WO2011140446A2 - Formulations pharmaceutiques - Google Patents

Formulations pharmaceutiques Download PDF

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Publication number
WO2011140446A2
WO2011140446A2 PCT/US2011/035529 US2011035529W WO2011140446A2 WO 2011140446 A2 WO2011140446 A2 WO 2011140446A2 US 2011035529 W US2011035529 W US 2011035529W WO 2011140446 A2 WO2011140446 A2 WO 2011140446A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
impurity
magnesium
esomeprazole
composition according
Prior art date
Application number
PCT/US2011/035529
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English (en)
Other versions
WO2011140446A3 (fr
Inventor
Irukulla Srinivas
Chakole Dinesh Dayaramji
Pradeep Kumar Reddy Chellekkagari
Gali Amar Babu
Mundada Veenu Piyush
Satuluri Satya Sivaram
Original Assignee
Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Dr. Reddy's Laboratories Ltd., Dr. Reddy's Laboratories, Inc. filed Critical Dr. Reddy's Laboratories Ltd.
Publication of WO2011140446A2 publication Critical patent/WO2011140446A2/fr
Publication of WO2011140446A3 publication Critical patent/WO2011140446A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • 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.
  • 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
  • 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
  • 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.
  • PPIs proton pump inhibitors
  • 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.
  • these drugs 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present application provides stable formulations comprising esomeprazole magnesium, together with one or more
  • 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.
  • the present application provides stable formulations prepared using esomeprazole magnesium in an amorphous form, crystalline form, or mixtures thereof as the starting active ingredient.
  • the present application provides stable formulations prepared using esomeprazole magnesium in a substantially amorphous form.
  • 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.
  • 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.
  • the present application provides multiple unit
  • 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.
  • 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.
  • 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.
  • a plasticizer is used in concentrations ranging from about 0-15%, or about 2-14%, by weight of enteric coating polymer.
  • 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.
  • the application provides a stable pharmaceutical composition
  • 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.
  • the present application provides multiple unit
  • 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.
  • the application provides a stable pharmaceutical composition
  • 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.
  • 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.
  • the application provides process for preparing a stable pharmaceutical composition
  • 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.
  • 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.
  • the application provides processes for producing stable formulations of esomeprazole magnesium, embodiments comprising:
  • esomeprazole magnesium formulations of the present application comprise particles.
  • particles according to the present application may be in the form of powders, granules, pellets, spheroids, extrudates, mini-tablets, and the like.
  • esomeprazole magnesium formulations of the present application are in the form of particles made into a unit dosage form such as tablets or capsules.
  • esomeprazole magnesium formulations of the present application are in the form of powders, granules, or pellets compressed into tablets or filled into capsules.
  • the present application provides esomeprazole
  • magnesium formulations prepared using an active ingredient having particle size distributions with D10 about 0.01 ⁇ to about 2 ⁇ , D50 about 2 ⁇ to about 9 ⁇ , and D90 about 2 ⁇ to about 50 ⁇ .
  • the present application provides stable formulations comprising esomeprazole magnesium, which are substantially free of drug degradation impurities.
  • 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.
  • 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.
  • the application provides stable formulations comprising esomeprazole magnesium, wherein levels of one or more of impurity A
  • 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.
  • HPLC high performance liquid chromatography
  • 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%.
  • the application provides processes for producing stable granules or pellets, including drying granules or pellets at temperatures of
  • the application provides processes for producing stable granules or pellets, wherein granules or pellets have water contents about 0.5-
  • 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.
  • the application provides stable pharmaceutical
  • formulations comprising esomeprazole magnesium and at least one
  • compositions 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.
  • formulations of the present application exhibit commercially acceptable chemical storage stability.
  • the active agent esomeprazole magnesium is contained in formulations during manufacture or storage, in an amorphous form, a crystalline form, or mixtures thereof.
  • 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.
  • a barrier coating layer is interposed between drug and enteric coating layers.
  • a barrier coating layer is below 30%, or below 15% w/w of drug-loaded pellets.
  • a barrier coating layer comprises sodium, potassium, calcium or magnesium as their oxides, hydroxides, or salts.
  • 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
  • Fig. 1 is an X-ray powder diffraction (XRPD) pattern of a tablet, as prepared Example 7.
  • benzimidazole compound 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,
  • the benzimidazole compound may be esomeprazole in the form of the free base, or a pharmaceutically acceptable salt thereof, in any polymorphic forms.
  • 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.
  • solid dosage forms of the present application comprising amorphous benzimidazole compounds having PPI activity, such as are
  • Formula I 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.
  • a non-toxic base such as a basic inorganic salt
  • 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.
  • acid-labile describes any compound, which is not stable in acidic conditions or which undergoes degradation or hydrolysis via acid or proton catalyzed reactions.
  • excipient means a component of a pharmaceutical product that is not an active ingredient, such as a filler, diluent, carrier, etc.
  • 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.
  • formulation refers to any solid oral dosage form such as a tablet or capsule, comprising a benzimidazole drug.
  • 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, ⁇ , ⁇ '- 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; n
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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:
  • R is COOH for the EUDRAGIT L products
  • R is COOCH 2 N(CH 3 )2 for the EUDRAGIT E products
  • R is COOCH 3 for the EUDRAGIT NE 30 D product
  • R is COOCH 2 CH 2 N + (CH 3 ) 3 Cr for the EUDRAGIT E and EUDRAGIT RS products.
  • the alkyl groups vary between different products, and have 1 -4 carbons.
  • methacrylic acid copolymer as a fully polymerized copolymer of methacrylic acid and an acrylic or methacrylic ester.
  • 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,
  • 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.
  • 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.
  • 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
  • Ludipress LCE comprises 96.5% ⁇ -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 ⁇ , 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.
  • 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.
  • directly compressible diluents including lactose, starch, cellulose derivatives, inorganic substances, polyalcohols, and sugar-based materials.
  • 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.
  • esomeprazole magnesium compositions of the present application are in the form of particles.
  • particles according to the present application may be in the form of powders, granules, pellets, spheroids, extrudates, mini-tablets, and the like.
  • esomeprazole magnesium formulations of the present application can be particles made into unit dosage forms such as tablets or capsules.
  • 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.
  • punches used to compress tablets are uncoated punches having modified capsule shape.
  • 40 mg strength esomeprazole magnesium tablets can use 1 7.5x8.5 mm modified capsule shaped tooling.
  • 20 mg strength esomeprazole magnesium tablets can use 14.7x6.8 mm modified capsule shaped tooling.
  • the present application provides pharmaceutical compositions comprising esomeprazole magnesium polymorphs, hydrates, esters, isomers, derivatives, or mixtures thereof, together with one or more
  • 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.
  • 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.
  • the present application provides esomeprazole
  • magnesium compositions prepared using esomeprazole magnesium as an active ingredient having particle size distributions with D50 about 1 ⁇ to about 40 ⁇ .
  • D50 values are maximum particle sizes for 50% of the particles in a sample.
  • the present application provides esomeprazole
  • magnesium compositions prepared using esomeprazole magnesium active ingredient having particle size distributions with D10 about 0.01 ⁇ to about 10 ⁇ , D50 about 2 ⁇ to about 20 ⁇ , and D90 about 5 ⁇ to about 80 ⁇ .
  • D10 values are maximum particle sizes for 10 percent of the particles
  • D90 values are maximum particle sizes for 90% of the particles.
  • 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.
  • 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.
  • 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.
  • 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 can be analyzed using a HPLC method with a 4.6x150 mm column containing a 3.5 ⁇ packing of octylsilane, chemically bonded to porous silica or ceramic micro-particles (e.g., a 150x4.6 mm Xterra, RP 8, 3.5 ⁇ 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.
  • a HPLC method with a 4.6x150 mm column containing a 3.5 ⁇ packing of octylsilane, chemically bonded to porous silica or ceramic micro-particles (e.g., a 150x4.6 mm Xterra, RP 8, 3.5 ⁇ or equivalent column), where the liquid chromatograph is equipped with a 305 nm UV detector, having a column temperature of 25°
  • 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.
  • Magnesium oxide (light) 1 1 .12 1 1 .12 1 1 .12
  • Hydroxypropyl cellulose 90 - -
  • Colloidal silicon dioxide (Aerosil® 200) 1 .6 - 1 .6
  • Opadry Pink 20A84821 is a coating product comprising hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, titanium dioxide, talc, iron oxide red, and iron oxide yellow.
  • HPMC hydroxypropyl methylcellulose
  • hydroxypropyl cellulose titanium dioxide
  • talc hydroxypropyl cellulose
  • iron oxide red iron oxide yellow
  • iron oxide yellow iron oxide yellow
  • 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.
  • Magnesium oxide (light) 1 1 .12 1 1 .12 -
  • Colloidal silicon dioxide (Aerosil 200) - - 4
  • 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.
  • 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.
  • Example 9 1 Disperse povidone K 90F, magnesium oxide, and magnesium stearate in methanol. Use this to coat the drug coated particles.
  • 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:
  • 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
  • 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.
  • 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.
  • Example 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:
  • Disintegration time 1 -2 minutes.
  • 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.
  • 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.
  • Microcrystalline cellulose (Avicel PH101 ) 250
  • Ethyl cellulose is dissolved in a mixture of methanol and methylene chloride. Magnesium stearate is added and mixed well.
  • Sugar spheres are sifted through 50 and 60 mesh sieves and the material retained on the 60 mesh sieve is used for further processing.
  • 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.
  • Meglumine is dissolved in the solution of step 1 .
  • 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.
  • Povidone K90 is dissolved in methanol and light magnesium oxide is dispersed in the solution.
  • 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.
  • Eudragit L100 55 is dissolved methanol.
  • Acetyl tributyl citrate is homogenized in methanol, then PEG 6000 and talc are added and the mixture is homogenized.
  • step 3 The solution of step 1 is added to the dispersion of step 2 with stirring.
  • 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.
  • HPMC 3 cps is mixed with methanol and talc is dispersed in the mixture.
  • 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.
  • Lactose monohydrate, microcrystalline cellulose, and crospovidone are sifted through a 40 mesh sieve and blended.
  • 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.
  • FBP fluid bed processor
  • Polyethylene glycol and crospovidone are sifted through a 40 mesh sieve and mixed, then Stage VI granules are added and the materials are blended.
  • Sodium stearyl fumarate is sifted through a 60 mesh sieve, and blended with the materials of step 1 .
  • step 3 The blend from step 2 is compressed into tablets containing 40 mg of esomeprazole.
  • Opadry Pink is dispersed in isopropyl alcohol and methylene chloride and used to coat the Stage VII tablets.
  • 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.
  • 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
  • Tablets prepared in Example 13 have the following properties: Water by Karl Fischer: 4.8%.
  • Disintegration time less than 1 minute.

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Abstract

La présente invention concerne une composition pharmaceutique formée de particules, pour une utilisation orale. Ladite composition comprend a) des noyaux comprenant une quantité efficace d'un médicament à base de benzimidazole substitué et un agent stabilisant, présent en une quantité efficace pour stabiliser le médicament, b) une couche intermédiaire/barrière et c) une couche de revêtement entérique externe. Les particules revêtues peuvent en outre être enrobées et cogranulées avec un ou plusieurs excipients.
PCT/US2011/035529 2010-05-06 2011-05-06 Formulations pharmaceutiques WO2011140446A2 (fr)

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Cited By (10)

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EP2345408A3 (fr) * 2010-01-08 2012-02-29 Dr. Reddy's Laboratories Ltd. Formulations de médicament labiles acides
EP2886110A1 (fr) * 2013-12-23 2015-06-24 Ranbaxy Laboratories Limited Compositions pharmaceutiques d'unités multiples, multicouches
CN105001199A (zh) * 2015-05-13 2015-10-28 济南大学 N-甲基埃索美拉唑的制备方法
US9522119B2 (en) 2014-07-15 2016-12-20 Isa Odidi Compositions and methods for reducing overdose
WO2017194577A1 (fr) * 2016-05-13 2017-11-16 Merck Patent Gmbh Utilisation de sucre aminé comme plastifiant
US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
JP2021046372A (ja) * 2019-09-19 2021-03-25 日医工株式会社 エソメプラゾール含有製剤
WO2021115649A1 (fr) * 2019-12-11 2021-06-17 Evonik Operations Gmbh Forme posologique à utiliser dans le traitement ou la prévention d'une maladie
US11730708B2 (en) 2019-12-11 2023-08-22 Evonik Operations Gmbh Dosage form for use in treating or preventing of a disease
US11986554B2 (en) 2015-04-29 2024-05-21 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions

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US20050214372A1 (en) * 2004-03-03 2005-09-29 Simona Di Capua Stable pharmaceutical composition comprising an acid labile drug
US20060024362A1 (en) * 2004-07-29 2006-02-02 Pawan Seth Composition comprising a benzimidazole and process for its manufacture
US20060051421A1 (en) * 2004-06-15 2006-03-09 Nava Shterman Stable pharmaceutical formulations of benzimidazole compounds
US20090208575A1 (en) * 2005-01-03 2009-08-20 Lupin Limited Pharmaceutical Composition Of Acid Labile Substances
WO2010041276A1 (fr) * 2008-10-06 2010-04-15 Jubilant Organosys Limited Compositions pharmaceutiques comprenant de l’ésoméprazole amorphe, formes pharmaceutiques et procédé associés

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US20050042277A1 (en) * 2003-07-17 2005-02-24 Irukulla Srinivas Pharmaceutical compositions having a swellable coating
US20050214372A1 (en) * 2004-03-03 2005-09-29 Simona Di Capua Stable pharmaceutical composition comprising an acid labile drug
US20060051421A1 (en) * 2004-06-15 2006-03-09 Nava Shterman Stable pharmaceutical formulations of benzimidazole compounds
US20060024362A1 (en) * 2004-07-29 2006-02-02 Pawan Seth Composition comprising a benzimidazole and process for its manufacture
US20090208575A1 (en) * 2005-01-03 2009-08-20 Lupin Limited Pharmaceutical Composition Of Acid Labile Substances
WO2010041276A1 (fr) * 2008-10-06 2010-04-15 Jubilant Organosys Limited Compositions pharmaceutiques comprenant de l’ésoméprazole amorphe, formes pharmaceutiques et procédé associés

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2345408A3 (fr) * 2010-01-08 2012-02-29 Dr. Reddy's Laboratories Ltd. Formulations de médicament labiles acides
EP2886110A1 (fr) * 2013-12-23 2015-06-24 Ranbaxy Laboratories Limited Compositions pharmaceutiques d'unités multiples, multicouches
US9801939B2 (en) 2014-07-15 2017-10-31 Isa Odidi Compositions and methods for reducing overdose
US9522119B2 (en) 2014-07-15 2016-12-20 Isa Odidi Compositions and methods for reducing overdose
US9700515B2 (en) 2014-07-15 2017-07-11 Isa Odidi Compositions and methods for reducing overdose
US9700516B2 (en) 2014-07-15 2017-07-11 Isa Odidi Compositions and methods for reducing overdose
US10653776B2 (en) 2014-07-15 2020-05-19 Intellipharmaceutics Corp. Compositions and methods for reducing overdose
US11986554B2 (en) 2015-04-29 2024-05-21 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
CN105001199A (zh) * 2015-05-13 2015-10-28 济南大学 N-甲基埃索美拉唑的制备方法
WO2017194577A1 (fr) * 2016-05-13 2017-11-16 Merck Patent Gmbh Utilisation de sucre aminé comme plastifiant
US11045550B2 (en) 2016-05-13 2021-06-29 Merck Patent Gmbh Use of an amino sugar as plasticizer
US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
JP2021046372A (ja) * 2019-09-19 2021-03-25 日医工株式会社 エソメプラゾール含有製剤
WO2021115649A1 (fr) * 2019-12-11 2021-06-17 Evonik Operations Gmbh Forme posologique à utiliser dans le traitement ou la prévention d'une maladie
US11730708B2 (en) 2019-12-11 2023-08-22 Evonik Operations Gmbh Dosage form for use in treating or preventing of a disease

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