WO2011140446A2 - Pharmaceutical formulations - Google Patents

Abstract

A particulate pharmaceutical composition for oral use comprising a) cores comprising an effective amount of a substituted benzimidazole drug and a stabilizing agent, present in an amount effective to stabilize the drug, b) an intermediate/barrier layer, and c) an outer enteric coating layer. Coated particleses may be further overcoated and co-granulated with one or more excipients.

Description

PHARMACEUTICAL FORMULATIONS

INTRODUCTION

Aspects of the present application relate to pharmaceutical formulations comprising at least one acid labile pharmaceutically active substance, for oral use, processes for the manufacture of formulations, and methods of preventing or treating diseases or disorders using the formulations. In aspects, this application provides methods for producing a gastric acid secretion inhibitory effect to a subject in need thereof, by administering an effective amount of the

pharmaceutical formulations. The present application, in particular aspects and embodiments, comprises at least one substituted benzimidazole derivative, such as esomeprazole magnesium, as an active agent.

Substituted benzimidazoles are potent inhibitors of gastric acid secretion. These compounds are susceptible to degradation and/or transformations in both acid and neutral media. The decomposition of these acid labile compounds can be due to acid catalyzed reactions. Therefore, such labile drugs need to be

formulated in a way to stabilize the compositions. Some acid-labile drugs are substituted benzimidazole gastric anti-secretory agents, such as omeprazole, esomeprazole, and pharmaceutically acceptable salts thereof. These agents are known as proton pump inhibitors (PPIs) with powerful inhibitory action against secretion of gastric acid. They are indicated for the treatment of various digestive tract ulcers. Esomeprazole is useful for inhibiting gastric acid secretion and has gastric mucosa-protective activity. In a more general sense, esomeprazole may be used for preventing and treating gastric acid related disorders in mammals, including man, e.g., gastroesophageal reflux disease, gastritis, gastric ulcer, duodenal ulcer, etc. Esomeprazole is susceptible to degradation/transformations in acidic reacting media. The stability of esomeprazole is also affected by moisture, heat, organic solvents, and to some degree by light.

When these drugs 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 commonly used involves coating the acid-labile compound, such as in its granules, pellets, or tablets, with an enteric polymer coating, which is insoluble in aqueous acidic conditions and soluble in aqueous 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 can occur even during the enteric coating process, which results in the coloration of surfaces of a drug-containing core. In order to avoid such problems, an inert barrier/intermediate coating, which is not acidic, is often required between the core and enteric coating, which increases the complexity and the cost of the formulation manufacturing processes involving acid-labile compounds.

An acid labile compound can be a substituted benzimidazole derivative such as esomeprazole. Esomeprazole has a chemical name 5-methoxy-2-[(S)-[(4- methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-benzimidazole-1 yl and has structural Formula I

Formula I

U.S. Patent No. 4,255,431 discloses omeprazole and therapeutically acceptable salts thereof. The advantages of using salts of omeprazole and particularly the magnesium salt are disclosed in U.S. Patent No. 4,738,974. The single isomers of omeprazole are reported to be more useful in therapy when compared to the racemic omeprazole.

European Patent No. 1020461 B1 describes the use of a magnesium salt of (-)-omeprazole for the manufacture of a medicament for the inhibition of gastric acid secretion.

European Patent Application No. 1960384 A1 describes various crystalline esomeprazole non-salt forms.

U.S. Patent No. 5,877,192 discloses the use of the (-)-enantiomer of omeprazole (esomeprazole), or a pharmaceutically acceptable salt thereof, in the treatment of gastric acid related diseases as a means to decrease inter-individual variation in plasma levels, compared to omeprazole. U.S. Patent No. 5,753,265 describes an oral pharmaceutical composition in the form of a multiple unit tablet comprising acid-labile compounds with an enteric coating layer.

U.S. Patent No. 5,817,338 discloses a multiple unit tableted dosage form containing omeprazole or one of its single enantiomers, or an alkaline salt of omeprazole or one of its single enantiomers, a method for the manufacture of such a formulation, and the use of same formulation in medicine.

U.S. Patent No. 6,013,281 discloses a separating layer that is formed in situ by direct application of an acidic enteric material onto an alkaline core containing benzimidazoles.

U.S. Patent Publication No. 2006/0057195 A1 describes stable

preparations for medicinal use containing amorphous benzimidazole compounds, which are produced by blending an amorphous benzimidazole compound with a nontoxic base such as a basic inorganic salt.

European Patent No. 706378 B1 discloses an oral enteric coated formulation containing a core material comprising magnesium salt of omeprazole.

U.S. Patent No. 5,900,424 discloses an omeprazole magnesium salt having a degree of crystallinity that is higher than 70%, as determined by X-ray powder diffraction.

U.S. Patent No. 6,858,725 discloses the preparation of multiple unit tablets comprising tableting modified release multiple units together with porous microcrystalline cellulose (MCC) cushioning granules, obtained by wet granulation of MCC with a granulating fluid that contains a mixture of water and a volatile, water miscible, polar organic solvent. Cushioning MCC granules preferably have particle sizes similar to the particle size range of modified release multiple units.

However, tableting of multiple drug-containing units together with pharmaceutically acceptable tableting excipients has problems of particle segregation. Particle segregation in a tableting mixture results in tableting problems, such as weight variation and poor content uniformity. Among the approaches used to solve this problem are: tableting of multiple units together with direct compression excipients such as filler-binders, binders, disintegrants, lubricants, etc.; and tableting of multiple units together with cushioning agglomerates obtained by agglomeration of particles of pharmaceutically acceptable excipients, such as fillers, binders, disintegrants, lubricants, etc.

Although there are several enteric coated formulations in the market, it is technically very difficult to formulate esomeprazole magnesium products, due to associated chemical, physical, and polymorphic instability. There exists a need for stable enteric coated formulations of esomeprazole magnesium. Particularly, there remains a need for developing coherent multiple unit tablets having appropriate friability and hardness, where drug release from multiple unit tablets is

comparable to the drug release from multiple units prior to tableting.

SUMMARY

Aspects of the present application relate to pharmaceutical formulations comprising at least one acid labile pharmaceutically active substance, including any of its salts, polymorphs, hydrates, esters, isomers, derivatives, and mixtures thereof, for oral administration, and processes for their preparation.

In embodiments, the present application provides stable formulations comprising esomeprazole magnesium, together with one or more

pharmaceutically acceptable excipients.

In embodiments, the present application provides stable formulations comprising esomeprazole magnesium in an amorphous form, crystalline form, or mixtures thereof, together with one or more pharmaceutically acceptable excipients.

In embodiments, the present application provides stable formulations prepared using esomeprazole magnesium in an amorphous form, crystalline form, or mixtures thereof as the starting active ingredient.

In embodiments, the present application provides stable formulations prepared using esomeprazole magnesium in a substantially amorphous form.

In embodiments, esomeprazole magnesium formulations of the present application comprise esomeprazole magnesium in an amorphous form, crystalline form, or mixtures thereof as the active ingredient, together with at least one basic compound such as an alkali metal or alkaline metal salt, also together with one or more other excipients. In embodiments, esomeprazole magnesium formulations of the present application comprise esomeprazole magnesium in an amorphous form as the active ingredient and one or more other excipients, wherein the esomeprazole magnesium is stable during formulation and on storage.

In embodiments, the present application provides multiple unit

pharmaceutical compositions comprising: (a) a pharmacologically inert core; (b) a drug layer over the core comprising a benzimidazole drug, at least one stabilizing agent, and one or more pharmaceutically acceptable excipients; (c) a barrier coating layer or intermediate layer over the drug layer, comprising at least one pharmaceutically acceptable excipient; (d) an enteric layer over the barrier coating layer or intermediate layer comprising an enteric coating polymer; and (e) optionally, an overcoating layer over the enteric coating layer.

In an aspect, the application provides a stable pharmaceutical formulations of an acid labile benzimidazole compound that inhibits gastric acid secretion, comprising: a) an inert inner core; b) a first coating over the inner core comprising the benzimidazole compound and an alkaline stabilizer; c) an intermediate coating over the first coating; and d) an outer enteric layer. In embodiments, the acid labile benzimidazole compound is amorphous esomeprazole magnesium, the inner core is a non-pareil sugar or microcrystalline cellulose sphere, an alkaline stabilizer is magnesium oxide light or meglumine, an enteric coating plasticizer ingredient is acetyl tributyl citrate, diethyl phthalate, polyethylene glycol, triethyl citrate, or any combinations thereof. In embodiments, a plasticizer is used in concentrations ranging from about 0-15%, or about 2-14%, by weight of enteric coating polymer. In embodiments, the formulations optionally comprise an overcoating layer over the enteric coating layer, and optionally are prepared using a co-granulation procedure with one or more excipients.

In an aspect, the application provides a stable pharmaceutical composition comprising: (a) a pharmacologically inert core; (b) a drug layer over the core comprising esomeprazole or pharmaceutically acceptable salt thereof, at least one stabilizing agent, and one or more pharmaceutically acceptable excipients; (c) a barrier coating layer or intermediate layer over the drug layer, comprising at least one alkaline compound; (d) an enteric coating layer over the barrier coating layer or intermediate layer comprising at least two plasticizers in amounts less than about 15% by weight of the enteric coating layer polymer and less than about 12% by weight of the enteric coating composition; and (e) optionally, an overcoating layer over the enteric coating layer.

In embodiments, the present application provides multiple unit

pharmaceutical compositions, comprising: (a) a pharmacologically inert core; (b) a drug layer over the core comprising esomeprazole magnesium, at least one stabilizing agent, and one or more additional pharmaceutically acceptable excipients; (c) a barrier/intermediate coating or intermediate layer over the drug layer, comprising at least one pharmaceutically acceptable excipient; and (d) an enteric layer over the barrier/intermediate coating, comprising an enteric coating polymer; optionally having an overcoating layer over the enteric coating layer; and optionally prepared using a co-granulation procedure with one or more excipients.

In an aspect, the application provides a stable pharmaceutical composition comprising: (a) a pharmacologically inert core; (b) a drug layer over the core comprising esomeprazole magnesium, at least one stabilizing agent, and one or more pharmaceutically acceptable excipients; (c) a barrier coating layer or intermediate layer over the drug layer, comprising at least one alkaline compound; (d) an enteric coating layer over the barrier coating layer or intermediate layer comprising at least two plasticizers in amounts less than about 15% by weight of the enteric coating layer polymer and less than about 12% by weight of the enteric coating composition; and (e) an overcoating layer over the enteric coating layer.

In embodiments, the application provides processes for preparing pharmaceutical formulations, comprising: (a) seal coating sugar spheres with a binder suspension to obtain inert cores; (b) applying a benzimidazole drug- containing layer onto the inert cores to obtain drug coated particles; (c) applying a barrier coating layer onto the drug coated particles; (d) applying an enteric coating layer onto the barrier coated particles; (e) optionally, applying an overcoating layer onto the enteric coated particles; and (f) optionally, co-granulating with one or more excipients.

In an aspect, the application provides process for preparing a stable pharmaceutical composition comprising: (a) a pharmacologically inert core; (b) a drug layer over the core comprising esomeprazole or pharmaceutically acceptable salt thereof, at least one stabilizing agent, and one or more pharmaceutically acceptable excipients; (c) a barrier coating layer or intermediate layer over the drug layer, comprising at least one alkaline compound; (d) an enteric coating layer over the barrier coating layer or intermediate layer comprising at least two plasticizers in amounts less than about 15% by weight of the enteric coating layer polymer and less than about 12% by weight of the enteric coating composition; and (e) optionally, an overcoating layer over the enteric coating layer.

In embodiments, the application provides processes for preparing esomeprazole magnesium formulations, comprising: (a) seal coating sugar spheres with a binder suspension; (b) applying an esomeprazole magnesium drug coating layer, comprising potassium hydroxide or meglumine as stabilizer, onto the seal coated cores; (c) applying a barrier/intermediate coating layer onto the drug layer; (d) applying an enteric coating layer; (e) optionally, applying an overcoating layer onto the enteric coated particles; and (f) optionally, co- granulating with one or more excipients.

In an aspect, the application provides processes for producing stable formulations of esomeprazole magnesium, embodiments comprising:

a) Coating pharmacologically inert particles with a dispersion

comprising ethylcellulose and magnesium stearate.

b) Coating particles of a) with a solution comprising povidone, meglumine, and esomeprazole magnesium.

c) Coating particles of b) with a dispersion comprising povidone, magnesium oxide, and magnesium stearate.

d) Applying an enteric coating to particles from c).

e) Overcoating particles of d) with a dispersion comprising HPMC and talc.

f) Optionally, co-granulating with one or more excipients

g) Blending particles of f) with suitable excipients.

h) Compressing the blend from g) into tablets.

i) Coating the tablets with a film.

In embodiments, esomeprazole magnesium formulations of the present application comprise particles. In embodiments, particles according to the present application may be in the form of powders, granules, pellets, spheroids, extrudates, mini-tablets, and the like. ln embodiments, esomeprazole magnesium formulations of the present application are in the form of particles made into a unit dosage form such as tablets or capsules.

In embodiments, esomeprazole magnesium formulations of the present application are in the form of powders, granules, or pellets compressed into tablets or filled into capsules.

In embodiments, the present application provides esomeprazole

magnesium formulations, prepared using an active ingredient having particle size distributions with D10 about 0.01 μιτι to about 2 μιτι, D50 about 2 μιτι to about 9 μιτι, and D90 about 2 μιτι to about 50 μιτι.

In embodiments, the present application provides stable formulations comprising esomeprazole magnesium, which are substantially free of drug degradation impurities.

In embodiments, formulations of the present application may contain any one or more of the impurities: N-oxide impurity; 2-mercaptobenzimidazole;

sulphone impurity; desmethoxy impurity; sulphide impurity; an impurity with mass number 283, and drug degradation impurities impurity A (desmethoxydehydro) and impurity C (N-methyl omeprazole), having structures described below, and any other drug-related impurities, in amounts such that any impurity does not substantially adversely affect the safety of the composition.

In embodiments, the application provides stable formulations comprising esomeprazole magnesium, wherein levels of one or more of the N-oxide impurity, 2- mercaptobenzimidazole, sulphone impurity, desmethoxy impurity, and sulphide impurity as described herein, are less than about 5%, or less than about 1 %, of the label esomeprazole content.

In embodiments, the application provides stable formulations comprising esomeprazole magnesium, wherein levels of one or more of impurity A

(desmethoxydehydro) and impurity C (N-methylomeprazole), as described herein, are less than about 5%, or less than about 1 %, of the label esomeprazole content.

In embodiments, the application relates to stable formulations wherein total impurities, as determined using high performance liquid chromatography (HPLC), are less than about 7%, or less than about 3%, of the label esomeprazole content. In embodiments, the application provides processes for producing stable granules or pellets, wherein granules or pellets are processed in an environment where the relative humidity (RH) is not more than about 70%.

In embodiments, the application provides processes for producing stable granules or pellets, including drying granules or pellets at temperatures of

50±20°C.

In embodiments, the application provides processes for producing stable granules or pellets, wherein granules or pellets have water contents about 0.5-

10% by weight, as determined using a Karl Fischer method.

In embodiments, the application provides processes for producing stable granules or pellets, wherein granules or pellets have a loss on drying in the range of about 0.25-10%, or about 0.5-5%, by weight.

In embodiments, the application provides stable pharmaceutical

formulations comprising esomeprazole magnesium and at least one

pharmaceutically acceptable excipient, wherein pH values of the compositions are less than about 14.

An aspect of the present application provides methods of preventing or treating diseases or disorders using formulations of the present application comprising at least one substituted benzimidazole derivative or its salts, or mixtures thereof.

An aspect of the application provides methods for producing a gastric acid secretion inhibitory effect in a subject in need thereof, by administering an effective amount of a pharmaceutical formulations comprising at least one substituted benzimidazole derivative or its salts or mixtures thereof.

In an aspect, formulations of the present application exhibit commercially acceptable chemical storage stability.

In embodiments, the active agent esomeprazole magnesium is contained in formulations during manufacture or storage, in an amorphous form, a crystalline form, or mixtures thereof.

In an aspect, enteric coatings provide protection against drug degradation in the acidic conditions of the stomach, and assist with releasing desired quantities of drug at the desired pH environments. ln an aspect, dissolution and protection is improved by using non-aqueous solvents, such as alcohols, in enteric coating.

In an aspect, a barrier coating layer is interposed between drug and enteric coating layers. In embodiments, a barrier coating layer is below 30%, or below 15% w/w of drug-loaded pellets.

In an aspect, a barrier coating layer comprises sodium, potassium, calcium or magnesium as their oxides, hydroxides, or salts.

In an aspect, a polymer-containing overcoating is provided on particles that are co-granulated and blended with powdered excipients, to prevent segregation during compression of the blend and to provide a cushioning effect.

An aspect of the application relates to enteric coating and barrier coating thicknesses, and ratios of plasticizer to enteric coating polymer, to provide tablets having hardness above 8-10 kiloponds (kp).

An aspect of the application relates the use of Ludipress^® and Prosolv^® products as diluents in powder compositions, to inhibit breakage during

compression.

Further features of the application will be apparent from the detailed description hereinbelow set forth.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 is an X-ray powder diffraction (XRPD) pattern of a tablet, as prepared Example 7.

DETAILED DESCRIPTION

Aspects of the present application provide pharmaceutical formulations including a benzimidazole compound, where a benzimidazole-containing layer is separated from an acidic enteric coating. The term "benzimidazole compound" as used herein refers to any of the compounds belonging to the category of substituted benzimidazoles that are used for treating gastrointestinal disorders, including omeprazole, esomeprazole, lansoprazole, dexlansoprazole,

rabeprazole, pantoprazole, leminoprazole, and pariprazole, and their

pharmaceutically acceptable salts, solvates, and mixtures. For example, the benzimidazole compound may be esomeprazole in the form of the free base, or a pharmaceutically acceptable salt thereof, in any polymorphic forms.

Like other substituted benzimidazole derivatives, esomeprazole is acid- labile, creating several problems in formulating into oral pharmaceutical dosage forms because of the acidic environment of the stomach. It has poor stability and would be rapidly decomposed and discolored under moist conditions, or in an acidic to neutral aqueous environment. It requires special techniques to avoid contact of the drug with gastric acid of the stomach. Even though stabilization techniques for substituted benzimidazole derivatives are known, there remains a need for alternate approaches to prepare stable and bio-available pharmaceutical compositions comprising esomeprazole magnesium. In aspects, the present application provides stable and bioavailable pharmaceutical compositions comprising substituted benzimidazole compounds, such as esomeprazole magnesium.

In an aspect, solid dosage forms of the present application comprising amorphous benzimidazole compounds having PPI activity, such as are

represented by Formula I above, which are unstable active ingredients, in particular, unstable in acid media, can be stabilized by blending with a non-toxic base, such as a basic inorganic salt, and furthermore by forming a barrier or intermediate coating and enteric coating layer on drug-containing core particles. Processes for the manufacture of a dosage form according to the present application represent a further aspect of the application.

Pharmacologically inert cores for use in the application may be in the form of pellets, granules, or beads. The cores may be acidic, alkaline, or neutral, depending on the type of formulation. The cores may contain one or more pharmaceutically acceptable excipients, such as pharmacologically inert carriers, binders, diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents, and any mixtures thereof. Cores may be coated with a benzimidazole compound and any one or more of binders, diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents, and mixtures thereof. The cores may comprise, without limitation, substances such as starch, microcrystalline cellulose, or sugar spheres such as nonpareil sugar seeds. The term "acid-labile" describes any compound, which is not stable in acidic conditions or which undergoes degradation or hydrolysis via acid or proton catalyzed reactions.

The term "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 pharmaceutical compositions are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable excipient" as used herein includes both one and more than one such excipient.

The term "formulation" refers to any solid oral dosage form such as a tablet or capsule, comprising a benzimidazole drug.

In embodiments, pharmaceutical formulations comprising esomeprazole magnesium further comprise a pharmaceutically acceptable basic substance. Organic stabilizing agent substances that may be used in the present application are pharmaceutically acceptable substances including, for example, meglumine, amines, and mixtures thereof. Amines include, but are not limited to, Ν,Ν'- dibenzylethylenediamine, diethanolamine, ethylenediamine, tromethamine and mixtures of any two or more thereof. The inorganic basic substances that can be used include alkali metal and alkaline earth metal compounds. These include, but are not limited to, lithium, sodium, and potassium compounds such as sodium hydroxide, potassium hydroxide, and mixtures thereof. Alkaline earth metal compounds include, but are not limited to, calcium and magnesium compounds such as calcium carbonate, calcium hydroxide, magnesium oxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, and any mixtures thereof.

Organic solvents that may be used as processing aids in the present application include, but are not limited to: halogenated hydrocarbons such as methylene chloride, 1 ,2-dichloroethane, chloroform, and carbon tetrachloride; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol (isopropyl alcohol), 1 - butanol, 2-butanol, and t-butyl alcohol; ketones such as acetone, methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether, and 1 ,4-dioxane; nitriles such as acetonitrile and propionitrile; and any mixtures of two or more thereof.

In embodiments, the active agent esomeprazole magnesium is contained in the compositions, during manufacture and storage, in an amorphous form, crystalline form, or mixtures thereof. In embodiments, the active agent

esomeprazole magnesium is contained in the compositions, during manufacture and storage for commercially relevant times, in an amorphous form.

A binder may be used in the formulations. In embodiments, the binder is a water soluble polymer such as a polyvinylalcohol, a polyvinylpyrrolidone, a methylcellulose, a hydroxypropyl cellulose, a hydroxymethyl cellulose, a copovidone, and the like, including any mixtures thereof.

An enteric coating agent may comprise a material that resists dissolution in acid media up to pH values about 5.5, such as a cellulose acetate phthalate, a hydroxypropyl methylcellulose phthalate, a polyvinyl acetate phthalate, a carboxymethylethylcellulose, Eudragit^® L30D-55, Eudragit^® L (poly(methacrylic acid methylnnethacrylate) 1 :1 ratio (Number aAv. MW 135,000, USP Type A), Eudragit^® L 100-55 (methacrylic acid ethylacrylate 1 :1 ratio copolymer), Eudragit^® S (poly(methacrylic acid, methylmethacrylate, 1 :2 ratio (Number Av. MW 135,000, USP Type B), or any mixtures thereof and other Eudragit^® grades. For example Eudragit^® L100-55 is a 100% polymer solids product while the Eudragit^® L30D-55 product is a 30% w/w aqueous dispersion of the polymer. Typical solvents that may be used to apply an enteric coating include isopropyl alcohol, acetone, methylene chloride, isopropyl alcohol mixtures with water, and the like, and any mixtures thereof. The enteric coating is applied either directly onto a core or onto barrier/intermediate coated cores, using conventional coating techniques such as, for instance, pan coating, or fluidized bed coating, using solutions of polymers in water and/or suitable organic solvents, or by using suspensions of said polymers. Generally, an enteric coating is applied in amounts about 5-100% by weight of the core or barrier coated composition.

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.

The 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 carbons.

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 also 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.

The coatings of the present application may comprise a plasticizer, typically present in amounts about 0.1 -15% w/w of the enteric coating composition.

Suitable plasticizers include, without limitation, acetyl triethyl citrate, dibutyl phthalate, dibutyl sebacate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, propylene glycol, triacetin, polyethylene glycols, and diethyl phthalate,

hydrogenated oil, cetyl alcohol, miglyol and meglumine and mixture thereof. Two or more plasticizers in combination can be used to protect the enteric and overcoated pellets from breakage during a compression procedure and provide good acid resistance, so that the tablets can withstand the gastric acid effects in the stomach and release the required quantity of drug. An example of a plasticizer combination is acetyl tributyl citrate and polyethylene glycol 6000 in weight ratios about 10:0.1 to about 0.1 :10. The enteric coating layer may further comprise a dispersant such as talc, and colorants and pigments may also be included as desired in an enteric coating layer.

The coating materials of the present application may comprise lubricants such as calcium stearate, magnesium stearate, stearic acid, Syloid^® silicas, coagulated aerosols of synthetic silica, pyrogenic silicon dioxide, etc.

The enteric coated and/or overcoated pellets, granules, or beads containing the active compounds as obtained above, can be co-granulated suitable pharmaceutically acceptable excipients, such as fillers, binders, disintegrants, and lubricants, in order to improve the uniformity of distribution. This mixture is compressed into a multiple unit tablet dosage form, according to the present application.

StarLac® is a spray-dried excipient composition of 85% a-lactose monohydrate and 15% maize starch, sold by Molkerei Meggle Wasserburg GmbH & Co. KG, of Wasserburg, Germany.

Ludipress® and Ludipress® LCE are co-processed diluent excipients, sold by BASF SE, Ludwigshafen, Germany. Ludipress comprises 93% a-lactose monohydrate, 3.5% polyvinylpyrrolidone, and 3.5% crospovidone, and Ludipress LCE comprises 96.5% α-lactose monohydrate and 3.5% polyvinylpyrrolidone.

A silicified microcrystalline cellulose excipient is an intimate physical mixture of microcrystalline cellulose and colloidal silicon dioxide, having particle sizes in the range of 20 to 200 μιτι, some products generally containing about 2% by weight of colloidal silicon dioxide. An example that is commercially available is Prosolv® SMCC in different grades, from JRS Pharma, Rosenberg, Germany, providing an improved compaction property as compared to microcrystalline cellulose.

In embodiments, using combinations of Ludipress, Ludipress LCE, and Prosolv diluents gives good mechanical strength to pellets and does not allow the pellets to break during compression to maintain proper flow and prevention of segregation during compression.

Compression into tablets can include use of co-processed diluents. Coprocessing means combining two or more materials by an appropriate process. The products so formed are physically modified in such a way that they do not lose their chemical structure and stability. Direct compression techniques have become well-accepted methods of tablet manufacturing. An extensive range of materials from various sources has been developed and marketed as directly compressible diluents, including lactose, starch, cellulose derivatives, inorganic substances, polyalcohols, and sugar-based materials. In addition to the

development of directly compressible excipients by modifying just a single substance, co-processing of two or more components has been applied to produce composite particles or co-processed excipients. The composite particles or co-processed excipients are introduced in order to provide better tableting properties than a single substance or the physical mixture.

Esomeprazole magnesium pharmaceutical compositions of the application can be further processed into various pharmaceutical dosage forms as prepared, or can be combined with one or more pharmaceutically acceptable excipients. In embodiments, esomeprazole magnesium compositions of the present application are in the form of particles. In embodiments, particles according to the present application may be in the form of powders, granules, pellets, spheroids, extrudates, mini-tablets, and the like. In embodiments, esomeprazole magnesium formulations of the present application can be particles made into unit dosage forms such as tablets or capsules. In embodiments, esomeprazole formulations of the present application are in the form of powders or granules compressed into tablets. Formulations may be in the form of immediate release, delayed release, controlled release, or their combinations.

Compressed tablets can optionally be covered with film-forming agents to obtain a smooth surface of the tablets and further enhance the stability of the tablets during packaging and transport. Such tablet coating layers may further comprise any of additives like anti-tacking agents, colorants, pigments, and other additives to obtain a tablet of good appearance. Tablet polishing can also be used to inprove the appearance of the tablets.

In embodiments, punches used to compress tablets are uncoated punches having modified capsule shape. For example, 40 mg strength esomeprazole magnesium tablets can use 1 7.5x8.5 mm modified capsule shaped tooling. For example, 20 mg strength esomeprazole magnesium tablets can use 14.7x6.8 mm modified capsule shaped tooling. ln embodiments, the present application provides pharmaceutical compositions comprising esomeprazole magnesium polymorphs, hydrates, esters, isomers, derivatives, or mixtures thereof, together with one or more

pharmaceutically acceptable excipients.

In embodiments, esomeprazole magnesium compositions of the present application comprise the use of esomeprazole magnesium in an amorphous form as the active agent, together with one or more other excipients.

In embodiments, esomeprazole magnesium compositions of the present application comprise esomeprazole magnesium in an amorphous form as the active agent, together with at least one or more other excipients, wherein the esomeprazole magnesium is stable during the manufacturing process and during storage for commercially relevant times.

In embodiments, the present application provides esomeprazole

magnesium compositions, prepared using esomeprazole magnesium as an active ingredient having particle size distributions with D50 about 1 μιτι to about 40 μιτι. D50 values are maximum particle sizes for 50% of the particles in a sample.

In embodiments, the present application provides esomeprazole

magnesium compositions, prepared using esomeprazole magnesium active ingredient having particle size distributions with D10 about 0.01 μιτι to about 10 μιτι, D50 about 2 μιτι to about 20 μιτι, and D90 about 5 μιτι to about 80 μιτι. D10 values are maximum particle sizes for 10 percent of the particles, and D90 values are maximum particle sizes for 90% of the particles.

In embodiments, the present application provides stable formulations comprising esomeprazole magnesium, which are substantially free of drug degradation impurities. The formulations of the present application may contain any one or more of an N-oxide impurity, 2-mercaptobenzimidazole, sulphone impurity, desmethoxy impurity, sulphide impurity, impurity A (desmethoxydehydro) and impurity C (N-methyl omeprazole), and any other drug-related impurities in amounts such that the safety of a formulation is not substantially adversely affected.

In embodiments, the application provides stable formulations comprising esomeprazole or its pharmaceutically acceptable salts, wherein levels of one or more of N-oxide impurity, 2-mercaptobenzimidazole, sulphone impurity, desmethoxy impurity, and sulphide impurity are less than about 5%, or less than about 1 %, of the label esomeprazole content.

In embodiments, the application provides stable formulations comprising esomeprazole or its pharmaceutically acceptable salts, wherein levels of one or both of impurity A (desmethoxydehydro) and impurity C (N-methylomeprazole), as described herein, are less than about 5%, or less than about 1 %, of the label esomeprazole content.

In embodiments, the application relates to stable formulations wherein total drug-related impurities are less than about 7%, or less than about 3%, of the label esomeprazole content.

Esomeprazole and its impurities, including the above-mentioned impurities, can be analyzed using a HPLC method with a 4.6x150 mm column containing a 3.5 μιτι packing of octylsilane, chemically bonded to porous silica or ceramic micro-particles (e.g., a 150x4.6 mm Xterra, RP 8, 3.5 μιτι or equivalent column), where the liquid chromatograph is equipped with a 305 nm UV detector, having a column temperature of 25°C, at a 1 mL per minute flow rate and with a run time of 60 minutes.

Structures and other information about certain of the potential impurity compounds are given below.

N-oxide impurity:

C-|₇H-_|9N₃0 S

Mol. Wt.: 361.42

2-Mercaptobenzimidazole

C₈H₈N₂OS

Mol. Wt.: 180.23 Sulphone impurity:

Ci₇HigN30₄S

Mol. Wt.: 361.42

Desmethoxy impurity:

Ci6H₁₇N₃02S Mol. Wt.: 315.39

Sulphide impurity:

C-| 7 H 1 gN302S

Mol. Wt.: 329.42

Impurity A (Desmethoxydehydro):

Impurity C (N-methylomeprazole):

PURITY ζ

Drug release profiles for dosage forms can be determined using Test 71 1 "Dissolution" in United States Pharmacopeia 29, United States Pharmacopeial Convention, Rockville, Maryland, 2005 ("USP"). In the test, a dosage form is immersed in an aqueous fluid and the concentration of drug in solution is determined at intervals. Many useful fluids are described in individual USP drug monographs and as buffers.

X-ray powder diffraction information described herein is obtained using copper Ka radiation.

Certain specific aspects and embodiments will be further described in the examples below, being provided only for purposes of illustration and not to be construed as limiting the scope of the application in any manner.

EXAMPLES 1 -3

Ingredient mg/Tablet

1 2 3

Stage I - Seal Coating

Sugar spheres 40-60 mesh 32 32 32

Ethylcellulose 7 cps 1 .28 1 .28 1 .28

Magnesium stearate 0.32 0.32 0.32

Methanol^* q.s. q.s. q.s.

Methylene chloride^* q.s. q.s. q.s.

Stage II - Drug Loading

Esomeprazole magnesium (amorphous) 44.5 45.73 45.73

Poloxamer 188 - 4 4 Povidone K 30 - 10.69 10.69

Povidone K 90 10.69 - -

Magnesium oxide (light) 1 1 .12 1 1 .12 1 1 .12

Methanol^* q.s. q.s. q.s.

Stage III - Barrier/intermediate Coating

Povidone K 90F 17.24 8.99 8.99

Magnesium oxide light 8.47 4.42 4.42

Magnesium stearate 4.54 2.37 2.37

Methanol^* q.s. q.s. q.s.

Stage IV - Enteric Coating

Eudragit® L 30 D-55 68.15 - -

Eudragit® L 100-55 - 57.64 54.75

Diethyl phthalate 6.71 5.63 5.35

Polysorbate 80 - 0.91 0.86

Talc 68.15 56.73 53.89

Water^* q.s. q.s. -

Methanol^* - - q.s.

Isopropyl alcohol^* - q.s. -

Stage V - Compression

StarLac® 105.5 105.5 105.5

Prosolve® SMCC HD 90 190.43 90

PEG 6000 fine powder 91 .62 92 92

Crospovidone 45 60 60

Hydroxypropyl cellulose (Klucel® EXF) 90 - -

Colloidal silicon dioxide (Aerosil® 200) 1 .6 - 1 .6

Magnesium stearate 6 6 6

Flowlac® 100 - 235.72 321 .75

Copovidone (VA64) - 45 45

Stage VI - Film Coating

Opadry® Pink 20A84821 ^** 25.2 - -

Isopropyl alcohol^* q.s. - -

Methylene chloride^* q.s. - - * Evaporates during processing.

^**Opadry Pink 20A84821 is a coating product comprising hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, titanium dioxide, talc, iron oxide red, and iron oxide yellow.

Manufacturing procedure:

STAGE I

1 . Sift sugar spheres and collect particles passing through a 40 mesh sieve and retained on a 60 mesh sieve.

2. Prepare a seal coating dispersion by dissolving ethylcellulose in methanol and dichloromethane, then disperse magnesium stearate in the solution with stirring. Coat the sifted sugar spheres with the dispersion.

STAGE II

1 . Dissolve specified polymers in methanol, disperse magnesium oxide in the solution, and add esomeprazole magnesium with stirring. Coat the seal coated sugar spheres with the dispersion.

STAGE III

1 . Combine povidone K 90F with methanol, then sequentially add magnesium oxide and magnesium stearate, with stirring. Use this dispersion to coat drug loaded particles.

STAGE IV

A. Example 1

1 . Prepare dispersion by homogenizing talc and diethyl phthalate in water and adding it to Eudragit L 30 D-55 dispersion, with stirring. Coat

barrier/intermediate coated particles with the dispersion.

B. Example 2

1 . Mix isopropyl alcohol and water. To half of this solvent, add Eudragit L 100-55 with stirring. To the other half of the solvent, add diethyl phthalate, polysorbate 80, and talc under homogenizing conditions. Combine the

homogenized mixture with the Eudragit L100-55 solution prepared above, with stirring. Coat barrier/intermediate coated particles with the dispersion.

C. Example 3

1 . Mix Eudragit L 100-55 with half of the methanol. Combine the other half of the methanol with diethyl phthalate, polysorbate 80 and talc under homogenizing conditions. Mix the homogenized material with the Eudragit L100- 55 solution. Coat barrier/intermediate coated particles with the dispersion.

STAGE V

1 . Blend the enteric coated pellets with the required ingredients, in a double cone blender (DCB).

2. Compress the blend into 40 mg strength tablets, to a target weight of 870 mg.

STAGE VI

1 . Coat the tablets with a dispersion of Opadry Pink in isopropyl alcohol and methylene chloride.

Tablets of 20 mg esomeprazole strength can also be made from similar proportions of ingredients, compressing the blends to a target weight of 435 mg.

EXAMPLES 4-6

Ingredient mg/Tablet

4 5 6

Stage I - Seal Coating

Sugar spheres 40-60 mesh 32 32 32

Ethylcellulose 7 cps 1 .28 1 .28 1 .28

Magnesium stearate 0.32 0.32 0.32

Methanol^* q.s. q.s. q.s.

Methylene chloride^* q.s. q.s. q.s.

Stage II - Drug Loading

Esomeprazole magnesium (amorphous) 45.23 45.23 45.23

Poloxamer 188 8 8 4

Povidone K 30 6.69 6.69 6.69

Meglumine - - 4

Magnesium oxide (light) 1 1 .12 1 1 .12 -

Methanol^* q.s. q.s. q.s.

Stage III - Barrier/intermediate Coating

Povidone K 90F 8.95 8.95 13.33

Magnesium oxide light 4.4 4.4 6.55 Magnesium stearate 2.35 2.35 3.51

Methanol^* q.s. q.s. q.s.

Stage IV - Enteric Coating

Eudragit L100-55 57.36 57.36 54.59

Diethyl phthalate 5.6 6.6 6.28

PEG 6000 fine powder - 0.86 0.82

Polysorbate 80 0.9 - -

Talc 56.46 55.52 52.83

Methanol^* q.s. q.s. q.s.

Stage V - Overcoating

Hypromellose 3 cps 7.7 7.7 7.62

Talc 1 .93 1 .93 1 .91

Methylene chloride^* - q.s. -

Methanol^* - q.s. q.s.

Water^* q.s. - q.s.

Stage VI - Compression

Ludipress® LCE 226.18 218.8 -

Prosolve SMCC HD 90 137 137 135

Prosolve SMCC 90 137 137 135

PEG 6000 fine powder 70 70 70

Crospovidone 45 45 45

Sodium stearyl fumarate 6 6 6

Colloidal silicon dioxide (Aerosil 200) - - 4

* Evaporates during processing.

Manufacturing procedure:

STAGE I

1 . Sift the sugar spheres and collect particles passing through a 40 mesh sieve and retained on a 60 mesh sieve.

2. Prepare a dispersion of ethylcellulose and magnesium stearate in methanol and dichloromethane. Coat the sugar spheres with the dispersion.

STAGE II 1 . Dissolve povidone K 30 in methanol, then sequentially add poloxamer, meglumine (if required), magnesium oxide (if required), and esomeprazole magnesium. Coat the seal coated spheres with this dispersion.

STAGE III

1 . Disperse povidone K 90F, magnesium oxide, and magnesium stearate in methanol. Coat the drug loaded particles with the dispersion.

STAGE IV

A. Example 4

1 . Mix Eudragit L100-55 with half of the methanol. Combine the other half of the methanol with diethyl phthalate, polysorbate 80, and talc under

homogenizing conditions. Add the homogenized material to the Eudragit L100-55 solution, with stirring. Use this dispersion to coat the barrier/intermediate coated particles.

B. Examples 5 and 6

1 . Mix Eudragit L100-55 with half of the methanol. Combine the other half of the methanol with diethyl phthalate, polyethylene glycol 6000, and talc under homogenizing conditions. Add the homogenized material to the Eudragit L100-55 solution prepared above, with stirring. Use this dispersion to coat the

barrier/intermediate coated particles.

STAGE V

1 . Combine the ingredients to form dispersion, and use the dispersion to coat the enteric coated particles.

STAGE VI

1 . Blend the required ingredients and overcoated pellets.

2. Compress the blend into 40 mg strength tablets to a target weight of 870 mg.

Tablets of 20 mg esomeprazole strength can also be prepared from similar proportions of ingredients, compressing the blends to a target weight of 435 mg. EXAMPLES 7-9

Ingredient mg/Tablet

7 8 9

Stage 1 - Seal Coating

Sugar spheres 40-60 mesh 32 32 32

Ethyl cellulose 7 cps 1 .28 1 .28 1 .28

Magnesium stearate 0.32 0.32 0.32

Methanol^* q.s. q.s. q.s.

Methylene chloride^* q.s. q.s. q.s.

Stage II - Drug Loading

Esomeprazole magnesium (amorphous) 45.76 45.79 45.76

Poloxamer 188 4 4 4

Povidone K 30 6.69 13 6.69

Meglumine 4 4 4

Methanol^* q.s. q.s. q.s.

Stage III - Barrier/intermediate Coating

Povidone K 90F 13.26 14.15 13.59

Magnesium oxide light 7.9 8.43 8.096

Magnesium stearate 7.05 7.53 7.23

Methanol^* - - q.s.

Isopropyl alcohol^* q.s. q.s. -

Methylene chloride^* q.s. q.s. -

Stage IV - Enteric Coating

Eudragit L100-55 64.87 69.24 68.7

Diethyl phthalate 7.45 7.95 7.88

PEG 6000 fine powder 0.97 1 .03 1 .02

Polaxomer 188 4.51 4.82 -

Talc 62.79 67.02 66.51

Methanol^* q.s. q.s. q.s.

Stage V - Overcoating

Hypromellose 3 cps 8.41 8.98 8.34

Talc 2.1 2.24 2.09 Methylene chloride^* q.s. q.s. q.s.

Methanol^* q.s. q.s. q.s.

Stage VI - Compression

Ludipress LCE 217.88 192.49 236.72

Prosolve SMCC HD 90 135 135 135

Prosolve SMCC 90 135 135 135

PEG 6000 fine powder 70 70 70

Crospovidone 20 20 20

Sodium stearyl fumarate 6 6 6

Colloidal silicon dioxide (Aerosil 200) 4 4 4

Stage VII - Film Coating

Opadry Pink 20A84821 26.1 - -

Isopropyl alcohol^* q.s. - -

Methylene chloride^* q.s. - -

* Evaporates during processing.

Manufacturing procedure:

STAGE I

1 . Sift sugar spheres and collect particles passing through a 40 mesh sieve and retained on a 60 mesh sieve.

2. Disperse ethylcellulose and magnesium stearate in methanol and methylene chloride. Coat the sugar spheres with this dispersion.

STAGE II

1 . Dissolve povidone in methanol, then sequentially add poloxamer, meglumine, and esomeprazole magnesium, with stirring. Coat the seal coated spheres with this dispersion.

STAGE III

A. Examples 7 and 8

1 . Disperse povidone K 90F, magnesium oxide, and magnesium stearate in isopropyl alcohol and methylene chloride. Use the dispersion to coat the drug coated particles.

B. Example 9 1 . Disperse povidone K 90F, magnesium oxide, and magnesium stearate in methanol. Use this to coat the drug coated particles.

STAGE IV

1 . Mix Eudragit L100-55 with half of the methanol. Combine the other half of the methanol with diethyl phthalate, polyethylene glycol 6000, and talc under homogenizing conditions. Add the homogenized material to the Eudragit L100-55 solution, with stirring. Coat the barrier/intermediate coated particles with this dispersion.

STAGE V

1 . Disperse hypromellose and talc in methanol and methylene chloride.

Coat the enteric coated particles with this dispersion.

STAGE VI

1 . Blend the listed ingredients and over coated pellets.

2. Compress the blend into 40 mg strength tablets to a target weight of 870 mg.

STAGE VII

1 . Mix Opadry Pink with isopropyl alcohol and methylene chloride, and use the mixture to coat tablets of Example 7.

Tablets of 20 mg esomeprazole strength can also be prepared from similar proportions of ingredients, compressing the blends to a target weight of 435 mg.

Tablets prepared in Example 7 have the following properties:

Water by Karl Fischer: 4.96%.

Disintegration time: 3-5 minutes, according to USP test 701 "Disintegration."

Dose uniformity: 99% (RSD: 4.1 %), according to USP test 905 "Uniformity of Dosage Units."

A crushed tablet prepared in Example 7 has an XRPD pattern as shown in Fig. 1 . The peaks all are attributed to excipients present in the formulation, indicating that the esomeprazole magnesium is in an amorphous form.

A drug release profile is determined by immersing tablets prepared in Example 7 in 500 mL of 0.1 N hydrochloric acid for 2 hours, followed by immersion in 500 mL of pH 6.5 simulated intestinal fluid, using the USP method and

Apparatus 2. Results from the immersion into pH 6.5 medium are shown in Table 1 ; release from immersion in the acidic medium is negligible. Table 1

Example 7 tablets are immersed sequentially in pH 5.1 , 4.5, 4.1 , and 3.5 aqueous media for 30, 30, 60, and 60 minutes, respectively, the percentage of drug remaining in the tablet is determined, and the average value calculated. Results are shown in Table 2.

Table 2

Tablets prepared in Example 7 are stored in a closed container at 40°C and 75% RH for three months. Samples are analyzed using HPLC, before and after storage, to determine the drug-related impurity contents, and results are shown in Table 3 where the values are percentages of the label drug content.

Table 3

Impurity Initial 3 Months

Process Impurities

N-oxide impurity ND ND

2-Mercaptobenzimidazole 0.008 0.105

Sulphone impurity 0.043 0.057 Desmethoxy impurity ND ND

Sulphide impurity 0.017 0.025

Degradation Impurities

Impurity A 0.050 0.225

Impurity C 0.025 0.158

Highest unidentified impurity 0.013 0.1701

Total Impurities 0.1755 1 .087

ND = Not detected.

EXAMPLES 10-12

Ingredient mg/Tablet

10 11 12

Stage I -Seal Coating

Sugar spheres 40-60 mesh 32 32 32

Ethylcellulose 7 cps 1 .28 1 .28 1 .28

Magnesium stearate 0.32 0.32 0.32

Methanol^* q.s. q.s. q.s.

Methylene chloride^* q.s. q.s. q.s.

Stage II - Drug Loading

Esomeprazole magnesium (amorphous) 45.79 45.79 45.23

Poloxamer 188 - - 12

Povidone K 30 13 13 6.69

Meglumine 4 4 -

Magnesium oxide light - - 1 1 .12

Methanol^* q.s. q.s. q.s.

Stage III - Barrier/intermediate Coating

Povidone K 90F 6.795 6.795 12.38

Magnesium oxide light 4.048 4.048 6.08

Magnesium stearate 3.614 3.614 3.26

Methanol^* q.s. q.s. q.s.

Stage IV - Enteric Coating

Eudragit L100-55 47.54 47.56 62.54 Diethyl phthalate 5.46 5.46 6.25

PEG 6000 fine powder 0.71 0.71 0.94

Polysorbate 80 - - 0.94

Talc 46.02 46.02 60.53

Methanol^* q.s. q.s. q.s.

Stage V - Overcoating

Hypromellose 3 cps 6.74 42.12 8.19

Talc 1 .68 10.53 2.05

Methylene chloride^* - - q.s.

Methanol^* q.s. q.s. q.s.

Stage VI - Compression

Ludipress LCE 236.72 280.96 -

Prosolve SMCC HD 90 135 135 135

Prosolve SMCC 90 135 135 135

PEG 6000 fine powder 70 70 70

Crospovidone 20 20 45

Sodium stearyl fumarate 6 6 6

Colloidal silicon dioxide (Aerosil 200) 4 4 4

Ludipress - - 197.06

Stage VII- Film Coating

Opadry Pink 20A84821 - 26.1 -

Isopropyl alcohol^* - q.s. -

Methylene chloride^* - q.s. -

* Evaporates during processing.

Manufacturing procedure:

STAGE I

1 . Sift sugar spheres and collect particles passing through a 40 mesh sieve and retained on a 60 mesh sieve.

2. Disperse ethyl cellulose and magnesium stearate in methanol and dichloromethane. Coat the sugar spheres with this dispersion.

STAGE II 1 . Dissolve povidone K30 in methanol, then sequentially add poloxamer (if required), meglumine (if required), magnesium oxide (if required) and

esomeprazole magnesium. Coat the seal coated spheres with this dispersion.

STAGE III

1 . Disperse povidone K 90F, magnesium oxide, and magnesium stearate in methanol. Use this dispersion to coat the drug loaded pellets.

STAGE IV

1 . Mix Eudragit L100-55 with half of the methanol. Combine the other half of the methanol with diethyl phthalate, polyethylene glycol 6000, polysorbate 80 (if required), and talc (if required) under homogenizing conditions. Add the

homogenized material to the Eudragit L100-55 solution, with stirring. Coat the barrier/intermediate coated particles with the mixture.

STAGE V

1 . Mix hypromellose and talc with the required solvent. Use the dispersion to coat enteric coated particles.

STAGE VI

1 . Blend the required ingredients with overcoated pellets.

2. Compress the blend into 40 mg strength tablets to a target weight of 870 mg.

STAGE VII

1 . Disperse Opadry pink in isopropyl alcohol and methylene chloride. Coat tablets of Example 1 1 with this dispersion.

Tablets of 20 mg esomeprazole strength can also be made from similar proportions of ingredients, compressing the blends to a target weight of 435 mg.

Tablets prepared in Example 1 1 have the following properties:

Water by Karl Fischer: 4.60%.

Disintegration time: 1 -2 minutes.

Dose uniformity: 101 .2% (RSD: 4.9%).

Tablets prepared in Example 1 1 are immersed in 500 mL of 0.1 N HCI for 2 hours, followed by immersion in 500 mL of pH 6.5 simulated intestinal fluid, using the USP method and apparatus 2. Results from the immersion into pH 6.5 medium are shown in Table 4; release from immersion in the acidic medium is negligible. Table 4

Example 1 1 tablets are sequentially immersed in pH 5.1 , 4.5, 4.1 , 3.5 aqueous media for 30, 30, 60, and 60 minutes, respectively, the percentage of drug remaining in the tablet is determined, and the average value calculated. Results are shown in Table 5.

Table 5

Tablets prepared in Example 1 1 are stored in a closed container at 40°C and 75% RH for three months. Samples are analyzed using HPLC, before and after storage, to determine the drug-related impurity content, and results are shown in Table 6, where the values are percentages of the label drug content.

Table 6

Impurity Initial 3 Months

Process Impurities

N-oxide impurity ND ND

2-Mercaptobenzimidazole 0.004 0.087

Sulphone impurity 0.033 0.045

Desmethoxy impurity ND 0.040 Sulphide impurity 0.008 0.019

Degradation Impurities

Impurity A 0.017 0.203

Impurity C ND 0.140

Highest unidentified impurity 0.024 0.093

Total Impurities 0.147 0.977

ND = Not detected.

EXAMPLE 13

Ingredient mg/Tablet

Stage I - Seal Coating

Sugar spheres 30

Ethylcellulose 7 cps 1

Magnesium stearate 0.3

Methanol^* q.s.

Methylene chloride^* q.s.

Stage II - Drug Coating

Esomeprazole magnesium 41 .4

Povidone K90 6

Meglumine 4

Methanol^* q.s.

Stage III - Barrier Coating

Magnesium oxide light 2

Magnesium Stearate 2

Povidone K90 4

Methanol^* q.s.

Stage IV - Enteric Coating

Poly(methacrylic acid, ethyl acrylate) 1 :1 (Eudragit L100 55) 40

Talc 38

Acetyl tributyl citrate 3

Polyethylene glycol 6000 0.5

Methanol^* q.s. Stage V - Overcoating

HPMC 3 cps 10

Talc 10

Methanol^* q.s.

Stage VI - Co-granulation

Microcrystalline cellulose (Avicel PH101 ) 250

Lactose monohydrate (impalpable) 190

Crospovidone 25

Povidone K 30 30

Water^* q.s.

Stage VII - Compression

Crospovidone 30

Polyethylene glycol 6000 (fine powder) 40

Sodium stearyl fumarate 4

Stage VIII - Coating

Opadry Pink 12

Isopropyl alcohol^* q.s.

Methylene chloride^* q.s.

* Evaporates during processing.

Manufacturing procedure:

STAGE I

1 . Ethyl cellulose is dissolved in a mixture of methanol and methylene chloride. Magnesium stearate is added and mixed well.

2. Sugar spheres are sifted through 50 and 60 mesh sieves and the material retained on the 60 mesh sieve is used for further processing.

3. Sugar spheres are coated in a bottom spray bowl with the seal coating ingredient mixture to achieve a target weight gain of 5% w/w. After drying, seal coated pellets are sifted through 50 and 60 mesh sieves, with the material retained on the 60 mesh sieve being used for further processing.

STAGE II

1 . Povidone K90 is dissolved in methanol.

2. Meglumine is dissolved in the solution of step 1 .

3. Esomeprazole magnesium is dissolved in the solution of step 2. 4. Stage I pellets are coated with the drug solution of step 3 in a bottom spray bowl. After drying, the pellets are sifted through 30 and 50 mesh sieves, and the material retained on the 50 mesh sieve is used for further processing.

STAGE III

1 . Povidone K90 is dissolved in methanol and light magnesium oxide is dispersed in the solution.

2. Magnesium stearate is added to the dispersion of step 1 .

3. Stage II pellets are coated with the dispersion of step 3 in a bottom spray bowl. After drying, the pellets are sifted through 30 and 50 mesh sieves, and the material retained on the 50 mesh sieve is used for further processing.

STAGE IV

1 . Eudragit L100 55 is dissolved methanol.

2. Acetyl tributyl citrate is homogenized in methanol, then PEG 6000 and talc are added and the mixture is homogenized.

3. The solution of step 1 is added to the dispersion of step 2 with stirring.

4. Stage III pellets are coated with the dispersion of step 3 in a bottom spray bowl. After drying, the coated pellets are sifted through 30 and 50 mesh sieves and material retained on the 50 mesh sieve is used for further processing.

STAGE V

1 . HPMC 3 cps is mixed with methanol and talc is dispersed in the mixture.

2. Stage IV pellets are coated with the dispersion of step 1 in a bottom spray bowl. After drying, the pellets are sifted through 24 and 40 mesh sieves and material retained on the 40 mesh sieve is used for further processing.

STAGE VI

1 . Povidone is dissolved in water.

2. Lactose monohydrate, microcrystalline cellulose, and crospovidone are sifted through a 40 mesh sieve and blended.

3. Stage V pellets and the material of step 2 are loaded into a fluid bed processor (FBP) with top spray and the solution of step 1 is sprayed to form granules. 4. The granules are dried in the FBP and sifted through an 18 mesh sieve.

STAGE VII

1 . Polyethylene glycol and crospovidone are sifted through a 40 mesh sieve and mixed, then Stage VI granules are added and the materials are blended.

2. Sodium stearyl fumarate is sifted through a 60 mesh sieve, and blended with the materials of step 1 .

3. The blend from step 2 is compressed into tablets containing 40 mg of esomeprazole.

STAGE VIII

1 . Opadry Pink is dispersed in isopropyl alcohol and methylene chloride and used to coat the Stage VII tablets.

The same proportions of ingredients can be used to prepare smaller tablets, containing 20 mg of esomeprazole.

A drug release profile is determined by immersing tablets in 500 mL of 0.1 N HCI for 2 hours, followed by immersion in 500 mL of pH 6.5 simulated intestinal fluid, using the USP method and apparatus 2. Results from the immersion into pH 6.5 medium are shown in Table 7; release from immersion in the acidic medium is negligible.

Table 7

Tablets prepared in Example 13 are analyzed using HPLC to determine the content of drug-related impurities, and results are shown in Table 8, where the values are percentages of the label drug content. Table 8

ND = Not detected.

Tablets prepared in Example 13 have the following properties: Water by Karl Fischer: 4.8%.

Disintegration time: less than 1 minute.

Dose uniformity: 99.88% (RSD: 3.1 %).

Claims

CLAIMS:

1 . A particulate pharmaceutical composition comprising: (a)

pharmacologically inert cores; (b) a drug layer over the cores, containing esomeprazole or a pharmaceutically acceptable salt thereof, at least one stabilizing agent, and one or more pharmaceutically acceptable excipients; (c) a barrier coating layer or intermediate layer over the drug layer, comprising at least one alkaline compound; (d) an enteric coating layer over the barrier coating layer or intermediate layer comprising two or more plasticizers, in amounts less than about 15% by weight of an enteric coating layer polymer and less than about 12% by weight of an enteric coating composition; and (e) optionally, an overcoating layer over the enteric coating layer.

2. The pharmaceutical composition according to claim 1 , wherein an enteric coating layer comprises two plasticizers.

3. The pharmaceutical composition according to claim 1 , wherein a plasticizer comprises triethyl citrate, dibutyl phthalate, dibutyl sebacate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, a propylene glycol, triacetin, a polyethylene glycol, diethyl phthalate, hydrogenated oil, cetyl alcohol, miglyol, or meglumine.

4. The pharmaceutical composition according to claim 1 , wherein a plasticizer comprises acetyl tributyl citrate and polyethylene glycol, in weight ratios about 10:0.1 to about 0.1 :10.

5. The pharmaceutical composition according to claim 1 , wherein a drug layer contains esomeprazole magnesium.

6. The pharmaceutical composition according to claim 1 , wherein a drug layer contains esomeprazole magnesium in a substantially amorphous form.

7. The pharmaceutical composition according to claim 1 , wherein an alkaline compound of (c) comprises a sodium, potassium, calcium, or magnesium oxide, hydroxide, or basic salt.

8. The pharmaceutical composition according to claim 1 , wherein a stabilizing agent in (b) comprises meglumine, N,N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, or tromethamine.

9. The pharmaceutical composition according to claim 1 , wherein a stabilizing agent in (b) comprises potassium hydroxide, sodium hydroxide, calcium carbonate, calcium hydroxide, magnesium oxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, or magnesium aluminate.

10. The pharmaceutical composition according to claim 1 , in the form of enteric coated or overcoated particles that are further granulated with one or more pharmaceutically acceptable excipients.

1 1 . The pharmaceutical composition according to any of claims 1 -10, being in the form of multiple particles made into a tablet or capsule unit dosage form.

12. The pharmaceutical composition according to any of claims 1 -10, prepared using esomeprazole magnesium having particle size distributions with D50 about 1 μιτι to about 40 μιτι.

13. The pharmaceutical composition according to any of claims 1 -10, prepared using esomeprazole magnesium having particle size distributions with D10 about 0.01 μηη to about 10 μπτι, D50 about 2 μηη to about 20 μπτι, and D90 about 5 μιτι to about 80 μιτι.

14. The pharmaceutical composition according to any of claims 1 -10, being substantially free of drug degradation impurities.

15. The pharmaceutical composition according to any of claims 1 -10, being substantially free of any one or more of an N-oxide impurity, 2- mercaptobenzimidazole, sulphone impurity, desmethoxy impurity, sulphide impurity, impurity A (desmethoxydehydro) and impurity C (N-methylomeprazole).

16. The pharmaceutical composition according to any of claims 1 -10, wherein the content of any combination of an N-oxide impurity, 2- mercaptobenzimidazole, sulphone impurity, desmethoxy impurity, and sulphide impurity, is less than about 5% of the label esomeprazole content.

17. The pharmaceutical composition according to any of claims 1 -10, wherein the content of one or both of impurity A (desmethoxydehydro) and impurity C (N-methylomeprazole) is less than about 5% of the label esomeprazole content.

18. A pharmaceutical composition, comprising: (a) pharmacologically inert cores; (b) a drug layer over the cores, comprising esomeprazole magnesium, at least one stabilizing agent, and one or more pharmaceutically acceptable excipients; (c) a barrier coating layer or intermediate layer over the drug layer, comprising at least one alkaline compound; (d) an enteric coating layer over the barrier coating layer or intermediate layer, comprising two or more plasticizers, in amounts less than about 15% by weight of an enteric coating layer polymer and less than about 12% by weight of an enteric coating composition; and (e) an overcoating layer over the enteric coating layer.

19. A process for preparing a particulate pharmaceutical composition, comprising: (a) providing a drug layer containing esomeprazole or a

pharmaceutically acceptable salt thereof, at least one stabilizing agent, and one or more pharmaceutically acceptable excipients, over a pharmacologically inert core; (b) providing a barrier coating layer or intermediate layer, comprising at least one alkaline compound, over the drug layer; (c) providing an enteric coating layer, comprising at least two plasticizers in amounts less than about 15% by weight of an enteric coating layer polymer and less than about 12% by weight of an enteric coating composition, over the drug layer; and (d) optionally, providing an overcoating layer over the enteric coating layer.

20. The process according to claim 19, further comprising: (e) co- granulating enteric coated or overcoated particles with one or more

pharmaceutically acceptable excipients; and (f) making the granules into a tablet or capsule unit dosage form.

21 . The process according to either of claims 19 or 20, wherein the drug layer contains amorphous esomeprazole magnesium.