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WO1994002140A1 - Composition pharmaceutique contenant un agent antiulcereux - Google Patents

Composition pharmaceutique contenant un agent antiulcereux Download PDF

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Publication number
WO1994002140A1
WO1994002140A1 PCT/JP1993/000920 JP9300920W WO9402140A1 WO 1994002140 A1 WO1994002140 A1 WO 1994002140A1 JP 9300920 W JP9300920 W JP 9300920W WO 9402140 A1 WO9402140 A1 WO 9402140A1
Authority
WO
WIPO (PCT)
Prior art keywords
undercoating
sodium
enteric
buffer
core portion
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1993/000920
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English (en)
Inventor
Naohiro Oishi
Toshiyuki Shibata
Kuniki Ikeda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tanabe Pharma Corp
AstraZeneca AB
Original Assignee
Yoshitomi Pharmaceutical Industries Ltd
Astra AB
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
Application filed by Yoshitomi Pharmaceutical Industries Ltd, Astra AB filed Critical Yoshitomi Pharmaceutical Industries Ltd
Priority to AU45133/93A priority Critical patent/AU4513393A/en
Publication of WO1994002140A1 publication Critical patent/WO1994002140A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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

  • This invention relates to a pharmaceutical composition containing an antiulcer agent, which composition is improved in stability and unchanged in dissolution property with time.
  • benzimidazole compounds having H + -K + ATPase inhibitory activity are useful as therapeutic agents for digestive ulcers which serve to suppress potently the secretion of gastric acid.
  • the inhibitory activity is so potent and lasting that they have attracted attention as a next- generation therapeutic agent for digestion ulcers which supersedes hystamine H 2 receptor antagonists such as cimetidine, etc.
  • benzimidazole compounds described in Japanese Patent First Publications [41783/1979, 50978/1986 and 6270/1989 have a potent gastric antiulcer activity and are corroborated to have clinical usefulness.
  • benzimidazole compounds disclosed have poor stability. That is, they are unstable, in the solid state, to heat, humidity and light, and are susceptible, in an acidic or neutral aqueous solution, to rapid decomposition and significant coloring. Further, in the form of preparations such as tablets, fine granules, granules, capsules and powders, the benzimidazole compounds are adversely affected by other ingredients than them in the preparations and becomes unstable, thus causing decrease in content thereof and color change with the lapse of time. Of these preparations, where the tablets or granules are applied with an enteric coating, the compatibility of the compounds with the enteric agent (e.g.
  • cellulose acetate/phthalate hydroxypropyl ethylcellulose phthalate, hydroxymethylcellulose acetate s ⁇ ccinate, methacrylic acid/acrylic acid copolymer
  • Japanese Patent First Publication 283964/1987 discloses a composition comprising a benzimidazole derivative and its 5% by weight or more of a basic substance (hydroxides or inorganic acid salts of alkali metals, alkali earth metals or aluminum) and its results of preservation stability (residue amount).
  • a basic substance hydrooxides or inorganic acid salts of alkali metals, alkali earth metals or aluminum
  • preservation stability residual amount
  • the new preparation is composed of ⁇ a core portion containing an active component, an intermediate coating on the core portion consisting of one or more layers and ® an enteric coating on the intermediate coating, thereby forming a three-coat oral enteric pharmaceutical preparation, wherein the core portion comprises an alkaline reactive compound, e.g. magnesium oxide, magnesium hydroxide, etc. and the intermediate coating comprises a pH buffering alkaline compound, e.g.
  • the preparation is characterized in that the core portion includes an alkaline reactive compound and the intermediate coating includes a pH buffering alkaline compound.
  • the Applicant of this invention is manufacturing and selling stable omeprazole preparations wherein magnesium hydroxide is selected as a best alkaline compound and synthetic hydrotalcite, as a pH buffering alkaline compound of the intermediate coating.
  • an enteric pharmaceutical composition containing antiulcer agent, improved in stablility and unchanged in dissolution property with the lapse of time, which composition comprises a core portion including a 2-[ (2-pyridyl Jmethylsulfinyl ]- benzimidazole compound that has antiulcer activity and is unstable to acid, and undercoating of one or two layers covering the core portion and an enteric coating further covering the undercoating, wherein said core portion and/or said undercoating comprise a stabilizer selected from the group consisting of aluminum hydroxide • sodium bicarbonate coprecipitate alone, a mixture of the aforementioned coprecipitate and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an amino acid and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer;
  • an enteric pharmaceutical composition improved in stability and unchanged in dissolution property with the lapse of time, which composition comprises a core portion including a 2-[(2- pyridyl )methylsulfinyl ] benzimidazole compound that has antiulcer activity and is unstable to an acid, an undercoating of one or two layers covering the core portion, and an enteric coating further covering the undercoating, wherein the core portion and/or the undercoating comprise aluminum hydroxide • sodium bicarbonate coprecipitate;
  • an enteric pharmaceutical composition improved in stability and unchanged in dissolution property with the lapse of time, which composition comprises a core portion including a 2-[(2- pyridyl Jmethylsulfinyl ] benzimidazole compound that has antiulcer activity and is unstable to an acid, an undercoating of one or two layers covering the core portion, and an enteric coating further covering the undercoating, wherein the core portion and/or the undercoating comprise aluminum hydroxide* sodium bicarbonate coprecipitate and a buffer;
  • the enterinc pharmaceutical composition as set forth in item 5, wherein the buffer is sodium tartarate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate or tripotassium phosphate;
  • an enteric pharmaceutical composition improved in stability and unchanged in dissolution property with the lapse of time, which composition comprises a core portion including a 2-[(2- pyridyl )methylsulfinyl ] benzimidazole compound that has antiulcer activity and is unstable to an acid, an undercoating of one or two layers covering the core portion, and an enteric coating further covering the undercoating, wherein the core portion and/or the undercoating comprise aluminum glycinate and a buffer;
  • the enteric pharmaceutical composition as set forth in item 8 wherein the buffer is sodium tartarate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate or tripotassium phosphate;
  • an enteric pharmaceutical composition improved in stability and unchanged in dissolution property with the lapse of time, which composition comprises a core portion including a 2-[(2- pyridyl )methylsulfinyl ] benzimidazole compound that has antiulcer activity and is unstable to an acid, an undercoating of one or two layers covering the core portion, and an enteric coating further covering the undercoating, wherein the core portion and/or the undercoating comprise a mixture of amino acid, an acid salt of an amino acid or an alkali salt of an amino acid and a buffer;
  • the enteric pharmaceutical composition as set forth in item 11, wherein the amino acid, acid salt of an amino acid or alkali salt of an amino acid is glycine, glycine hydrochloride, L-alanine, DL-alanine, L-threonin, DL-threonin, L-isoleucine, L-valine, L-phenylalanine, L-glutamic acid, L-glutamic acid hydrochloride, sodium L-glutamate, L-asparagic acid, sodium L- asparagate, L-lysine or L-lysine-L-glutamate; and the buffer is an alkaline metal salt of phosphoric acid, sodium tartarate, sodium acetate, sodium bicarbonate, sodium polyphosphate, sodium pyrophosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate or calcium carbonate;
  • the amount of the aluminum hydroxide • sodium bicarbonate coprecipiate to be incorporated for the core portion is preferably in the range of 0.01 to 1 part by weight based on 1 part by weight of the benzimidazole compound, but is not limited to this range.
  • the above-mentioned stabilizer may contain further additives used generally in the preparation of pharmaceutical preparations, such as a vehicle, e.g. lactose, mannitol, corn starch, microcrystall ine cellulose, a binder, e.g. hydroxypropylcellulose, a disintegrating agent, e.g. low substituted hydroxypropylcellulose, sodium carboxymethylstarch
  • the core portion can be obtained by admixing homogeneously a benzimidazole compound, aluminum hydroxide - sodium bicarbonate coprecipitate as a stabilizer and, whenever necessary, additives as mentioned above.
  • a benzimidazole compound aluminum hydroxide - sodium bicarbonate coprecipitate
  • additives as mentioned above.
  • admixing for example, to a mixture of the benzimidazole compound and the stabilizer may be added the additives, or to a mixture of the benzimidazole compound and the additives may be added the stabilizer.
  • the mixture thus obtained is made into powders according to wet granulating method, and then tableted to give core tablets.
  • the mixture is wet kneaded, subsequently granulated with an extrusion-granulator, and then made into core granules with the aid of Marumerizer (ex Fuji Powdal Co. ).
  • Marumerizer ex Fuji Powdal Co.
  • the amount of the aluminum hydroxide • sodium bicarbonate coprecipitate to be incorporated for the core portion is preferably in the range of 0.01 to 0.5 part by weight based on 1 part by weight of the benzimidazole compound, but is not limited to this range.
  • the above-mentioned stabilizer may contain further additives used generally in the preparation of pharmaceutical preparatioons, such as a vehicle, e.g. lactose, mannitol, corn starch, microcrystall ine cellulose, a binder, e.g. hydroxypropylcellulose, a disintegrating agent, e.g.
  • sodium carboxymethylstarch (tradename of Exprotab by Kimura Sangyo), calcium carboxymethylcellulose, a surfactant, e.g. sodium laurylsulfate, Tween 80 (tradename), a lubricant, e.g. magnesium stearate, talc, etc.
  • a preferred disintegrating agent is sodium carboxymethylstarch.
  • the aluminum hydroxide- sodium bicarbonate coprecipitate can be used in admixture with an water-soluble buffer agent thereby to enhance its stability.
  • the buffer means a substance added to the coprecipitate to control its pH to 8-9 (weak alkali) and includes, for example, sodium tartarate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, dipotassium hydrogenphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, trisodium phosphate or tripotassium phosphate.
  • the amount of the buffer agent to be added is preferably in the range of 0.01 to 2 parts by weight per 1 part by weight of the benzimidazole compound, but is not limited to this range.
  • the buffer to be used in the preparations includes, for example, sodium tartarate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium polyphosphate, dipotassium hydrogenphosphate, sodium pyrophosphate, disodium hydrogenphosphate, trisodium phosphate or tripotassi ium phosphate, among which disodium hydrogenphosphate is preferred.
  • the amounts of aluminum glycinate and the buffer are preferably in the range of 0.01 ⁇ 2 parts by weight and 0.01 ⁇ 2 parts by weight, respectively, based on 1 part by weight of the benzimidazole compound.
  • the stabilizer in this invention may be used together with pharmaceutically acceptable additives, for example, an excipient such as lactose, mannitol, cornstarch, crystalline cellulose, etc. ; a binder such as hydroxypropylcellulose, etc. ; a disintegrator, e.g. low substituted hydroxypropylcellulose, sodium carboxymethylstarch (tradename: Explotab by Kimura Sangyo Co.), calcium carboxy ethylcellulose, a -starch, etc. ; a surfactant, e.g. sodium laurylsulfate, Tween 80 (tradename), etc. ; a lubricant such as magnesium stearate, talc, etc.
  • an excipient such as lactose, mannitol, cornstarch, crystalline cellulose, etc.
  • a binder such as hydroxypropylcellulose, etc.
  • a disintegrator e.g. low substituted hydroxypropylcellulose, sodium carb
  • the amino acid, acid salt of an amino acid, or alkali salt of an amino acid in this invention include, for example, glycine, glycine hydrochloride, L-alanine, DL-alanine, L- threonine, DL-threonine, L-isoleucine, L-valine, L- phenylalanine, L-glutamic acid, L-glutamic acid hydrochloride, sodium L-glutamate, L-asparagic acid, sodium L-asparagate, L- lysine or L-lysine-L-glutamate alone or in admixture thereof.
  • glycine, glycine hydrochloride, L-alanine, DL-alanine or sodium L-glutamate are preferred.
  • the buffer here means a substance added to the amino acid, etc. to control its pH to 8—9 (weak alkali) and includes, for example, an alkaline metal salt of phosphoric acid (disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium dihydrogenphosphate, potassium dihydrogenophosphate, etc. ), sodium tartarate, sodium acetate, sodium carbonate, sodium bicarbonate, sodium polyphosphate, sodium pyrophosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate or calcium carbonate. Most preferred is disodium hydrogenphosphate.
  • the amounts of the amino acid or the like and the buffer to be incorporated are preferably in the range of 0.01 —2 parts by weight and 0.01—2 parts by weight, respectively, based on 1 part by weight of the benzimidazole compound, but are not limited thereto.
  • the stabilizer in this invention may be used together with pharmaceutically acceptable additives, for example, an excipient such as mannitol, cornstarch, crystalline cellulose, etc. ; a binder such as hydroxypropylcellulose, etc. ; a disintegrator, e.g. low substituted hydroxypropylcellulose, sodium carboxymethylstarch (tradename: Exprotab by Kimura Sangyo Co. ), calcium carboxymethylcellulose, etc. ; a surfactant, e.g. sodium laurylsulfate, Tween 80 (tradename), etc. ; a lubricant such as magnesium stearate, talc, etc.
  • an excipient such as mannitol, cornstarch, crystalline cellulose, etc.
  • a binder such as hydroxypropylcellulose, etc.
  • a disintegrator e.g. low substituted hydroxypropylcellulose, sodium carboxymethylstarch (tradename: Exprotab by Kimura Sangyo Co
  • the undercoating agent includes polymers, preferably, pharmaceutically acceptable water-soluble polymers selected from hydroxypropylmethylcellulose, hydroxypropylcel lulose,polyvinylp yrrolidone, gelatine, etc., or saccharides such as purified sucrose, mannitol, lactose, etc. Further, additives such as talc, titanium oxide, light silicic acid anhydride may be added.
  • the undercoating is preferably composed of two layers.
  • the one undercoating layer on the core portion side comprises aluminum hydroxide - sodium bicarbonate coprecipitate, a polymer or saccharide and additives such as talc, whereas the other undercoating layer on the enteric coating side comprises a polymer or saccharide and, whenever necessary, addiitives such as talc.
  • the amount of the stabilizer to be incorporated in the undercoating is preferably in the range of 0.01 to 10 parts by weight based on 100 parts by weight of the core portion, but is not limited to the range.
  • the intermediate product thus obtained can be covered with an enteric coating to give an enteric pharmaceutical preparation.
  • an enteric coating there may be mentioned cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, methacrylic acid/acrylic acid copolymer (tradename : Eudragit), etc., and a plasticizer and a pigment may also be incorporated.
  • the 3-coat pharmaceutical preparation comprising the core portion, undercoating and enteric coating
  • a stabilizer namely aluminum hydroxide- sodium bicarbonate coprecipitate, etc.
  • the intended preparation cannot be obtained.
  • the pharmaceutical preparations according to Japanese Patent First Publication 258320/1987 if magnesium hydroxide added to the core portion is incorporated also in the undercoating, the enteric coating will be affected adversely thereby. In order to avoid it, in a best preparation of them, a synthetic hydrotalcite is therefore used for the undercoating.
  • a stabilizer such as aluminum hydroxide - sodium bicarbonate coprecipitate added to the core portion is also incorporated in the undercoating.
  • the film formability of the undercoating agent e.g. hydroxypropylmethylcellulose
  • a stabilizer such as aluminum hydroxide - sodium bicarbonate coprecipitate and talc in the undercoating, slip of the undercoating during its manufacture is improved and impact during the manufacture is minimized, whereby the occurrence of deficiency of the film is impeded and no rejects of browned tablets are produced accordingly.
  • dosage forms suitable for oral administration namely enteric tablets, granules and capsules encapsulating therein granules.
  • the pharmaceutical preparations in the dosage forms thus obtained have the following characteristics:
  • the pharmaceutical preparations of this invention have good gastric antisecretory activity and antiulcer activity, so that they can be used for the treatment of ulcers of digestive organs, etc. in mammals inclusive of the human.
  • Fig. 1 is a graphical representation showing the profile of dissolution of omeprazole tablets obtained in Reference Example 1-1;
  • Fig. 2 is a graphical representation showing the profile of dissolution of omeprazole tablets of this invention obtained in Example 1-2;
  • Fig. 3 is another graphical representation showing the profile of dissolution of omeprazole tablets obtained in Reference Example 1-1;
  • Fig. 4 is another graphical representation showing the profile of dissolution of omeprazole tablets of this invention obtained in Example 1-2;
  • Fig. 5 is a graphical representation showing appearance change of Samples 4, 5, 6 and 7 in Experimental Example 1-4, when preserved, in terms of ⁇ E value.
  • Fig. 6 is a graphical representation showing the profile of dissolution of omeprazole tablets of this invention obtained in Example 2-2;
  • Fig. 7 is another graphical representation showing the profile of dissolution of omeprazole tablets of this invention obtained in Example 2-2;
  • Tablets (135 mg) containing 20 mg of omeprazole and magnesium hydroxide were formed by means of a rotary tableting machine.
  • the core tablets thus obtained were applied with an undercoating of hydroxypropylmethyl cellulose containing 0.3 mg of synthetic talcite to form a first undercoating layer and further applied with an undercoating solution of hydroxypropylmethyl cellulose to form a second undercoating layer.
  • an enteric coating solution containing hydroxypropylmethyl cellulose phthalate was applied onto the second undercoating layer to give enteric tablets.
  • composition given below was placed into a kneader to mix it for about 20 minutes and kneaded with an adequate amount of purified water.
  • the mixture was extruded, granulated with a granulating machine (screen diameter of 1.0 mm) and made into spherical granules with Marumerizer (ex Fuji Powdal).
  • the granules were dried in a fluidized bed drier at an air supply temperature of 50 °c for 30 minutes and passed through a sieve to give core granules of 14 to 24 meshes.
  • the core granules were applied with coatings given below to give enteric granules.
  • the first and second undercoatings were applied in a fluidized spray drier (manufactured by
  • Omeprazole, aluminum hydroxide • sodium bicarbonate coprecipitate, lactose, sodium carboxymethylstarch, sodium laurylsulfate and hydroxypropylmethyl cellulose in respective amounts given below were mixed homogeneously, kneaded with an adequate amount of purified water and dried in a fluidized bed drier at an air supply temperature of 50°C for 30 minutes. After granulating, the granules were passed through a screen of 24 meshes and mixed with magnesium stearate. The mixture was tableted with a rotary tableting machine to give tablets (core tablets) each of 135 mg.
  • enteric tablets To the core tablets are applied coatings as given below to give enteric tablets.
  • the first and second undercoatings were applied with Highcoater (by Freund Sangyo) at an air supply temperature of 70°C and an exhaust temperature of 40°C at a pan revolution number of 15 rp .
  • the enteric coating was applied at an air supply temperature of 55°C and an exhaust temperature of 37°c .
  • Enteric tablets of omeprazole comprising the following compositions are produced according to the method of Example 1-
  • Enteric tablets of omeprazole comprising the compositions given below are produced according to the method of Example 1-
  • Example 1-5 Enteric preparation having the compositions given below is produced according to the method of Example 1-2.
  • Core tablets having the compositions given below is produced according to the method of Example 1-2.
  • Enteric preparation of omeprazole having the compositions given below is produced according to the method of Example 2.
  • Enteric preparation of omeprazole having the compositions given below is produced according to the method of Example 1-2.
  • Enteric preparation of omeprazole having the compositions below is produced according to the method of Example 1-2. (Sample 1) Core tablets
  • Enteric preparation of omeprazole having the compositions given below is produced according to the method of Example 1-2.
  • Enteric tablets of lansoprazole of the following composition are produced according to the method of Reference
  • Enteric tablets of 2-[ (3, 5-dimethyl-4-methoxy-2-pyridyl )- methylsulfinyl ]-lH-benzimidazol (designated as Compound 1) comprising the following compositions are produced according to the method of Reference Example 1-1.
  • Core tablets of 2-[ (3, 5-dimethyl-4-methoxy-2-pyridyl )- methylsulfinyl ]-lH-benzimidazol designated as Compound 1
  • Enteric tablets are produced similarly by using 2-[(4-(3- methoxypropoxy)-3-methy1-2-pyridyl]methylsulfinyl ]-lH- benzimidazole (designated as Compound 2) instead of Compound 1.
  • Enteric tablets of lansoprazole having the compositions below are produced according to the method of Example 1-2.
  • Enteric preparation of lansoprazole having the compositions given below is produced according to the method of Example 1-2.
  • Enteric preparation of lansoprazole having the compositions given below is produced according to the method of Example 1-2.
  • Enteric tablets of 2-[ (3, 5-dimethyl-4-methoxy-2-pyridyl )- methylsulfinyl ]-lH-benzimidazole (Compound 1) are produced according to the method of Example 2.
  • Core tablets of 2-[ (3, 5-dimethyl-4-methoxy-2-pyridyl )- methylsulfinyl ]-lH-benzimidazole (Compound 1) are produced according to the method of Example 2.
  • Undercoating 1 Onto the core tablets, Undercoating 1, Undercoating 2 and Enteric coating having the compositions given below were applied according to Example 1-2. Undercoating 1
  • core tablets were similarly produced by wet granulating method except that magnesium hydroxide, magnesium oxide or calcium hydroxide was used instead of aluminum hydroxide-sodium bicarbonate coprecipitate, and then similarly applied with film coatings to give enteric tablets.
  • the enteric tablets thus obtained were preserved for 1 week at 50°C, 75% RH or for 2 weeks at 40°C, 75% RH and thereafter, determined of disintegration time according to the test of the Pharmacopoeia of Japan with the 2nd fluid without using the auxiliary disk. The results obtained are shown in Table 1-5.
  • the enteric tablets of this invention using aluminum hydroxide-sodium bicarbonate coprecipitate exhibited good disintegration property immediately after preparation (at initial stage) and during preservation in a high temperature, humidified condition. In contrast, those of magnesium hydroxide were deteriorated significantly under humidification at high temperature.
  • the enteric tablets using magnesium oxide and calcium hydroxide, respectively, were poor in disintegration property from the initial stage thereof as prepared.
  • composition given below was placed in a kneader and mixed for about 20 minutes, and kneaded together by adding an appropriate amount of purified water. After granulation with an extrusion-granulator (screen diameter: 1.0 mm), the granules were made into spherical granules with Marumerizer (manufactured by Fuji Powdal). The granules were dried in a fluidized drier at 50 °C for 30 min. and passed through a sieve of 14 to 24 meshes to give core granules.
  • Trisodium phosphate Na 3 P0 4 -12H 2 0
  • Undercoating 1 and Undercoating 2 were applied in a fluidized spray drier (manufactured by Ohkawara) at an air supply temperature of 75°c and an exhaust temperature of 45°C ; and the enteric coating was applied at an air supply temperature of 65°c and an exhaust temperature of 40°c .
  • Core granules were applied in a fluidized spray drier (manufactured by Ohkawara) at an air supply temperature of 75°c and an exhaust temperature of 45°C ; and the enteric coating was applied at an air supply temperature of 65°c and an exhaust temperature of 40°c .
  • Core granules were produced in a similar procedure to Example 2-1 except that mannitol was used instead of aluminum hydroxide-sodium bicarbonate coprecipitate and trisodium phosphate. Then, coatings similar to Example 2-1 except that talc was additionally incorporated instead of the aluminum hydroxide-sodium bicarbonate coprecipitate in Undercoating 1 were applied to yield enteric granules of omeprazole.
  • Example 2-1 The enteric granules of omeprazole obtained in Example 2-1 and Reference Example 2-1 were placed in a glass bottle and preserved sealingly at 60°c or under open condition of 75% RH at 40°C for 2 weeks. The change in appearance is shown in
  • Example 2-2 the enteric granules, which contain aluminum hydroxide-sodium bicarbonate coprecipitate and the buffer agent in the core granules aluminum hydroxide-sodium bicarbonate coprecipitate in the undercoating layer, showed no change in appearance even under severe conditions.
  • Example 2-2 the enteric granules, which contain aluminum hydroxide-sodium bicarbonate coprecipitate and the buffer agent in the core granules aluminum hydroxide-sodium bicarbonate coprecipitate in the undercoating layer, showed no change in appearance even under severe conditions.
  • Example 2-2 the enteric granules, which contain aluminum hydroxide-sodium bicarbonate coprecipitate and the buffer agent in the core granules aluminum hydroxide-sodium bicarbonate coprecipitate in the undercoating layer, showed no change in appearance even under severe conditions.
  • composition aluminum hydroxide-sodium bicarbonate coprecipitate, lactose, sodium carboxymethylstarch, sodium laurylsulfate and hydroxypropylcellulose were mixed homogeneously, and an appropriate amount of purified water dissolving therein sodium pyrophosphate was added.
  • the mixture was kneaded and dried in a fluidized bed drier at 50°C for 30 minutes.
  • the dried powders were passed through a sieve of 24 meshes, and magnesium stearate was further added thereto and mixed. Then, the mixture was made into tablets (core tablets) each of 135 mg with a rotary tableting machine.
  • the coatings given below were applied to the core tablets thus obtained to give enteric tablets.
  • Undercoatings 1, 2 were applied with Highcoater (Freund Sangyo) at an air supply temperature of 70 ⁇ c and an exhaust temperature of 40°C, at a pan revolution number of 13 rpm.
  • the enteric coating was applied at an air supply temperature of 55°C and an exhaust temperature of 37°c.
  • Enteric tablets of omeprazole of the composition given below are produced according to the method of Example 2-2.
  • a quantity of 100 mg of omeprazole, aluminum glycinate and disodium hydrogenphosphate as a buffer were dispersed in 20 ml of water and preserved at 25°c .
  • the resulting white suspension was observed of the appearance change with the lapse of day.
  • Control solutions containing no aluminum glycinate and no buffer, respectively were also prepared and observed of the change in appearance at 25°c with the lapse of day.
  • composition mentioned below was charged into a kneader for mixing for about 20 minutes, kneaded by adding an appropriate amount of purified water, granulated on an extrusion granulator (screen diameter of 1.0 mm), and made into spherical granules with the aid of Marumerizer (Fuji Powdal Co. ).
  • the granules thus obtained were dried in a fluidized bed drier at an air feed temperature of 50 °C for 30 minutes and filtered through a sieve to give granules of 14—24 meshes.
  • composition given below was made into granules according to Example 3-1.
  • disodium hydrogenphosphate was incorporated by dissolving it in purified water.
  • Example 3-2 The granules obtained in Example 3-2 were applied with the coatings given below to give enteric granules.
  • Undercoatings 1 and 2 were applied in a fluidized spray drier (Okawara Co. ) at an air feed temperature of 75°C and an exhaust temperature of 55°C whereas Enteric coating was applied in the same drier at an air feed temperature of 65°C and an exhaust temperature of 50°C.
  • omeprazole, aluminum glycinate, mannitol, a -starch, sodium laurylsulfate and hydroxypropylcellulose were homogeneously mixed, and to the mixture, an appropriate amount of purified water dissolving therein sodium pyrophosphate was added to carry out kneading, followed by drying in a fluidized drier at 50°c for 30 minutes.
  • the dried granules thus obtained were passed through a sieve of 24 mesh and added and mingled with magnesium stearate. Then the granules were made into tablets (core) of 135 mg per one tablet by means of a rotary tableting machine.
  • Example 3-4 The tablets (core) obtained in Example 3-4 were applied with coatings of the compositions given below to give enteric tablets. Undercoatings 1 and 2 were applied with High-coater
  • Core granules of the composition given below were produced according to Example 3-1.
  • the sodium pyrophosphate used was incorporated by dissolving it in purified water.
  • aluminum glycinate and Na 2 HP0 4 -12H 2 0 were incorporated in Undercoating 1.
  • Coating was conducted by the use of a fluidized bed drier (Okawara Co. ). Undercoatings 1 and 2 were applied at an air feed temperature of 75°C. an exhaust temperature of 55°C and Enteric coating was likewise applied at an air feed temperature of 55°c and an exhaust temperature of 40°C.
  • Core granules were produced according to Example 3-1.
  • the sodium pyrophosphate used was incorporated by dissolving it in purified water.
  • aluminum glycinate and Na 2 HP0 4 -12H 2 0 were incorporated in Undercoating 1.
  • Coating was conducted by the use of a fluidized bed drier (Okawara Co. ). Undercoatings 1 and 2 were applied at an
  • Tablets were produced from the composition given below according to Example 3-4.
  • Example 3-5 The tablets (core tablets) thus obtained were applied with the film coatings in Example 3-5 to yield enteric tablets.
  • Example 3-4 The core tablets obtained in Example 3-4, the enteric tablets in Example 3-5, the core tablets and enteric tablets in Reference Example 3-1 and the core tablets and enteric tablets in Reference Example 3-2 were respectively placed in a glass bottle, and allowed to stand for 2 weeks with the bottles sealingly stoppered under 60°C condition and opened under 40 °C , 75% RH conditions, respectively.
  • the results obtained of the change in appearance are shown in Table 3-2.
  • Tablets were produced in the formulation given below according to Example 3-4 (Sample A).
  • Tablets (core tablets) containing no stabilizer were produced in the formulation given below according to Example 3-4
  • Sample A and Control A were preserved under 40°c , 75% RH conditions for 4 weeks and then measured of change in appearance with a colorimeter to determine ⁇ E values. The results obtained are shown below.
  • a quantity of 100 mg of omeprazole, 100 mg of various amino acid and 100 mg of disodium hydrogenphosphate as a buffer were dispersed in 20 ml of water and preserved at 25°C • The resulting white suspension was observed of the appearance change with the lapse of day.
  • omeprazole crystalline cellulose, low substituted hydroxypropylcellulose, hydroxypropylcellulose and mannitol were charged into a kneader and mixed for ca. 20 minutes. An appropriate amount of purified water dissolving therein glycine and disodium hydrogenphosphate was further added and kneaded. The resulting mixture was dried in a fluidized drier at 50°C for 30 minutes. Thereafter, granules of 14—24 meshes were obtained by the use of a sieve.
  • Omeprazole 5.0 mg
  • composition of the formulation given below was made into granules according to Example 4-1.
  • the sodium L-glutamate and sodium pyrophosphate dissolved in purified water were incorporated.
  • Example 4-1 granules were produced according to Example 4-1.
  • the L-alanine and dipottasiu hydrogenphosphate were incorporated by dissolving them in purified water.
  • Example 4-3 The granules obtained in Example 4-3 were applied with coatings of the compositions given below to give enteric granules. Undercoatings 1, 2 were applied in a fluidized bed drier (Okawara Co. ) at an air feed temperature of 75°C and an exhaust temperature of 55°c and Enteric coating was applied similarly at an air feed temperature of 65°C and an exhaust temperature of 50°C •
  • Undercoatings 1, 2 were applied in a fluidized bed drier (Okawara Co. ) at an air feed temperature of 75°C and an exhaust temperature of 55°c and Enteric coating was applied similarly at an air feed temperature of 65°C and an exhaust temperature of 50°C •
  • omeprazole, mannitol, sodium carboxymethylstarch, sodium laurylsulfate and hydroxypropylcellulose were mixed uniformly.
  • An appropriate amount of purified water dissolving therein L-isoleucine and sodium pyrophosphate was added to the mixture and kneaded together, and then dried in a fluidized drier at 50°C for 30 minutes.
  • the dried particles were passed through a sieve of 24 mesh and mixed with magnesium stearate, and then produced into tablets (core tablets) of 135 mg per one tablet by means of a rotary tableting machine.
  • Example 4-5 The tablets (core tablets) obtained in Example 4-5 were applied with coatings of the compositions given below to yield enteric tablets. Undercoatings 1, 2 were applied by means of High-coater (Freund Sangyo Co. ) at an air feed temperature of 70°C and an exhaust temperature of 40°C , at a pan revolution number of 13 rpm. Enteric coating was likewise applied at an air feed temperature of 55°c and an exhaust temperature of 37 °C Tablets in Example 4-5 135.0 mg Undercoating 1
  • Core granules were produced according to Example 4-1 from the composition given below.
  • the glycine and sodium pyrophosphate as a stabilizer was incorporated by dissolving them in purified water.
  • aluminum hydroxide »sodium bicarbonate coprecipitate and disodium hydrogenphosphate were incorporated.
  • Coating was conducted by the use of a fluidized bed drier (Okawara Co.). Undercoatings 1 and 2 were applied at an air feed temperature of 75°C and an exhaust temperature of 55°C while Enteric coating was applied at an air feed temperature of 55°C and an exhaust temperature of 40°C .
  • Core granules were produced according to Example 4-1 from the composition given below.
  • the glycine and sodium pyrophosphate as a stabilizer was incorporated by dissolving them in purified water.
  • aluminum hydroxide »sodium bicarbonate coprecipitate and disodium hydrogenphosphate were incorporated.
  • Coating was conducted by the use of a fluidized bed d
  • Tablets were produced in the formulation given below according to Example 4-5 (Sample B).
  • the pharmaceutical preparations of this invention exhibit a superior inhibitory activity to secretion of gastric acid and superior antiulcer activity and can be used for the treatment of digestive ulcers, etc. of human or other mammals.

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Abstract

Une composition pharmaceutique entérique contient un agent antiulcéreux et présente une stabilité améliorée et une propriété de dissolution inchangée dans le temps. Elle comprend un c÷ur qui inclut un composé de 2-[(2-pyridyl)méthylesulfinyle] benzimidazole doté d'une activité antiulcéreuse et se révélant instable aux acides, une sous-couche simple ou double recouvrant ce c÷ur et un revêtement entérique recouvrant à son tour cette sous-couche. Le c÷ur et/ou la sous-couche comprennent un stabilisateur choisi entre un coprécipité hydroxyle d'aluminium-bicarbonate de sodium seul, et un mélange de ce coprécipité avec un tampon tel qu'hydrogénophosphate de disodium.
PCT/JP1993/000920 1992-07-17 1993-07-02 Composition pharmaceutique contenant un agent antiulcereux Ceased WO1994002140A1 (fr)

Priority Applications (1)

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AU45133/93A AU4513393A (en) 1992-07-17 1993-07-02 Pharmaceutical composition containing antiulcer agent

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JP21343692 1992-07-17
JP4/213436 1992-07-17
JP5/143028 1993-05-20
JP14302893 1993-05-20

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000114A3 (fr) * 1996-06-28 1998-02-26 Klinge Co Chem Pharm Fab Forme stable de medicament pour administration par voie orale, a base de derives de benzimidazole comme principe actif, et son procede de productionn
WO1998040069A3 (fr) * 1997-03-13 1998-12-17 Hexal Ag Stabilisation de benzimidazoles sensibles aux acides avec des combinaisons amino-cyclodextrine
US6077541A (en) * 1997-11-14 2000-06-20 Andrx Pharmaceuticals, Inc. Omeprazole formulation
WO2001024777A1 (fr) * 1999-10-04 2001-04-12 American Home Products Corporation Nouvelles compositions pharmaceutiques
EP0993830A3 (fr) * 1995-02-01 2001-10-04 Laboratorios Del Dr. Esteve, S.A. Nouvelles compositions galéniques stabilisées comprenant un benzimidazole sensible à l'acide et son procédé de préparation
US6391342B1 (en) 1998-03-20 2002-05-21 A/S Gea Farmaceutisk Fabrik Pharmaceutical formulation comprising a 2- [(2-pyridinyl) methyl] sulfinyl benzimidazole having anti-ulcer activity and a process for the preparation of such formulation
US6576258B1 (en) 1997-07-14 2003-06-10 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Pharmaceutical formulation with controlled release of active substances
US6623759B2 (en) 1996-06-28 2003-09-23 Astrazeneca Ab Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof
US6699885B2 (en) * 1996-01-04 2004-03-02 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and methods of using same
SG103334A1 (en) * 2002-01-24 2004-04-29 Il Yang Pharm Co Ltd Tablet for oral administration comprising 2-[(4-methoxy-2-methyl)-2-pyridinyl]methylsulfinyl-5-(1h-pyrrol-1-yl)-1h-benzimidazole
US6780882B2 (en) * 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
WO2005046634A3 (fr) * 2003-11-14 2005-10-13 Siegfried Generics Int Ag Forme galenique resistant au suc gastrique
WO2005051348A3 (fr) * 2003-11-25 2006-04-27 Egyt Gyogyszervegyeszeti Gyar Comprimes de pantoprazole a enrobage enterique
EP1681052A1 (fr) * 2005-01-18 2006-07-19 Dr. Reddy's Laboratories Ltd. Formes galéniques solides pour réduire l'effet alimentaire sur la biodisponibilité
WO2005092297A3 (fr) * 2004-03-03 2006-10-12 Teva Pharma Composition pharmaceutique stable comprenant un medicament labile en milieu acide
US7402321B2 (en) 1998-08-12 2008-07-22 Nycomed Gmbh Oral administration form for pyridin-2-ylmethylsulfinyl-1H-benzimidazoles
US7544370B2 (en) 2003-10-01 2009-06-09 Wyeth Pantoprazole multiparticulate formulations
EP1252887A4 (fr) * 2000-01-27 2009-07-29 Mitsubishi Tanabe Pharma Corp Preparation a liberation prolongee et son procede de fabrication
WO2009113090A3 (fr) * 2008-01-17 2009-11-05 Alkem Laboratories Ltd. Procédé de préparation d’une formule orale d’un médicament à base de benzimidazole sensible à l’acide
EP1513505A4 (fr) * 2002-04-12 2011-02-16 Mayne Pharma Int Pty Ltd Preparation a liberation modifiee amelioree
EP1300160B1 (fr) * 2000-05-24 2014-03-12 Otsuka Pharmaceutical Co., Ltd. Procede servant a stabiliser une preparation
US8765176B2 (en) * 2001-06-20 2014-07-01 Takeda Pharmaceutical Campany Limited Method of manufacturing tablet
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
CN113384547A (zh) * 2021-06-25 2021-09-14 上海信谊万象药业股份有限公司 一种奥美拉唑铝碳酸镁复合片及其制备工艺

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EP0248634A2 (fr) * 1986-06-02 1987-12-09 Nippon Chemiphar Co., Ltd. Dérivé stabilisé de benzimidazole et composition
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EP0237200A2 (fr) * 1986-02-13 1987-09-16 Takeda Chemical Industries, Ltd. Utilisation de sels basiques mineraux de magnesium ou calcium pour la stabilisation de derives du benzimidazole
EP0247983B1 (fr) * 1986-04-30 1993-01-07 Aktiebolaget Hässle Préparation pharmaceutique pour utilisation orale
EP0248634A2 (fr) * 1986-06-02 1987-12-09 Nippon Chemiphar Co., Ltd. Dérivé stabilisé de benzimidazole et composition
ES2024993A6 (es) * 1990-12-31 1992-03-01 Genesis Para La Investigacion Procedimiento de obtencion de un preparado farmaceutico oral conteniendo omeprazol.

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0993830A3 (fr) * 1995-02-01 2001-10-04 Laboratorios Del Dr. Esteve, S.A. Nouvelles compositions galéniques stabilisées comprenant un benzimidazole sensible à l'acide et son procédé de préparation
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6780882B2 (en) * 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6699885B2 (en) * 1996-01-04 2004-03-02 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and methods of using same
US6623759B2 (en) 1996-06-28 2003-09-23 Astrazeneca Ab Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof
US7276253B2 (en) 1996-06-28 2007-10-02 Astrazeneca Ab Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof
WO1998000114A3 (fr) * 1996-06-28 1998-02-26 Klinge Co Chem Pharm Fab Forme stable de medicament pour administration par voie orale, a base de derives de benzimidazole comme principe actif, et son procede de productionn
US6248758B1 (en) * 1997-03-13 2001-06-19 Hexal Ag Pharmaceutical antacid
WO1998040069A3 (fr) * 1997-03-13 1998-12-17 Hexal Ag Stabilisation de benzimidazoles sensibles aux acides avec des combinaisons amino-cyclodextrine
US6576258B1 (en) 1997-07-14 2003-06-10 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Pharmaceutical formulation with controlled release of active substances
US6780435B2 (en) 1997-11-14 2004-08-24 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6096340A (en) * 1997-11-14 2000-08-01 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6077541A (en) * 1997-11-14 2000-06-20 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6391342B1 (en) 1998-03-20 2002-05-21 A/S Gea Farmaceutisk Fabrik Pharmaceutical formulation comprising a 2- [(2-pyridinyl) methyl] sulfinyl benzimidazole having anti-ulcer activity and a process for the preparation of such formulation
US8465767B2 (en) 1998-08-12 2013-06-18 Takeda Gmbh Oral administration form for pyridin-2-ylmethylsulfinyl-1H benzimidazoles
US7402321B2 (en) 1998-08-12 2008-07-22 Nycomed Gmbh Oral administration form for pyridin-2-ylmethylsulfinyl-1H-benzimidazoles
WO2001024777A1 (fr) * 1999-10-04 2001-04-12 American Home Products Corporation Nouvelles compositions pharmaceutiques
EP1252887A4 (fr) * 2000-01-27 2009-07-29 Mitsubishi Tanabe Pharma Corp Preparation a liberation prolongee et son procede de fabrication
EP1300160B1 (fr) * 2000-05-24 2014-03-12 Otsuka Pharmaceutical Co., Ltd. Procede servant a stabiliser une preparation
US8765176B2 (en) * 2001-06-20 2014-07-01 Takeda Pharmaceutical Campany Limited Method of manufacturing tablet
SG103334A1 (en) * 2002-01-24 2004-04-29 Il Yang Pharm Co Ltd Tablet for oral administration comprising 2-[(4-methoxy-2-methyl)-2-pyridinyl]methylsulfinyl-5-(1h-pyrrol-1-yl)-1h-benzimidazole
EP1513505A4 (fr) * 2002-04-12 2011-02-16 Mayne Pharma Int Pty Ltd Preparation a liberation modifiee amelioree
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US7550153B2 (en) 2003-10-01 2009-06-23 Wyeth Pantoprazole multiparticulate formulations
US7553498B2 (en) 2003-10-01 2009-06-30 Wyeth Pantoprazole multiparticulate formulations
US7838027B2 (en) 2003-10-01 2010-11-23 Wyeth Llc Pantoprazole multiparticulate formulations
US7544370B2 (en) 2003-10-01 2009-06-09 Wyeth Pantoprazole multiparticulate formulations
WO2005046634A3 (fr) * 2003-11-14 2005-10-13 Siegfried Generics Int Ag Forme galenique resistant au suc gastrique
WO2005051348A3 (fr) * 2003-11-25 2006-04-27 Egyt Gyogyszervegyeszeti Gyar Comprimes de pantoprazole a enrobage enterique
WO2005092297A3 (fr) * 2004-03-03 2006-10-12 Teva Pharma Composition pharmaceutique stable comprenant un medicament labile en milieu acide
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
EP1681052A1 (fr) * 2005-01-18 2006-07-19 Dr. Reddy's Laboratories Ltd. Formes galéniques solides pour réduire l'effet alimentaire sur la biodisponibilité
WO2009113090A3 (fr) * 2008-01-17 2009-11-05 Alkem Laboratories Ltd. Procédé de préparation d’une formule orale d’un médicament à base de benzimidazole sensible à l’acide
CN113384547A (zh) * 2021-06-25 2021-09-14 上海信谊万象药业股份有限公司 一种奥美拉唑铝碳酸镁复合片及其制备工艺
CN113384547B (zh) * 2021-06-25 2024-03-19 上海信谊万象药业股份有限公司 一种奥美拉唑铝碳酸镁复合片及其制备工艺

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