. The dispersion of step 3 is sprayed onto subcoated pellets to achieve a weight gain of 80±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

6. The dried pellets are sifted through a 16 mesh sieve, and then a 24 mesh sieve, and particles retained on the 24 mesh sieve are used for further processing.

B. Overcoating

1. Triethyl citrate is dissolved in methanol.

2. Eudragit® L100 -55 and Eudragit RL PO are added to the solution of step 1 , with stirring.

4. The dispersion of step 3 is sprayed onto enteric-coated pellets to achieve a weight gain of 10±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

C. Lubrication and Encapsulation

1. Blend the pellets of step B6 with talc.

2. Fill 1 14 mg of pellets from Example 1 and 153.6 mg of step 1 pellets into a capsule. EXAMPLE 1 1 : Omeprazole formulation.

Ingredient Grams

Subcoated pellets from Example 1 77.95

A. Enteric Coating Eudragit L 100 55 52.06

Triethyl citrate 5.206

Talc 5.206

Isopropyl alcohol* q.s.

B. Overcoating

Eudragit RL PO 6.77

Eudragit L 100 55 4.52

Talc 1.69

Triethyl citrate 1.13

Methanol^* q.s.

C. Lubrication

Talc 0.5

^* Evaporates during processing.

Manufacturing procedure:

A. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit L 100 55 is added to the solution of 1 , with stirring.

4. The dispersion of step 3 is sprayed onto subcoated pellets, to achieve a weight gain of 80±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

B. Overcoating

1. Triethyl citrate is dissolved in methanol.

4. The dispersion of step 3 is sprayed onto enteric-coated pellets to achieve a weight gain of 10±3% after drying, using a FBP (bottom spray). 5. The pellets are cured in the FBP for 2 hours at 40°C.

C. Lubrication and Filling

1 . Blend the pellets with talc.

2. Fill 1 14 mg of pellets from Example 1 and 155 mg of step 1 pellets into a capsule. EXAMPLE 12: Omeprazole capsule formulation.

Ingredient mg/Capsule

Pellets from Example 3 147.216

A. Subcoating 1

Hypromellose, 5 cps (Methocel E5 Premium) 17.2

Talc 2.6

Titanium dioxide 2.6

Water* q.s.

B. Drug Coating

Omeprazole 20

Hypromellose, 5 cps (Methocel E5 Premium) 5

Meglumine 2.5

Poloxamer 407 (Pluronic F127) 2.5

Water* q.s.

C. Subcoating 2

Hypromellose, 5 cps (Methocel E5 Premium) 17.2

Talc 2.6

Titanium dioxide 2.6

Water* q.s

D. Enteric Coating

Eudragit L 100 55 30

Triethyl citrate 3

Talc 3

Isopropyl alcohol* q.s. E. Lubrication

Talc 1.3

* Evaporates during processing.

Manufacturing procedure:

A. Subcoating 1

1. Hypromellose is dissolved in water.

2. Talc and titanium dioxide are homogenized in water.

3. The dispersion of step 2 is mixed with the polymer solution of step 1.

4. The dispersion is sprayed onto Example 3 pellets, using a FBP, to achieve a weight gain of 16+2% after drying.

B. Drug Loading

1. Hypromellose, poloxamer 407, and meglumine are dissolved in water.

2. Omeprazole is added to the dispersion of step 1 with stirring for at least 15 minutes.

3. Subcoated pellets from step A4 are coated with the dispersion of step 2 using a FBP.

C. Subcoating 2

1. Hypromellose is dissolved in water.

2. Talc and titanium dioxide are homogenized in water.

3. The dispersion of step 2 is mixed with the polymer solution of step 1.

4. The solution is sprayed onto drug loaded pellets, using a FBP, to achieve a weight gain of 12% after drying.

D. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100 55 is added to the solution of step 1 , with stirring.

4. The dispersion of step 3 is sprayed onto subcoated pellets from step C4 to achieve a weight gain of 17±2% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

6. The dried pellets are sifted through a 12 mesh sieve, then through a 20 mesh sieve, and particles retained on the 20 mesh sieve are used for further processing. E. Lubrication and Encapsulation

1. Blend the pellets of step D6 with talc.

2. Fill the pellets of step 1 into capsules.

In each of Examples 3-11 , combinations of the polymers Eudragit L 100 55 and Eudragit RL PO are used for overcoating. These polymers can be used in weight ratios of 1 :9 to 9:1 , in variations of the formulations. Further, in these examples Eudragit L 100 55 can be replaced with Eudragit L 100, and Eudragit RL PO can be replaced with Eudragit RS PO, and they can be used in the same ratios.

In variations, pellets from either of Examples 1 and 2 can be combined with pellets prepared in any of Examples 3-1 1 , and these pellet mixtures can optionally be blended with polyethylene oxide and filled into capsules.

This application also encompasses formulations comprising enteric coated pellets obtained from Example 1 , equivalent 10-20 mg of active agent, and pellets obtained from any of Examples 3-8, equivalent to 20-50 mg of active agent, the pellets being combined and filled into a capsule. Various permutations and combinations will be made, based upon the desired weight of active agent in a unit dose, e.g., ranging from 40-60 mg. EXAMPLE 13: Omeprazole 60 mg capsule formulation.

mg/Capsule

Ingredient Type A Type B

Pellets (DR) Pellets (ER)

Seal Coa ting

Sugar spheres (25-30 mesh) 35 70

Hydroxypropyl methylcellulose, 5 cps

1.75 3.5

(Methocel E5 Premium)

Water* q.s.

Drug Coating

Omeprazole 20 40

Hydroxypropyl methylcellulose, 5 cps

5 10

(Methocel E5 Premium)

Meglumine 2.5 5 Poloxamer 407 (Pluronic F127) 2.5 5

Water* q s.

Subcoating

Hydroxypropyl methylcellulose, 5 cps

8.6 17.2 (Methocel E5 Premium)

Talc 1.3 2.6

Titanium dioxide 1 .3 2.6

Water* q s. q.s.

Enteric Coating

Methacrylic acid copolymer, type C

20 97.62 (Eudragit L 100-55)

Triethyl citrate 2 9.78

Talc 2 9.78

Isopropyl alcohol* q.s. q.s.

Extended Release Coating

Ammonio methacrylate copolymer,

- 20.98 Type A (Eudragit RLPO)

Methacrylic acid copolymer, type C

- 5.24 (Eudragit L 100-55)

Talc - 3.94

Triethyl citrate - 2.62

Methanol* - q.s.

Lubrication

Talc 1 1

* Evaporates during processing.

Manufacturing procedure:

A. Seal Coating

1. Hypromellose is dissolved in water and sprayed onto sugar spheres, using a fluid bed processor (FBP).

B. Drug Loading '

1. Hypromellose, poloxamer 407, and meglumine are mixed with water.

2. Omeprazole is added to the dispersion of step 1. 3. Seal coated pellets from step A1 are coated with the dispersion of 2, using a FBP.

C. Subcoating

1. Hydroxypropyl methylcellulose is dissolved in water.

2. Talc and titanium dioxide are homogenized in water.

D. Enteric Coating

1. Triethyl citrate is dissolved in isopropyl alcohol.

2. Eudragit^® L 100 55 is added to the solution of step 1 , with stirring.

3. Talc is added to the solution of step 2 and the mixture is continuously stirred throughout the coating process.

4. The dispersion of 3 is sprayed onto subcoated pellets from step C4 to achieve a weight gain of 20±5% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

E. Extended Release Coating

1. Triethyl citrate is dissolved in methanol.

4. The dispersion of step 3 is sprayed onto over coated pellets from step D6 to achieve a weight gain of 15±3% after drying, using a FBP (bottom spray).

5. The pellets are cured in the FBP for 2 hours at 40°C.

F. Lubrication

1. Blend the pellets of step D6 and step E with talc. G. Encapsulation

1. Lubricated pellets of Type A and Type B are filled into capsules.

The capsules are packaged in aluminum foil blisters and stored for one month at 40°C and 75% RH. The samples are analyzed before and after storage, giving results as tabulated below. Values for the drug assay and impurities are percentages of the label drug content, and the loss on drying is expressed as a percentage of the formulation weight.

The identified impurities have the following structures.

Name Chemical Structure

N-oxide impurity

(Impurity 1 )

H

Benzimidazole impurity

(Impurity 2)

Six of the capsules as prepared, and after the storage for one month at °C and 75% RH, are subjected to drug dissolution testing in 500 mL of 0.1 N HCI for 2 hours, then in 900 mL of pH 7.0 phosphate buffer with 5 mM SLS for 105 minutes, using a paddle apparatus with 75 rpm stirring, and the results are tabulated below.

The dissolution profile of the formulation as prepared is shown in Fig. 2, from a test according to the USP method using 0.1 N HCI for the first 2 hours, then a pH 6.5 FaSSIF buffer for the remainder of the test, with 900 mL of media and a paddle apparatus stirred at 75 rpm. The y-axis is cumulative percentage of the contained drug dissolved, and the x-axis is minutes.

Claims

CLAIMS:

1 . A pharmaceutical formulation comprising, in combination:

a) one or more particles containing omeprazole or a salt thereof and having a drug release modifying coating comprising one or more of the polymers hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate,

carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate, or shellac, the coating being soluble at pH values about 5 to about 7.5; and

b) one or more particles containing omeprazole or a salt thereof and having a polymer coating that is soluble at pH values about 5 to about 6.

2. A pharmaceutical formulation according to claim 1 , wherein a particle of a) is a tablet.

3. A pharmaceutical formulation according to claim 1 , wherein particles of a) are granules.

4. A pharmaceutical formulation according to claim 1 , wherein a particle of b) is a tablet.

5. A pharmaceutical formulation according to claim 1 , wherein particles of b) are granules or pellets.

6. A pharmaceutical formulation according to claim 1 , wherein particles of a) and b) are granules or pellets.

7. A pharmaceutical formulation according to claim 1 , wherein particles of a) and b) have intermediate coatings that do not substantially affect drug release, upon which a polymer coating is applied.

8. A pharmaceutical formulation according to claim 1 , wherein a drug release modifying coating of a) is soluble at pH values between 5.5 and 7.

9. A pharmaceutical formulation according to claim 1 , wherein a polymer coating in b) comprises a combination of two or more methyl

methacrylate-methacrylic acid copolymers that individually provide different drug release properties.

10. A pharmaceutical formulation according to claim 1 , wherein a drug release modifying coating in a) is pH independent, and a polymer coating in b) comprises a combination of pH independent and pH dependent polymers.

1 1 . A pharmaceutical formulation according to claim 1 , containing about 50 to about 70 mg of omeprazole.

12. A pharmaceutical formulation according to claim 1 , containing about 60 mg of omeprazole.

13. A pharmaceutical formulation according to claim 1 , wherein a) contains about 20 mg of omeprazole and b) contains about 40 mg of omeprazole.

14. A pharmaceutical formulation according to any of claims 1 -13, which is in the form of a capsule.

15. A pharmaceutical formulation according to any of claims 1 -13, comprising:

(i) at least one particle comprising a proton pump inhibitor, the particle being coated with a pH-dependent polymer coating; and

(ii) at least one particle comprising a proton pump inhibitor, the particle being coated with a pH-independent polymer coating, and further coated with a pH-dependent extended release coating;

and producing a maximum plasma concentration of the proton pump inhibitor at least two hours after oral administration of the formulation.