WO2005034924A1 - Pastilles a enrobage enterique comprenant de l'esomeprazole, capsule de gelatine dure renfermant celles-ci et procede de preparation associe - Google Patents

Pastilles a enrobage enterique comprenant de l'esomeprazole, capsule de gelatine dure renfermant celles-ci et procede de preparation associe Download PDF

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Publication number
WO2005034924A1
WO2005034924A1 PCT/IN2003/000335 IN0300335W WO2005034924A1 WO 2005034924 A1 WO2005034924 A1 WO 2005034924A1 IN 0300335 W IN0300335 W IN 0300335W WO 2005034924 A1 WO2005034924 A1 WO 2005034924A1
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Prior art keywords
composition
coating
pharmaceutical composition
derivatives
cellulose
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PCT/IN2003/000335
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English (en)
Inventor
Khadgapathi Podili
Nannapaneni Venkaiah Chowdary
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Natco Pharma Limited
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Priority to AU2003272086A priority Critical patent/AU2003272086A1/en
Priority to PCT/IN2003/000335 priority patent/WO2005034924A1/fr
Publication of WO2005034924A1 publication Critical patent/WO2005034924A1/fr

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    • 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
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, 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
    • A61K9/48—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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to an improved stable pharmaceutical composition .
  • the 5 pharmaceutical composition containing enantiomers , salts of the enantiomers of omeprazole such as esomeprazole.
  • the present invention particularly relates to an improved pharmaceutical composition in the form of hard gelatin capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole which is useful in the treatment of gastric and duodenal ulcers and a process for its preparation.
  • the pharmaceutical composition of the present invention guarantees the integrity of the composition until it reaches the proximal part of the small intestine, where the composition will be disaggregated to facilitate the absorption of the enantiomers , salts of the enantiomers of omeprazole such as esomeprazole contained therein.
  • This invention also involves a process of preparing the above mentioned pharmaceutical 15 composition ( hard capsules)
  • the present invention provides a stable pharmaceutical composition containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole, in the form of hard gelatin capsules useful for treating gastro intestinal ulcers.
  • the pharmaceutical 20 composition of the present invention is in the form of hard gelatin capsules suitable for oral administration.
  • the composition of the present invention would dissolve in the intestine to facilitate absorption in the neutral / alkali environment.
  • Benzimidazolic compounds such as omeprazole (5-methoxy-2(((4-methoxy-3, 5-di met hyl -2-pyridinyl)-methyl-sulf ⁇ nyl)lH-benzimidazole), lansoprazole (2-((3-methyl- 4-(2,2,2-trifluoro etoxy) -2-piridyl)methyl (sulfinyl lH-benzimidazole) (U.S. Pat No. 4,628,098), pantoprazole (U.S. Pat. No.
  • omeprazole solution The maximum stability of omeprazole solution is reached at pH 11 [Drug. Dev. Ind. Pharm., 21(8), 965 (1995)]. Degradation occurs very quickly below a pH of 7.0. On the other hand, it is necessary that the formulations dissolve quickly in the intestine, where the benzimidazolic compounds should be absorbed, i.e. when the pH becomes higher than 6.8.
  • U.S. Pat. No. 4,786,505 proposes the mixture of a mass of cellulose derivatives and disaggregants, with an appropriate amount of omeprazole and alkaline agents or alkaline salts of the drug, in order to obtain, by extrusion, a core which is spheronized and coated with gastroresistant agents dissolved in alcoholic solutions also containing considerable percentages of acetone.
  • the pellets obtained may be extremely irregular in shape and dimensions, and this can have repercussions on a relative dispersion of the average weight of the capsules and of the respective dosage.
  • the US Patent no 6,248,355 describes a composition of omeprazole without the use of alkaline- reacting compounds and in which the active ingredient is granulated together and compressed together along with inert ingredients followed by a coating of intermediate coat containing one or several inert water soluble layer or layers which rapidly disintegrate in aqueous medium and contains non-acid inert pharma excipients.
  • This layer comprises at least one polymer conventionally used in application where a film is provided by coating with such materials as sugars, polyethyleneglycol, polyvinylalcohol, hydroxy propyl methyl cellulose, an intermediate coat, and an enteric coating containing entero- soluble gastro resistants made of latex suspension of polymers such as cellulose acetate phthalate, mefhacrylic acid, methacrylic esters, methacrylic acid copolymers.
  • This process involves multi-step processing such as preparation of core, intermediate layer and enteric coatings and may involve a number of controlling points like dry mixing of the drug with inert excipients, granulation of the mass, lubrication, compression, followed by a coating of intermediate layer and finally coating by an enteric layer, thereby making the process a multi-step process with each step subjected to the active ingredient analysis thereby not only making the process cumbersome but also increasing the cost of the product.
  • US Patent no 5,714,504 provides methods for the preparation of pure crystalline enantiomeric salts of omeprazole which is having a dosage strength of equivalent 20 mg base and eqivalent 40 mg base in the form of oral delayed release tablets or granules.
  • the US patent no 5,877,192 describes a method for the treatment of gastric acid related diseases and production of medication using enantiomer of omeprazole by a method of inhibiting gastric acid secretion comprising the oral administration of a pharmaceutical compositions which is having a dosage strength of equivalent 20 mg base and equivalent 40 mg base in the form of oral delayed release tablets or granules.
  • the US Patent no 6,132,770 provide a tableted multiple unit effervescent dosage form comprising esomeprazole or an alkaline salt of esomeprazole, in which the active substance is in the form of enteric coating layered units compressed together with effervescent tablet excipients into such an effervescent tablet.
  • the US Patent no 6,132,771 describes a preparation comprise a gastric acid suppressing agent, such as a proton pump inhibitor selected from esomeprazole , in combination with one or more prokinetic agents such as mosapride, cisapride in a new fixed unit dosage form, especially a tablet.
  • the US Patent no 6,136,344 discloses a preparations which comprise an acid susceptible proton pump inhibitor, esomeprazole magnesium salt in combination with one or more antibacterial compounds in a new fixed unit dosage form, especially a tableted dosage form.
  • the US Patent no 6,183,776 provides oral, fixed unit dosage forms, i.e. multiple unit tableted dosage forms, layered formulations comprising an enteric coating layered tablet core, multilayered tablets or a sachet filled with pharmaceutically active compound selected from S-omeprazole magnesium salts.
  • the US Patent no 6,328,993 discloses an oral administration form such as tablet, an effervescent, tablet, powder in a sachet, a coated tablet or a capsule made of a proton pump inhibitor selected from the group consisting of pantoprazole, omeprazole, esomeprazole, lansoprazole and rabeprozole.
  • the US Patent no 6,365,184 provides oral adminstration such as fixed unit dosage forms, i.e. multiple unit tableted dosage forms, enteric coating layered tablets, multilayered tablets or capsules filled with pharmaceutically active compound such as esomeprazole magnesium salt, lansoprazole, pantoprazole.
  • the US Patent no 6,428,810 discloses a oral pharmaceutical formulation with a core comprising active pharmaceutical ingredients selected from omeprazole or enantiomers of omeprazole, a separating layer and an enteric layer.
  • the dosage forms are pellets filled in hard gelatin capsules or tablets.
  • the US Patent 6,489,346 provides a solid pharmaceutical composition in a dosage form that is not enteric-coated having active ingredients selected from omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole and leminoprazole or an enantiomer such as esomeprazole and at least one buffering agent for treating gastrointestinal disorder. Due to the absence of enteric coating, the stability of the drug may not be optimum.
  • the said invention has been developed based on our finding as a result of sustained R & D work, that the incorporation of benzimidazole derivatives, particularly useful for the treatment of duodenal ulcers, without the necessity of using an alkali agent or alkali salt of the substituted benzimidazole for the stability of the formulation.
  • Such a composition will have an advantage over the existing form of the formulation as the available dosage forms for benzimidazole derivatives are having the total amount of active ingredient in the form of solid particles engulfed in a solid matrix of excipients preferably hydrophilic substances, further coated with protective and gastric resistant enteric polymer coatings. It may take some time to dissolve these coats before the benzimidazole derivative is dissolved into the surronding intestinal fluid and gets absorbed.
  • composition containing benzimidazole derivatives, particularly omeprazole, more particularly esomeprazole and other enentiomers of omeprazole or its salts for the treatment of duodenal ulcers, there is a need for the development of pharmaceutical composition containing said derivatives having stability for an extended period during which period the composition does not get discoloured and / or degraded.
  • the main objective of the present invention is, therefore , to provide an improved stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole useful in the treatment of gastric and duodenal ulcers .
  • Another objective of the present invention is to provide an improved stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers , salts of the enantiomers of omeprazole such as esomeprazole containing useful in the treatment of gastric and duodenal ulcers without the necessity of using an alkali agent or alkali salt of the substituted benzimidazole for the stability of the formulation.
  • Yet another objective of the present invention is to provide an improved stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers , salts of the enantiomers of omeprazole such as esomeprazole useful in the treatment of gastric and duodenal ulcers by using most commonly available inert and non-acid / non-alkaline and safe pharmaceutical excipients to create an appropriate microenvironment for the active drug , since they are unstable in acidic / neutral environment and to release the active ingredient only in an alkaline environment .
  • Still another objective of the present invention is to provide an improved stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole useful in the treatment of gastric and duodenal ulcers which does not release the drug in the stomach ( acidic environment) but releases the drug (esomeprazole) in the intestine (alkaline environment ).
  • Still another objective of the present invention is to provide an improved and stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole capsules useful in the treatment of gastric and duodenal ulcers to facilitate to disaggregate quickly in the neutral to alkaline environment in the intestine with complete dissolution of the active drug in the intestine.
  • Yet another objective of the invention is to provide a process for the preparation of an improved and stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers , salts of the enantiomers of omeprazole such as esomeprazole useful in the treatment of gastric and duodenal ulcers as described above useful for oral adminstration in capsule form.
  • the present invention has been developed based on our finding that when some of the most commonly available pharmaceutically inert, non-alkaline / non-acid pharmaceutical excipients such as dioctyl sodiumsulphosuccinate, talc, titaniumdioxide, starch, sodium lauryl sulphate, micro crystalline cellulose powder, magnesium stearate and the like are mixed judiciously along with enantiomers , salts of the enantiomers of omeprazole such as esomeprazole and processed resulting in a composition which is stable during its passage through the stomach and remains in a microenvironment that is not acidic or lower than pH 7.0, at the same time when the composition exits from the stomach and reaches the proximal part of the intestine, the drug dissolves rapidly.
  • non-alkaline / non-acid pharmaceutical excipients such as dioctyl sodiumsulphosuccinate, talc, titaniumdioxide, starch, sodium lauryl
  • the present invention provides a composition composed of an inert core coated with a layer which contains the active ingredient(s) devoid of any alkali reacting compounds, coated in turn with an intermediate coat, also devoid of any alkali reacting compounds and a final external gastro resistant or enteric coating.
  • the composition of the present invention is also characterized in that it does not dissolve in an acid medium, but dissolves quickly at an alkaline pH and present good stability in terms of dosage and in gastroresistance and dissolution in the small intestine.
  • the present invention provides an improved stable pharmaceutical composition as a hard gelatin capsule dosage containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole constituted by a succession of layers arranged around an inert, spherical core prepared from sugar and starch.
  • composition of the present invention in the dosage hard gelatin capsule form which comprises 1) An inert core
  • the inert core are constituted by pharmaceutically acceptable inert excipients and which are coated with a layer containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole in microionised form , mixed with pharmaceutically acceptable inert excipients, so that this layer quickly disaggregates.
  • This drug layer is covered by intermediate coating comprising of a neutral film-forming agent and finally this layer is coated with an enteric coating.
  • the pellets have spherical symmetry and have a moisture level that guarantees good stability under normal storage conditions. The pellets are placed in hard gelatine capsules and it is in this form that they are administered to patients.
  • the present invention provides an improved stable pharmaceutical composition containing enantiomers , salts of the enantiomers of omeprazole such as esomeprazole enantiomers in microionised form useful for the treatment of gastric and duodenal ulcers in the form of hard gelatine capsules which comprises 1) An inert core comprising of sugar and starch.
  • the inert core having an active coating comprising enantiomers , salts of the enantiomers of omeprazole such as esomeprazole in micronised form with an inert pharmaceutically acceptable film forming agent and inert non-acidic / non- alkaline pharmaceutical excipients.
  • the resulting product having a coating of an intermediate coating comprising the same film forming agent as used for the coating of the inert core and the same inert non-acidic / non-alkaline pharmaceutical excipients and .
  • a process for the preparation of an improved and stable pharmaceutical composition comprising enantiomers , salts of the enantiomers of omeprazole such as esomeprazole in micronised form in the form of hard gelatin capsules useful for treating gastric and deuodonal ulcers which comprises a) Forming an inert core comprising of sugar and starch in the form of spherical or nearly spherical pellets.
  • b) Providing to the inert core an active coating comprising enantiomers , salts of the enantiomers of omeprazole such as esomeprazole in micronised form , an inert pharmaceutically acceptable film forming agent and inert non-acidic / non- alkaline pharmaceutical excipients. c) Providing the resulting spherical or nearly spherical pellets with an intermediate coating comprising of the same film forming agent as used in step (ii) above and the same inert non-acidic / non-alkaline pharmaceutical excipients.
  • the sugar used for the inert core may consist of sugars such as sucrose, mannitol, lactose and the like.
  • the core may be formed in a spherical or nearly spherical shape pellets.
  • the amount of sugars and starch may range from 150.0 mg to 800.0 mg and lOO.Omg to 600.0 mg per gram of composition preferably may range from 200.0 mg to 600.0 mg and 150.0 mg to 500.0 mg.
  • the active pharmaceutical agents employed may be selected from enantiomers , salts of the enantiomers of omeprazole such as esomeprazole in micronised form.
  • the amount of the active drug may range from 30 .0 mg to 200.0 mg preferably may range from 50.0 mg to 150.0 mg per gram of the composition.
  • the film forming agent used in the active coating for binding the active pharmaceutical ingredient to the inert core is selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and polyvinyl pyrrolidone derivatives and alginate derivatives or a mixture thereof.
  • the amount of film forming agent may range from 20.0 mg to 200.0 mg preferably may range from 25.0 mg to 150.0 mg per gram of composition.
  • the excipients when used in the active coating may be selected from materials such as microcrystalline cellulose powder, sodium lauryl sulphate, dioctyl sodium sulpho succinate, alginic acid, talc, magnesium stearate, titanium dioxide, starch and a mixture thereof and the coating solvent employed for active coating is purified water.
  • the amount of the excipient may range from 0.2 mg to 100.0 mg preferably may range from l.Omg to 80.0 mg per gram of composition.
  • the intermediate coating consists of a film forming agent.
  • the film forming agent is selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxy methyl cellulose, carboxy methylcellulose, polyvinyl pyrrolidone derivatives and alginate derivatives or a mixture thereof.
  • the amount of the film forming agent may range from 20.0 mg to 200.0 mg preferably may range from 25.0 mg to 150.0 mg per gram of composition.
  • the intermediate cores may also contain excipients.
  • the excipient used may be selected from materials such as microcrystalline cellulose powder, sodium lauryl sulphate, dioctyl sodium sulfosuccinate, alginic acid, talc, magnesium stearate, titanium dioxide, starch, etc or a mixture thereof.
  • the amount of excipient employed may range from 1.0 mg to 100.0 mg preferably may range from 2.0 mg to 80.0 mg per gram.
  • the polymer used for the enteric coating of the composition may be those such as cellulose derivatives or methacrylic acid derivatives or the mixture thereof.
  • the enteric polymeric composition also contains plasticizer and anti-adherents. Further it may also optionally contain colorants and opacifiers.
  • the amount of polymer employed for the enteric coating may range from 20.0 mg to 300.0 mg preferably may range from 50.0 mg to 250.0 mg per gram of composition.
  • the cellulose derivatives used in the enteric coating may be selected from materials such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and methacrylic acid derivatives such as Eudragit L 100 - 55, Eudragit L 30D-55.
  • the plasticizer used may be selected from materials such as fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol or phthalate derivatives such as diethyl phthalate, dipropyl phthalate, dibutyl phthalate, dioctyl phthalate or polyethelene glycol derivatives.
  • fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol or phthalate derivatives such as diethyl phthalate, dipropyl phthalate, dibutyl phthalate, dioctyl phthalate or polyethelene glycol derivatives.
  • the amount of plasticizer employed for enteric coating may range from 1.0 mg to 60.0 mg, preferably may range from 2.0 mg to 50.0 mg per gram of composition.
  • the anti-adherents used in the enteric coating may be selected from materials such as talc, stearate, stearic acid, hydrogenated castor oil or the mixture thereof
  • the colorants and opacifiers may be selected from iron oxides, titanium dioxide, or mixture thereof.
  • the amount of anti-adherents if employed may range from 2.0 mg to 120.0 mg, preferably may range from 4.0 mg to 100.0 mg per gram of composition.
  • the amount of opacifiers may range from 0.1 mg to 40.0 mg preferably may range from 0.5 to 30.0 mg per gram of composition.
  • the solvent used for enteric coating may be selected from aqueous or organic solvents or mixture thereof.
  • the aqueous solvents used may be purified water and the organic solvents such as isopropyl alcohol, acetone, ethanol or mixture thereof may be used. They are present in traces after processing is completed.
  • the composition is made in the form of pellets, which are then filled, into hard gelatin capsules of suitable size depending upon the assay and required therapeutic dose of the drug.
  • Automatic or semi automatic equipments can be used for filling the composition for preparing the hard gelatin capsules.
  • Inert core may be used as fillers or excipients to adjust the fill weight of the capsules.
  • the hard gelatin capsules comes in various sizes such as 00, 0, 1, 2, 3, etc., to accommodate various amounts of the composition.
  • esomeprazole size '2' is selected as capsule size for holding the composition , namely 20 mg of esomeprazole is distributed over a number of coated pellets, before filling into the capsule, we need to analyse the coated pellets to find out how many of these coated pellets shall be filled into size '2' capsule to achieve 20mg of esomeprazole .
  • Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and the micronised mixture of esomeprazole , microcrystalline cellulose, starch, talc and titanium dioxide were added to it with continuous stirring.
  • a perforated coating pan was loaded with the inert cores and the drug suspension prepared as described above was sprayed on to the inert cores. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.
  • Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and microcrystalline cellulose with starch was added to it.
  • Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring.
  • a perforated coating pan was loaded with the active coating pellets prepared and described as above and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in a coating pan to a moisture content below 2% w/w.
  • enteric coated pellets are filled into hard gelatin capsules size "2" after dilution with inert core, to obtain the dose of 20mg of esomeprazole., depending on the assay.
  • Example 2
  • Hydroxypropyl methylcellulose E5 and sodium lauryl sulphate were dissolved in water.
  • Microcrystalline cellulose powder , titanium dioxide and talc were sifted through 200# and added to the polymer solution with continuous stirring.
  • a perforated coating pan was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets.
  • the resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.
  • enteric coated pellets are filled into hard gelatin capsules size "0" after dilution with inert core, to obtain the dose of 40 mg of esomeprazole., depending on the assay .
  • Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and the micronised mixture of esomeprazole , starch, magnesium stearate and titanium dioxide were added to it with continuous stirring.
  • a fluidbed coater was loaded with the inert cores and the drug suspension was sprayed on to the inert cores.
  • the resulting pellets were dried in the fluidbed coater to a moisture content below 2% w/w.
  • Polyethlene glycol 6000 was dissolved in water and added to Eudragit L-30D-55 dispersion with continuous stirring and added triethyl citrate.
  • Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring.
  • the intermediate coated pellets were loaded in fluid bed coater and the enteric coating dispersion was applied on to the pellets.
  • the resulting pellets were dried to a moisture content below 2% w/w.
  • enteric coated pellets are filled into hard gelatin capsules size "2" after dilution with inert core, to obtain the dose of 20mg of esomeprazole., depending on the assay
  • Hydroxypropyl methylcellulose E5 and dioctyl sodium sulpho succinate were dissolved in water and the micronised mixture of esomeprazole , microcrystalline cellulose, starch, talc and titanium dioxide were added to it with continuous stirring.
  • a perforated coating pan was loaded with the inert cores and the drug suspension on to the inert core was sprayed on to the inert cores.
  • the resulting pellets were dried in the perforated coating pan to a moisture content reached below 2% w/w.
  • Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and microcrystalline cellulose with starch was added to it.
  • Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring.
  • a perforated coating pan was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.
  • C. Enteric coating Diethyl phthalate and cetyl alcohol were dissolved in a solvent blend of isopropyl alcohol and acetone followed by Hydroxypropyl methylcellulose phthalate .
  • Talc and titanium dioxide were sifted through 200# and added to the polymer solution.
  • the intermediate coated pellets were loaded in a perforated coating pan and the enteric coating dispersion was applied on to these pellets.
  • the resulting pellets were dried to a moisture content below 2% w/w.
  • enteric coated pellets are filled into hard gelatin capsules size "3" after dilution” with inert core, to obtain the dose of 10 mg of esomeprazole ., depending on the assay.
  • Example 5
  • enteric coated pellets are filled into hard gelatin capsules size " 1 " after dilution with inert core, to obtain the dose of 30 mg of esomeprazole., depending on the assay.
  • Example 6
  • Titanium dioxide 3.00
  • Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and the micronised mixture of esomeprazole , starch, magnesium stearate and titanium dioxide were added to it with continuous stirring.
  • a fluid bed coater was loaded with the inert cores and the drug suspension was sprayed on to the inert cores.
  • the resulting pellets were dried in the coating pan to a moisture content below 2% w/w.
  • Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water. Titanium dioxide , starch and magnesium stearate were sifted through 200# and added to the polymer solution with continuous stirring. A fluid bed coater was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in the coating pan to a moisture content below 2% w/w.
  • enteric coated pellets are filled into hard gelatin capsules size "1" after dilution with inert core, to obtain the dose of 30 mg of esomeprazole., depending on the assay.
  • Example 7
  • Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and microcrystalline cellulose with starch was added to it.
  • Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring.
  • a perforated coating pan was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.
  • Hydroxypropyl methylcellulose E5 and sodium lauryl sulphate were dissolved in water and the micronised mixture of esomeprazole, microcrystalline cellulose powder , titanium dioxide and talc was added to it with continuous stirring.
  • a perforated coating pan was loaded with the inert cores and the drug suspension was applied on to the inert cores.
  • the resulting pellets are dried in the perforated coating pan to a moisture content below 2% w/w.
  • enteric coated pellets are filled into hard gelatin capsules size "2" after dilution with inert core, to obtain the dose of 20 mg of esomeprazole., depending on the assay.
  • Example 9
  • Polyethlene glycol 6000 was dissolved in water and added to Eudragit L-30D-55 dispersion with continuous stirring and added triethyl citrate.
  • Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring.
  • the intermediate coated pellets were loaded in a perforated coating pan and the enteric coating dispersion was applied on to these pellets.
  • the resulting pellets were dried to a moisture content below 2% w/w.
  • enteric coated pellets are filled into hard gelatin capsules size "1" after dilution with inert cores, to obtain the dose of 40 mg of esomeprazole., depending on the assay.
  • composition is stable.
  • composition does not employ any alkali agent.
  • composition is simple, commercially viable, economical and highly reproduceable. 4. All the materials used in the composition , particularly those used for preparing the active coating and intermediate coating are widely available, pharmaceutically inert, economical and have a high degree of safety.
  • the active ingredient is not released in the stomach but released only in the intestine ( namely in an alkaline environment). In other words, the composition is protected in the acidic environment of the gastric system and is released in the alkaline environment of the intestinal system.
  • the pellets can be processed in any type of available equipments , for example , from the perforated coating pan to automatic fluidised bed pelletisation and coating equipments making the preparation of the composition simple and versatile. 7.
  • the pellets can be processed free from organic solvents thereby making it safe to handle for operational staff as it is non hazardous.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des préparations pharmaceutiques améliorées comprenant un noyau inerte, comprenant de l'amidon et du sucre, entouré d'un enrobage actif renfermant des énantiomères, des sels des énantiomères d'oméprazole, telle que l'ésoméprazole dans une forme micronisée, mélangée avec des excipients non alcalins et inertes acceptables sur le plan pharmaceutique, puis d'un enrobage intermédiaire et d'un enrobage entérique, afin de garantir l'intégrité du produit jusqu'à ce que celui-ci atteigne la partie proximale du petit intestin. L'invention concerne également un procédé de préparation de la composition susmentionnée.
PCT/IN2003/000335 2003-10-14 2003-10-14 Pastilles a enrobage enterique comprenant de l'esomeprazole, capsule de gelatine dure renfermant celles-ci et procede de preparation associe WO2005034924A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003272086A AU2003272086A1 (en) 2003-10-14 2003-10-14 Enteric coated pellets comprising esomeprazole, hard gelatin capsule containing them, and method of preparation
PCT/IN2003/000335 WO2005034924A1 (fr) 2003-10-14 2003-10-14 Pastilles a enrobage enterique comprenant de l'esomeprazole, capsule de gelatine dure renfermant celles-ci et procede de preparation associe

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000335 WO2005034924A1 (fr) 2003-10-14 2003-10-14 Pastilles a enrobage enterique comprenant de l'esomeprazole, capsule de gelatine dure renfermant celles-ci et procede de preparation associe

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WO2005034924A1 true WO2005034924A1 (fr) 2005-04-21

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PCT/IN2003/000335 WO2005034924A1 (fr) 2003-10-14 2003-10-14 Pastilles a enrobage enterique comprenant de l'esomeprazole, capsule de gelatine dure renfermant celles-ci et procede de preparation associe

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AU (1) AU2003272086A1 (fr)
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH699302A1 (de) * 2008-08-11 2010-02-15 Mepha Ag Orale pharmazeutische Formulierung für Omeprazol enthaltend eine spezifische Trennschicht.
WO2012017074A1 (fr) 2010-08-06 2012-02-09 Valpharma S.P.A. Formulations pharmaceutiques orales d'ésoméprazole sous la forme de comprimés mups (multi unit pellets system)
EP2345408A3 (fr) * 2010-01-08 2012-02-29 Dr. Reddy's Laboratories Ltd. Formulations de médicament labiles acides
EP2618822A1 (fr) * 2010-09-23 2013-07-31 MonoSol Rx, LLC Procédé et système de formation d'un produit pharmaceutique directement sur une surface d'emballage
WO2013122554A1 (fr) * 2012-02-14 2013-08-22 Mahmut Bilgic Formulations de pastilles comprenant de l'ésoméprazole
WO2017084680A1 (fr) * 2015-11-17 2017-05-26 Rontis Hellas S.A. Composition pharmaceutique contenant un médicament anti-inflammatoire non stéroïdien et un inhibiteur de pompe à protons
US10076494B2 (en) 2016-06-16 2018-09-18 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
US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions

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WO1994027988A1 (fr) * 1993-05-28 1994-12-08 Astra Aktiebolag Sels optiquement purs de composes de pyridinylmethyle sylfinyl-ih-benzimidazole
EP0773025A1 (fr) * 1995-02-01 1997-05-14 Esteve Quimica, S.A. Nouvelles formulations galeniques stables comprenant un compose de benzimidazole acide-labile, et procede de production
US5877192A (en) * 1993-05-28 1999-03-02 Astra Aktiebolag Method for the treatment of gastric acid-related diseases and production of medication using (-) enantiomer of omeprazole
US5997903A (en) * 1991-06-17 1999-12-07 Byk Gulden Lomberg Chemische Fabrik Gmbh Oral-administration forms of a medicament containing pantoprazol
WO2001014367A1 (fr) * 1999-08-26 2001-03-01 Applied Analytical Industries, Inc. Composes benzimidazole substitues par un alcoxy, preparations pharmaceutiques contenant ces derniers, et procedes d'utilisation
EP1086694A2 (fr) * 1999-09-13 2001-03-28 Laboratorios Del Dr. Esteve, S.A. Formulation pharmaceutique solide pour administration orale contenant un composé de benzimidazole sensible aux acides
WO2002039980A2 (fr) * 2000-11-20 2002-05-23 Lek, Tovarna Farmacevtskih In Kemiènih Izdelkov, D.D. Nouvelle formulation pharmaceutique sous forme de capsules de cellulose, adaptee pour des derives de benzimidazole

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Publication number Priority date Publication date Assignee Title
US5997903A (en) * 1991-06-17 1999-12-07 Byk Gulden Lomberg Chemische Fabrik Gmbh Oral-administration forms of a medicament containing pantoprazol
WO1994027988A1 (fr) * 1993-05-28 1994-12-08 Astra Aktiebolag Sels optiquement purs de composes de pyridinylmethyle sylfinyl-ih-benzimidazole
US5877192A (en) * 1993-05-28 1999-03-02 Astra Aktiebolag Method for the treatment of gastric acid-related diseases and production of medication using (-) enantiomer of omeprazole
EP0773025A1 (fr) * 1995-02-01 1997-05-14 Esteve Quimica, S.A. Nouvelles formulations galeniques stables comprenant un compose de benzimidazole acide-labile, et procede de production
WO2001014367A1 (fr) * 1999-08-26 2001-03-01 Applied Analytical Industries, Inc. Composes benzimidazole substitues par un alcoxy, preparations pharmaceutiques contenant ces derniers, et procedes d'utilisation
EP1086694A2 (fr) * 1999-09-13 2001-03-28 Laboratorios Del Dr. Esteve, S.A. Formulation pharmaceutique solide pour administration orale contenant un composé de benzimidazole sensible aux acides
WO2002039980A2 (fr) * 2000-11-20 2002-05-23 Lek, Tovarna Farmacevtskih In Kemiènih Izdelkov, D.D. Nouvelle formulation pharmaceutique sous forme de capsules de cellulose, adaptee pour des derives de benzimidazole

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH699302A1 (de) * 2008-08-11 2010-02-15 Mepha Ag Orale pharmazeutische Formulierung für Omeprazol enthaltend eine spezifische Trennschicht.
EP2345408A3 (fr) * 2010-01-08 2012-02-29 Dr. Reddy's Laboratories Ltd. Formulations de médicament labiles acides
WO2012017074A1 (fr) 2010-08-06 2012-02-09 Valpharma S.P.A. Formulations pharmaceutiques orales d'ésoméprazole sous la forme de comprimés mups (multi unit pellets system)
EP2618822A1 (fr) * 2010-09-23 2013-07-31 MonoSol Rx, LLC Procédé et système de formation d'un produit pharmaceutique directement sur une surface d'emballage
EP2618822A4 (fr) * 2010-09-23 2014-10-01 Monosol Rx Llc Procédé et système de formation d'un produit pharmaceutique directement sur une surface d'emballage
WO2013122554A1 (fr) * 2012-02-14 2013-08-22 Mahmut Bilgic Formulations de pastilles comprenant de l'ésoméprazole
US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US11986554B2 (en) 2015-04-29 2024-05-21 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
WO2017084680A1 (fr) * 2015-11-17 2017-05-26 Rontis Hellas S.A. Composition pharmaceutique contenant un médicament anti-inflammatoire non stéroïdien et un inhibiteur de pompe à protons
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
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

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