WO2003103638A1 - Compositions pharmaceutiques stabilisees contenant des composes de benzimidazole - Google Patents

Compositions pharmaceutiques stabilisees contenant des composes de benzimidazole Download PDF

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Publication number
WO2003103638A1
WO2003103638A1 PCT/US2003/017705 US0317705W WO03103638A1 WO 2003103638 A1 WO2003103638 A1 WO 2003103638A1 US 0317705 W US0317705 W US 0317705W WO 03103638 A1 WO03103638 A1 WO 03103638A1
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WIPO (PCT)
Prior art keywords
enteric
single core
pharmaceutical composition
compression coating
oral pharmaceutical
Prior art date
Application number
PCT/US2003/017705
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English (en)
Inventor
Mahendra R. Patel
Amol Singh Matharu
Chuanbin Wu
Ashish Anilbhai Patel
Original Assignee
Geneva Pharmaceuticals, 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.)
Filing date
Publication date
Priority claimed from US10/164,744 external-priority patent/US20030228363A1/en
Application filed by Geneva Pharmaceuticals, Inc. filed Critical Geneva Pharmaceuticals, Inc.
Priority to AU2003238896A priority Critical patent/AU2003238896A1/en
Publication of WO2003103638A1 publication Critical patent/WO2003103638A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the present invention relates to new, stabilized compositions containing proton-pump inhibitors (PPI) from the benzimidazole class of compounds.
  • PPI proton-pump inhibitors
  • Certain benzimidazoles are anti-ulcerous compounds known for decreasing gastric acid secretion.
  • these compounds also known as PPI
  • PPI are susceptible to degradation/transformation in acidic reacting and neutral media. The degradation is catalyzed by acidic reacting compounds and the PPIs are usually stabilized in mixtures with alkaline reacting compounds.
  • those in an oral solid dosage form must be protected from contact with the acidic reacting gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is less acidic, neutral or alkaline and where rapid absorption of the pharmaceutically active substance, i.e., the benzimidazole derivative, can occur.
  • U.S. Patent No. 4,853,230 has shown that a pharmaceutical dosage form of these benzimidazole derivatives can be protected from contact with acidic gastric juice by an enteric coating layer.
  • enteric coating layer Such preparations contain an alkaline core material comprising the active substance, a separating layer and an enteric coating layer.
  • Ordinary enteric coating layers comprise compounds which contain acidic groups. If covered with such an enteric coating layer, the acid labile substance may rapidly decompose by direct or indirect contact with the acidic groups resulting in discoloration of the content and loss in content of the active compound with the passage of time. The discoloration can be avoided by applying some type of separating layer between the core material comprising the susceptible these benzimidazole derivatives and the enteric coating layer.
  • U.S. Patent No. 6,013,281 also discloses that a separating layer is formed in situ by direct application of an acidic enteric material on to the alkaline core containing the PPI.
  • WO 98/00115 teaches the use of aqueous application of partially neutralized enteric polymer applied directly onto the reactive core. Similar application was disclosed in U.S. Patent No. 5,225,202.
  • Applicants have developed an oral pharmaceutical composition in the form of a tablet that avoids the need to use a separating layer to separate the tablet core containing the PPI from the enteric coating layer in a tablet dosage form.
  • the present invention is directed toward an oral pharmaceutical composition in a solid dosage form comprising: a) a single core comprising a proton pump inhibitor and a lubricant, wherein said single core has an exterior surface; b) an enteric compression coating comprising a polymer and a lubricant, wherein said enteric compression coating is on the exterior surface of said single core, without a separating layer between said single core and said enteric compression coating; and c) optionally, a polymer overcoating on said enteric compression coating.
  • the present invention is directed towards an oral pharmaceutical composition in a solid dosage form comprising: a) a single core comprising a proton pump inhibitor, a disintegrant, a filler and a lubricant, wherein said single core has an exterior surface; b) an enteric compression coating comprising a polymer and a lubricant, wherein said enteric compression coating is on the exterior surface of said single core, without a separating layer between said single core and said enteric compression coating; and c) optionally, a polymer overcoating on said enteric compression coating
  • the present invention is directed toward an oral pharmaceutical composition in a solid dosage form comprising: a) a single core comprising a proton pump inhibitor and a lubricant, said single core being essentially free of an alkaline reacting agent, wherein said single core has an exterior surface; b) an enteric compression coating comprising a polymer and a lubricant, wherein said enteric compression coating is on the exterior surface of said single core, without a separating layer between said single core and said enteric compression coating; and c) optionally, a polymer overcoating on said enteric compression coating.
  • the present invention is directed towards a process for preparing an oral pharmaceutical composition in a solid dosage form comprising: a) forming a single core comprising a proton pump inhibitor and a lubricant, wherein said single core has an exterior surface; b) compression coating an enteric polymer comprising a proton pump inhibitor and a lubricant onto the exterior surface of said single core, in the absence of water and organic solvents, and without forming a separating layer between said single tablet core and said enteric coating; and c) optionally, applying a polymer overcoating on said enteric compression coating.
  • the single tablet core may contain a PPI selected from the group consisting of rabeprazole, omeprazole, esomeprazole, lansoprazole, leminoprazole, pantoprazole or mixtures thereof.
  • the enteric coating may contain a polymer selected from cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate (HP CAS), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinylacetate phthalate, carboxymethylethylcellulose, acrylic acid polymers and co-polymers and methacrylic acid polymers and co-polymers or combinations thereof.
  • the present invention has the advantage of providing an oral pharmaceutical composition containing a labile PPI in the form of a tablet that can provide improved stability of the PPI contained therein against degradation and/or discoloration by moisture and/or heating.
  • Another advantage of the present invention is that it provides an oral pharmaceutical composition containing a labile PPI in the form of a tablet whose design and/ or construction is greatly simplified over other known tableted compositions.
  • Another advantage of the present invention is that it provides an oral pharmaceutical composition containing a labile PPI that allows control of the release rate of said labile PPI within wide margins.
  • Another advantage of the present invention is that it provides a process for preparing an oral pharmaceutical composition containing a labile PPI, that can eliminate the use of water or organic solvents during coating of the tablet core, i.e., can be solvent-free.
  • Another advantage of the present invention is that it provides a process for preparing an oral pharmaceutical composition containing a labile PPI that can eliminate the need for heating during process, i.e., can be processed at ambient temperatures.
  • Another advantage of the present invention is that it provides an oral pharmaceutical composition and a process for preparation thereof, containing a labile PPI in the form of a tablet that does not require a separating layer to separate the core unit containing the acid- labile PPI from the enteric coating.
  • Another advantage of the present invention is that it provides a process for preparing an oral pharmaceutical composition, containing a labile PPI in the form of a tablet that can prevent the in situ formation of a separating layer between the core unit containing the acid-labile PPI from the enteric coating.
  • Another advantage of the present invention is that it provides a process for preparing an oral pharmaceutical composition containing a labile PPI in the form of a tablet, that can be carried out or produced using conventional pharmaceutical equipment.
  • the PPI in an oral solid dosage form should be protected from contact with the acid reacting gastric juice and the active substance should be transferred in intact form to that part of the gastrointestinal tract where the pH is less acidic, neutral or alkaline and where rapid absorption of the pharmaceutically active substance can occur.
  • tablette core tablette
  • core tablet core tablet
  • single tablet core or “single tablet core unit”
  • benzimidazole benzimidazole compound
  • PPI proto pump inhibitor
  • Suitable benzimidazole compounds that can be employed as an active ingredient in the composition of the present invention include those of formula (I)
  • R 1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl;
  • R 2 is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl;
  • R 3 and R 5 are the same or different and each can be hydrogen, alkyl, alkoxy or alkoxyalkoxy;
  • R 4 is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy; and m is an integer of 0 through 4.
  • PPIs include rabeprazole, omeprazole, esomeprazole, pariprazole, lansoprazole, leminoprazole, pariprazole, pantoprazole or mixtures thereof.
  • the PPIs employed in the present invention may be used in neutral form or in the form of an alkaline metal salt, such as for instance, the salt of potassium, sodium, lithium, magnesium and/or calcium.
  • the benzimidazole compounds cited above may be used in a neutral form, in a racemic mixture, in the form of a substantially pure enantiomer thereof, as an alkaline salt of the racemic mixture or a single enantiomer, or combinations thereof.
  • the amount of PPI can range from about 5% to about 75% by weight, from about 10% to about 70% by weight or from about 15% to about 60% by weight of the oral pharmaceutical composition.
  • the oral pharmaceutical composition or tablet can contain a known mass of the PPI, such as 10, 15, 20, 30 or 40 mg.
  • labile refers to the property that the PPI are susceptible to degradation in the presence of acid and neutral media, humidity and/or elevated temperatures.
  • degradation of PPI can be catalyzed by acids or acid containing compounds.
  • the PPI may also be unstable in the presence of water or high humidity.
  • Suitable inert fillers that can be used in the core include lactose, mannitol, starch, sucrose, glucose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, ethylcellulose, hydroxypropyl methylcellulose phthalate, diacetylated monoglycerides, talc, titanium dioxide and other excipients.
  • the amount of filler can range from about 10% to about 90% by weight of the tablet.
  • Suitable disintegrants that can be used in the core can include sodium starch glycolate or sodium crosscarmellose.
  • the amount of disintegrant can range from about 0.5% to about 30% by weight of the tablet.
  • Suitable lubricants that can be used in the core can include dry or solid lubricants, such as magnesium stearate, calcium stearate, sodium stearate, sodium stearyl fumarate and waxes, such as polyethylene glycol (solid form) and carnauba wax.
  • the lubricant can be employed in both the enteric compression coating and in the core.
  • the amount of lubricant can range from about 0.5 to about 30% by weight of each tablet or solid dosage form component, also from about 5 to about 25 percent by weight, also from about 10 to about 15 percent by weight.
  • the amount of lubricant in the pharmaceutical composition can range from about 0.1% to about 10 - 20%, also about 0.2% to about 6% by weight.
  • the amount of lubricant in the tablet can range from about 0.01 parts to about 1.5 parts by weight of the lubricant per one part PPI (about 0.01-1.5 parts lubricanfcone part PPI).
  • the PPI is mixed with suitable pharmaceutical constituents, such as those described above for the fillers, disintegrants and lubricants and the resulting mixture is compressed into the core or tablet core unit.
  • the core tablet core of the present invention should be essentially free of alkaline reacting agents or compounds, such as those cited in U.S. Patent No. 6,013,281.
  • the PPI should not be seeded or layered prior to being compressed into the core unit.
  • the size of the formulated core material is approximately between about one and about 20 mm and preferably between about 3 mm and about 15 mm.
  • the manufactured core tablet containing the PPI can be covered with an enteric outer coating or layer. After . preparation, the single core tablet has an exterior surface where the enteric outer coating is applied or coated.
  • enteric coating should be inert or substantially non- interacting with the single, tablet core containing the PPI.
  • the enteric coating may contain ingredients, such as one or more polymers, release rate agents, lubricants, anti-tacking agents, colorants, pigments or other additives to obtain a tablet of good appearance.
  • the amount of enteric coating in the tablet can range from about 0.1 - 0.4 parts to about 3 parts by weight of enteric coating per one part by weight tablet core (about 0.1 - 0.4 to 3 parts by weight enteric coating:one part tablet core).
  • the enteric outer coating does not contain any PPI or other active drug ingredient.
  • Suitable polymers that can be used in the enteric coating can include anionic co-polymers based on methacrylic acid esters, commercially available as Eudragit L 100 and Eurdragit S 100, trademarks of Rohm, GmbH & Co., KG, Darmstadt, Germany. This enteric coating is insoluble below pH 5 and is thus resistant to gastric fluid. By salt formation in the neutral or weakly alkaline medium of the intestinal fluid, the enteric coating dissolves stepwise at pH values greater than 5.5-7.5.
  • Another suitable polymer that can be used includes HPMCP or HPMCAS, commercially available from the Shin-Etsu Chemical Co. Ltd. A sole polymer can be employed such as HPMCAS or a mixture of polymers can be used, such as Eudragit and HPMCP.
  • polymers can be cellulose acetate phthalate, HPMCAS, HPMCP, polyvinylacetate phthalate, carboxymethylethylcellulose, acrylic acid polymers and co- polymers and methacrylic acid polymers and co-polymers.
  • the non-interacting property of such enteric coatings can be obtained or enhanced by neutralizing free acids in the enteric polymer with an inorganic or organic alkaline material, such as sodium hydroxide, magnesium hydroxide, meglumine and the like.
  • the neutralized polymer results in enhanced stabilization of the tablet core.
  • the amount of each polymer employed in the enteric coating can range from about 5% to about 99% by weight of the composition.
  • Suitable release rate agents that can be used in the enteric coating can include lactose, mannitol, starch, sucrose, glucose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, ethylcellulose, HPMCP, diacetylated monoglycerides, talc or titanium dioxide.
  • the amounts of release agent employed in the enteric coating can range from about 0.5% to about 95% by weight of the composition.
  • Suitable lubricants that can be used in the core can include dry or solid lubricants, such as magnesium stearate, calcium stearate, silicon dioxide, or sodium stearate and waxes, such as carnauba wax.
  • the lubricant can be employed in both the enteric compression coating and in the core or tablet core.
  • the amount of lubricant in either the enteric coating layer or in the core can range from about 0.5 to about 30% by weight of each tablet or solid dosage form component, also from about 5 to about 25 percent by weight, also from about 10 to about 5 percent by weight.
  • the amount of lubricant in the pharmaceutical composition can range from about 0.1% to about 10 - 20%, also about 0.2% to about 6% by weight.
  • the amount of lubricant in the tablet can range from about 0.01 parts to about 1.5 parts by weight of the lubricant per one part PPI (about 0.01-1.5 parts lubricanfcone part PPI).
  • the ingredients used in the enteric coating are dry or solid (with the exception of the optional polymer over-coating, discussed below) and can be blended or mixed together in the absence of water or organic solvents.
  • the dry blend or mixture can be compressed (i.e., compression-coated) directly onto the exterior surface of the core or tablet core, using conventional procedures.
  • One skilled in the art can utilize a range of compression forces or tablet hardnesses which provide the desired attributes for the enteric compression coating, such as acid protection or release in the post-stomach region. For example, one can prepare a series of tablet samples at different compression forces or tablet hardnesses and select a range which meets desired physical and performance attributes, such as tablet friability an d dissolution profiles.
  • the range of hardnesses for a tablet with the enteric compression coating can range from about 4 SCU to about 30 SCU, also from about 7 to about 15 SCU.
  • the compressive forces can range from about 0.1 ton to about 3 tons, also from about 0.3 to about 2 tons, also from about 0.5 ton to about 1.5 tons.
  • the dry mixture can be sprayed or dispersed directly onto the core or tablet core and then compressed as described above. The dry blend or mixture that is compressed onto the exterior surface of the core or tablet core forms the enteric compression coating for the pharmaceutical composition. After the enteric compression coating is applied to the core or tablet core, there is no separating layer between the core and the enteric compression coating.
  • Tablets with the enteric coating are then covered with optionally one or more finishing polymer over-coating or tablet film coat(s) or layer(s) to obtain tablets of good appearance, smoothness, color or functionality, such as modified release.
  • the maximum thickness of the applied over-coating layer(s) is normally limited by processing conditions and the desired dissolution or release profile.
  • the tablet film(s) can be a thin coat as compared to the enteric coating.
  • the polymer over-coating can be water soluble or water soluble/swellable in water or have a solubility that is pH dependent. Further, the overcoating can be rapidly disintegrating or even insoluble in water.
  • the materials for the overcoating layer can be pharmaceutically acceptable excipients, such as the same polymers used in the enteric coating layer, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, acrylic acid co-polymers, carboxymethylcellulose sodium, phthalate, HPMCAS, Eudragit (Rohm Pharma Co., West Germany, acrylate co-polymer, amionic in character), polyvinylacetaldiethylaminoacetate, water soluble salts of enteric coating polymers, and waxes, used alone or in mixtures.
  • pharmaceutically acceptable excipients such as the same polymers used in the enteric coating layer, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxyprop
  • Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the over-coating layer(s).
  • the polymer over-coating does not contain any PPI or other active drug ingredient.
  • the amount of polymer coating in the tablet can range from about 0.01 parts to about 1 part by weight of polymer coating per one part by weight tablet core (about 0.4-3 parts by weight enteric coating:one part tablet core).
  • the polymer over-coating or tablet film coat can be applied to the enteric coating layered tablet by spraying, coating or layering procedures in suitable equipment, such as coating pan, coating granulator or in a fluidized bed apparatus. In such procedures, water or other solvents may be used to solubilize the materials used for the polymer over-coating or tablet film coat.
  • the tablet core is prepared by dry mixing rabeprazole sodium with lactose F.F., sodium starch glycolate and magnesium stearate. The dry mixture is compressed with a suitable tablet press into 200 mg core tablets containing 20 mg of rabeprazole sodium which are 0.31" (7.9 mm) in diameter and 0.16" (4.1 mm) in thickness.
  • the enteric coating is prepared by dry blending or mixing Eudragit L100-55, HPMCP HP-55, Lactose F.F. and magnesium stearate.
  • the core tablet is compression-coated using the resulting dry blend to produce 600 mg tablets, 0.40" (10.2 mm) in diameter and 0.25" (6.35 mm) in thickness.
  • the compression-coated tablets are over-coated with 5% hydroxypropylmethylcellulose based on the total tablet weight.
  • the release of the drug from the tablets is monitored using a dissolution tester, in which 900 mL of simulated gastric fluid (SGF), without enzyme is maintained at 37°C and used as the dissolution medium for the first 2 hours.
  • SGF simulated gastric fluid
  • the USP 2 dissolution method is used at a rotation speed of 50 rpm.
  • phosphate buffer is used as a media. Delayed release of rabeprazole sodium is obtained after a period of about 2 hours in SGF dissolution media.
  • Example 2-5 the dimensions of the tablet cores and polymer coat are the same as those in Example 1.
  • Delayed-release tablets are prepared and tested as for Example 1.
  • Delayed release of the active ingredient is obtained after a period of about 2 hours in SGF and about 1 hour in phosphate buffer solution.
  • Delayed-release tablets are prepared and tested as for Example 1, except that the compression-coated tablets are over-coated with 3% Eudragit polymer based on the total tablet weight.
  • the release of the drug from the tablets is monitored using a dissolution, in which 900 mL of SGF, without enzyme, is maintained at 37°C and used as the dissolution medium for the first 2 hours.
  • the USP 2 dissolution method is used at a rotation speed of 50 rpm.
  • phosphate buffer is used as a media.
  • the tablet core is prepared by dry mixing rabeprazole sodium with lactose F.F., sodium starch glycolate and magnesium stearate. The dry mixture is compressed with a suitable tablet press into 200 mg core tablets containing 20 mg of rabeprazole sodium which are 0.31" (7.9 mm) in diameter and 0.16" (4.1 mm) in thickness.
  • the enteric outer layer is prepared by dry blending or mixing the above excipients and compression-coating the core tablet with the resulting blend to produce 600 mg tablets, 0.40" (10.2 mm) in diameter and 0.25" (6.35 mm) in thickness.
  • the compression-coated tablets are over-coated with 5% hydroxypropylmethylcellulose based on the total tablet weight.
  • the release of the drug from the tablets is monitored using a dissolution, in which 900 mL of SGF, without enzyme is maintained at 37°C and used as the dissolution medium for the first 2 hours.
  • the USP 2 dissolution method is used at a rotation speed of 50 rpm.
  • phosphate buffer is used as a media.
  • Delayed-release tablets are prepared and tested as for Example 1.
  • Delayed release of the active ingredient is obtained after a period of about 2 hours in SGF and about 1 hour in phosphate buffer solution.
  • Delayed-release tablets are prepared and tested as for Example 1.
  • Delayed release of the active ingredient is obtained after a period of about 2 hours in SGF and about 1 hour in phosphate buffer solution.
  • Delayed-release tablets are prepared and tested as for Example 1. Delayed release of the active ingredient is obtained after a period of about 2 hours in SGF and about 1 hour in phosphate buffer solution.
  • Delayed-release tablets are prepared and tested as for Example 1.
  • Delayed release of the active ingredient is obtained after a period of about 2 hours in SGF and about 1 hour in phosphate buffer solution.
  • Magnesium stearate 2.00 Delayed-release tablets are prepared and tested as for Example 1.
  • Delayed release of the active ingredient is obtained after a period of about 2 hours. in SGF and about 1 hour in phosphate buffer solution.
  • Delayed-release tablets are prepared and tested as for Example 1.
  • Delayed release of the active ingredient is obtained after a period of about 2 hours in SGF and about 1 hour in phosphate buffer solution.
  • Magnesium stearate 2.00 Delayed-release tablets are prepared and tested as for Example 1.
  • Delayed release of the active ingredient is obtained after a period of about 2 hours in SGF and about 1 hour in phosphate buffer solution.
  • Enteric coating As a technique for delayed drug release using enteric polymers. Enteric coating has been typically achieved by using film coating with pH sensitive polymers.
  • Drug-containing tablets were coated with enteric coating polymer by using compression coating technique. Delayed release properties, compressibility, and stability were evaluated by applying different compression coating formulations, coating levels, and enteric coating polymer types. Drug release is monitored in vitro in 0.1 N HCI solution for 2 hours and then in pH 7.4 phosphate buffer medium for another 60 minutes using USP apparatus II. Formulation stability is evaluated by comparing compression coating formulation and aqueous enteric coating formulation and by storing at room temperature and at 40 °C775% relative humidity conditions for 3 months. Impurity of the drug in the formulations was determined at initial time, one month, two months, and three months of storage time by HPLC method.
  • Acid protection is achieved and found to be dependent upon enteric coating levels and compression forces.
  • drug release rate in the pH 7.4 phosphate buffer medium are also affected with higher enteric coating level and compression force, which could be ascribed to lower permeability of the compression coating layer.
  • Dissolution results for the optimized formulation show adequate enteric protection and resistance to drug release in 0.1 N HCI while greater than 80% drug is released in pH 7.4 phosphate buffer medium in 60 minutes. This is comparable to enteric polymer coated tablets produced by aqueous coating method. Stability data showed that the total impurity of the formulation could be significantly improved as compared to the aqueous film coating formulation for an acid labile drug.
  • the novel delayed release formulation could be optimized and developed by compression coating with enteric coating polymer formulations. This technique of providing enteric protection is particularly useful where the drug is highly reactive to an aqueous environment during processing.

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Abstract

L'invention concerne une composition pharmaceutique orale sous forme dosifiée solide comprenant: un noyau unique qui comporte un inhibiteur de la pompe à protons et un lubrifiant, ce noyau unique présentant une surface extérieure; b) un enrobage gastro-résistant comprimé comprenant un polymère et un lubrifiant, ledit enrobage gastro-résistant comprimé étant situé sur la surface extérieure dudit noyau unique, sans couche de séparation entre ledit noyau unique et ledit enrobage gastro-résistant comprimé; et c) éventuellement un second enrobage polymère situé sur ledit enrobage gastro-résistant comprimé.
PCT/US2003/017705 2002-06-07 2003-06-05 Compositions pharmaceutiques stabilisees contenant des composes de benzimidazole WO2003103638A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003238896A AU2003238896A1 (en) 2002-06-07 2003-06-05 Stabilized pharmaceutical compositions containing benzimidazole compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10/164,744 2002-06-07
US10/164,744 US20030228363A1 (en) 2002-06-07 2002-06-07 Stabilized pharmaceutical compositons containing benzimidazole compounds
US10/431,271 US20030236285A1 (en) 2002-06-07 2003-05-07 Stabilized pharmaceutical compositions containing benzimidazole compounds
US10/431,271 2003-05-07

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004066982A1 (fr) * 2003-01-31 2004-08-12 Ranbaxy Laboratories Limited Compositions orales stables de benzimidazole et leurs procedes de preparation
WO2004093849A1 (fr) * 2003-04-23 2004-11-04 Sandoz Ag Compositions pharmaceutiques a liberation retardee contenant des inhibiteurs de la pompe a protons
WO2005077342A1 (fr) * 2004-02-17 2005-08-25 Sandoz Ag Microcomprimes de lansoprazole gastroresistants
US7790755B2 (en) 2002-10-16 2010-09-07 Takeda Pharmaceutical Company Limited Controlled release preparation
US9023391B2 (en) 1999-06-22 2015-05-05 Dexcel Ltd. Stable benzimidazole formulation

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WO2000078284A1 (fr) * 1999-06-22 2000-12-28 Dexcel Ltd. Formulation de benzimidazole stable
US6174548B1 (en) * 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
WO2002026210A2 (fr) * 2000-09-29 2002-04-04 Geneva Pharmaceuticals Inc. Formulation d'inhibiteur de la pompe à protons

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Publication number Priority date Publication date Assignee Title
US6174548B1 (en) * 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
WO2000078284A1 (fr) * 1999-06-22 2000-12-28 Dexcel Ltd. Formulation de benzimidazole stable
WO2002026210A2 (fr) * 2000-09-29 2002-04-04 Geneva Pharmaceuticals Inc. Formulation d'inhibiteur de la pompe à protons

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9023391B2 (en) 1999-06-22 2015-05-05 Dexcel Ltd. Stable benzimidazole formulation
US7790755B2 (en) 2002-10-16 2010-09-07 Takeda Pharmaceutical Company Limited Controlled release preparation
SG164281A1 (en) * 2002-10-16 2010-09-29 Takeda Pharmaceutical Controlled release preparation
WO2004066982A1 (fr) * 2003-01-31 2004-08-12 Ranbaxy Laboratories Limited Compositions orales stables de benzimidazole et leurs procedes de preparation
WO2004093849A1 (fr) * 2003-04-23 2004-11-04 Sandoz Ag Compositions pharmaceutiques a liberation retardee contenant des inhibiteurs de la pompe a protons
WO2005077342A1 (fr) * 2004-02-17 2005-08-25 Sandoz Ag Microcomprimes de lansoprazole gastroresistants

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