WO2008018825A1 - Oral polyvinyl alcohol capsules comprising proton pump inhibitors - Google Patents
Oral polyvinyl alcohol capsules comprising proton pump inhibitors Download PDFInfo
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- WO2008018825A1 WO2008018825A1 PCT/SE2007/000710 SE2007000710W WO2008018825A1 WO 2008018825 A1 WO2008018825 A1 WO 2008018825A1 SE 2007000710 W SE2007000710 W SE 2007000710W WO 2008018825 A1 WO2008018825 A1 WO 2008018825A1
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- Prior art keywords
- dosage form
- oral pharmaceutical
- pharmaceutical dosage
- polyvinyl alcohol
- proton pump
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- ZBFDAUIVDSSISP-UHFFFAOYSA-N Cc1cnc(CS(c([nH]2)nc(cc3)c2nc3OC)=O)c(C)c1OC Chemical compound Cc1cnc(CS(c([nH]2)nc(cc3)c2nc3OC)=O)c(C)c1OC ZBFDAUIVDSSISP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
-
- 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
- A61K9/4816—Wall or shell material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Definitions
- WO 02/39980 discloses pharmaceutical formulations in the form of cellulose capsules comprising an active pharmaceutical ingredient.
- EP 1323404 discloses hard capsules made of a polymer or copolymer of at least one vinyl monomer and polyvinyl alcohol and/or a derivative thereof.
- the capsules may be filled with a solvent for dissolving a sparingly soluble active ingredient.
- a suitable method is: the polyvinyl alcohol or the polyvinyl alcohol derivate or a mixture thereof is added to water and dissolved by heating, then at least one polymerizable vinyl monomer is added to the solution and polymerization occurs whereupon a resin is obtained.
- a polymerization initiator can also be added together or after with the at least one polymerizable vinyl monomer.
- Suitable polymerization initiator is conventional initiators, such as azo compounds (e.g. 2,2- azobis(2-amidinopropane) hydrochloride), AIBN (azoisobutyronitrile), persulfates (e.g.
- the proton pump inhibitors may also be selected from a potassium competitive acid blocker for example disclosed in WO 99/55706, WO 04/113338, WO 04/113339, WO 04/113340, WO 00/17200, WO 95/19980 and WO 96/05177.
- potassium competitive acid blockers may be used in their neutral form or in the form of a pharmaceutically acceptable salt, including pharmaceutically acceptable acid addition salts.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an oral pharmaceutical dosage form comprising a proton pump inhibitor characterized in that the dosage form is in the form of a capsule comprising a pharmaceutical formulation containing a proton pump inhibitor, optionally other pharmaceutically acceptable excipient(s) and optionally additional pharmaceutically active substance(s), and the capsule material comprises a polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof. The present invention also relates to a process for manufacturing the oral pharmaceutical dosage form and to the use in medicine thereof.
Description
NEW COMPOSITION 2PP\
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an oral pharmaceutical dosage form in the form of a capsule comprising a pharmaceutical composition comprising a proton pump inhibitor and optionally other pharmaceutically acceptable excipient(s) and optionally additional pharmaceutically active substance(s), and the capsule material comprises a polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof. The present invention also relates to a process for manufacturing the oral pharmaceutical dosage form, i.e. the capsule containing the proton pump inhibitor, optionally other pharmaceutically acceptable excipient(s) and optionally additional pharmaceutical active substance(s), and to the use thereof in medicine.
BACKGROUND OF THE INVENTION
WO 02/39980 discloses pharmaceutical formulations in the form of cellulose capsules comprising an active pharmaceutical ingredient.
EP 1323404 discloses hard capsules made of a polymer or copolymer of at least one vinyl monomer and polyvinyl alcohol and/or a derivative thereof. The capsules may be filled with a solvent for dissolving a sparingly soluble active ingredient.
EP 1062274 (=WO99/46329) discloses film-forming compositions consisting of polyvinyl alcohol and a setting system. The setting system affects the gelling properties of the polyvinyl alcohol. The composition is used in pharmaceutical, veterinary, food, cosmetic or other products like films for wrapping food, aspics or jellies, preferably for predosed formulations like soft or hard capsules.
EP 0247983 discloses pharmaceutical preparations containing omeprazole together with an alkaline compound in the core material and the core material is covered by an enteric coating and with one or more subcoating layers between the core material and the enteric coating.
EP 0180287 discloses medicinal capsule shaped from a polymeric composition comprising water-soluble cellulose ether of which the etherifying group is alkyl or hydroxyalkyl and polyvinyl alcohol.
5 JP 2001170137 discloses hard capsules consisting of a film comprising polyvinyl alcohol and a gelling agent.
US 3984494 discloses capsule for drugs wherein the capsule material is composed of a modified polyvinyl alcohol being a partially saponified graft copolymer of vinyl acetate ono polyethylene oxide.
Polyvinyl alcohol (PVA) film compositions have extremely low water permeability, the lowest among known film forming material, and it is used for coating compositions, especially for pharmaceutical formulations like tablets as described in WO96/01874.5
For pharmaceutically active substances that among other things have properties like poor water solubility, fast and extensive degradation in an acidic medium and which are unstable in the presence of moisture, e.g. due to hydrolysis, solvents or acidic substances, there exists a constant need for new pharmaceutical formulations, such as for instance newo capsule formulations.
OUTLINE OF THE INVENTION
The present invention relates to an oral pharmaceutical dosage form wherein said dosage form is in the form of a capsule comprising a proton pump inhibitor, which capsule5 material comprises polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof.
The present invention also relates to an oral pharmaceutical dosage form wherein said dosage form is in the form of a capsule comprising a proton pump inhibitor and a capsuleo material, which capsule material comprises at least one vinyl monomer and polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof. Said vinyl monomer is a polymerizable vinyl monomer.
The present invention also relates to an oral pharmaceutical dosage form, wherein said dosage form is in the form of a capsule comprising a proton pump inhibitor and a capsule material, wherein said capsule material has been obtained by polymerizing at least one polymerizable vinyl monomer in the presence of polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof.
According to one embodiment of the present invention, said polyvinyl alcohol or polyvinyl alcohol derivative is a copolymer. According to another embodiment of the present invention, said polyvinyl alcohol or polyvinyl alcohol derivative is a homopolymer.
A further embodiment of the present invention provides that the oral pharmaceutical dosage form of the present invention also comprises one or more pharmaceutically acceptable excipient.
Another embodiment of the present invention provides that the oral pharmaceutical dosage form of the present invention comprises one or more additional pharmaceutically active substance.
The present invention also relates to a capsule for oral use, characterized in that said capsule material comprises polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof, and in that said capsule is filled with a proton pump inhibitor as the active substance and optionally pharmaceutically excipient(s) and optionally additional pharmaceutically active substance(s).
Another aspect of the present invention also relates to a capsule for oral use characterized in that said capsule material comprises at least one polymerizable vinyl monomer and polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof, and in that said capsule is filled with a proton pump inhibitor as the active substance and optionally pharmaceutically excipient(s) and optionally additional pharmaceutically active substance(s).
Furthermore, the present invention relates to a pharmaceutical formulation characterized in that it comprises: a) a capsule of a material comprising polyvinyl alcohol or a polyvinyl alcohol derivate or a mixture thereof; 5 b) a proton pump inhibitor; c) optionally one or more pharmaceutically acceptable excipient; and d) optionally one or more additional pharmaceutically active substance.
The present invention also relates to a pharmaceutical formulation characterized in that itQ comprises: a) a capsule of a material comprising at least one polymerizable vinyl monomer and polyvinyl alcohol or a polyvinyl alcohol derivate or a mixture thereof ; b) a proton pump inhibitor; c) optionally one or more pharmaceutically acceptable excipient; and s d) optionally one or more additional pharmaceutically active substance.
According to one embodiment of the present invention, said capsule is a hard capsule.
A further embodiment of the present invention relates to an oral pharmaceutical dosageo form, a capsule for oral use or a pharmaceutical formulation wherein the proton pump inhibitor is an acid susceptible proton pump inhibitor, which may be protected by one or more enteric coating layer.
Another embodiment of the present invention relates to an oral pharmaceutical dosage5 form, a capsule for oral use or a pharmaceutical formulation wherein the acid susceptible proton pump inhibitor is protected by one or more enteric coating layer and one or more subcoating layer separating the enteric coating from said proton pump inhibitor.
The present invention also relates to a process for the manufacture of an oral Q pharmaceutical dosage form according to the present invention, characterized in that the proton pump inhibitor is filled into a capsule having a capsule material which is obtainable by polymerizing at least one polymerizable vinyl monomer in the presence of polyvinyl
alcohol or a polyvinyl alcohol derivative or a mixture thereof. According to one embodiment of the present invention, said capsule is also filled with pharmaceutically acceptable excipient(s).
The present invention also relates to a process for the manufacture of an oral pharmaceutical dosage form according to the present invention characterized in that: i) the proton pump inhibitor; ii) pharmaceutically acceptable excipient(s); iii) optionally additional pharmaceutically active substance(s) are filled into a capsule having a capsule material, which is obtainable by polymerizing at least one polymerizable vinyl monomer in the presence of polyvinyl alcohol or a polyvinyl alcohol derivate or a mixture thereof.
According to another embodiment of the present invention, additional pharmaceutically active substance is also filled into the capsule. According to a further embodiment of the present invention, said additional pharmaceutically active substance is acetyl salicylic acid.
The present invention also relates to a process for the manufacture of an oral pharmaceutical dosage form characterized in that proton pump inhibitor, optionally one or more pharmaceutically acceptable excipient and optionally one or more additional pharmaceutically active substance is/are filled into a capsule, which capsule material comprises polyvinyl alcohol or a polyvinyl alcohol derivate or a mixture thereof, further characterized in that the capsule is obtained by polymerizing at least one polymerizable vinyl monomer in the presence of polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof.
According to another embodiment of the present invention, the proton pump inhibitor is formulated in the form of enteric coating layered units and the units are filled into said capsule together with optionally one or more pharmaceutical excipient and optionally one or more additional pharmaceutically active substance(s). According to another embodiment of the present invention, the proton pump inhibitor is protected by enteric coating layer(s) and subcoating layer(s) separating the enteric coating layer(s) from the proton pump
inhibitor. According to a further embodiment of the present invention, said the proton pump inhibitor is acid susceptible.
The present dosage form will provide a good stability during storage.
The term "unit(s)" as used herein, is intended to include e.g. "pellet(s)", "granule(s)", "bead(s)" and mini-/tablets (meaning minitablets or small tablets).
The term "gastrointestinal disorders" as used herein, is intended to include gastric-acid related diseases in mammals and man, e.g. reflux oesophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and Zollinger-EUison syndrom, gastrointestinal complications and gastro-oesophageal reflux disease (GORD or GERD). The term is also intended to include patients on NSAID therapy, patients with Non Ulcer Dyspepsia, and in patients with symptomatic GORD or GERD and also patients in intensive care situations, patients with acute upper gastrointestinal bleeding, pre-and postoperatively to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, they may be useful for prevention and treatment of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, laryngitis, Barret's syndrome, sleep apnea, sleep disturbance, psoriasis as well as being useful for prevention and treatment of Helicobacter infections and diseases related to the above.
The term "gastrointestinal complications", as used herein, is intended to include ulcer in the stomach or duodenum, complications to said ulcers, such as bleeding, perforation and/or obstruction, and dyspeptic symptoms, such as epigastric pain and/or discomfort.
The term "prevention", as used herein, is also intended to include inhibition of "gastrointestinal complications" or "gastrointestinal disorders". The term "reduction" as used herein, is intended to also include the "risk reduction of "gastrointestinal complications".
The term "PPI", as used herein, is an abbreviation for proton pump inhibitor.
The term "PVA", as used herein, is an abbreviation for polyvinyl alcohol.
The term "polymer" is intended to include, unless stated otherwise, homopolymer and copolymer.
5
The capsule
The capsule material according to the present invention comprises polyvinyl alcohol or a polyvinyl alcohol derivate or a mixture thereof. The capsule material according to the present invention can also comprise at least one polymerizable vinyl monomer. Accordingo to one embodiment of the present invention the capsule material has been obtained by polymerizing at least one polymerizable vinyl monomer in the presence of polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof.
According to one embodiment of the present invention the polyvinyl alcohol derivative iss polyvinyl alcohol having a thiol group as an end group.
According to another embodiment of the present invention at least one of the polymerizable vinyl monomer(s) that can be used in the present invention include, is selected from the group consisting of: o Subgroup (1) acrylic acid, methacrylic acid, fumaric acid, maleic acid, and itaconic acid; Subgroup (2) sodium salts, potassium salts, ammonium salts and alkylamine salts of the compounds of (1); and
Subgroup (3) methyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, butyl acrylate, isobutyl methacrylate, isobutyl acrylate, cyclohexyl5 methacrylate, cyclohexyl acrylate, 2-ethylhexyl methacrylate, 2-ethylhexyl acrylate, acrylonitrile, acrylamide, dimethylacrylamide, styrene, vinyl acetate, hydroxyethyl methacrylate, hydroxyethyl acrylate, an ester formed by polyethylene glycol and methacrylic acid, an ester formed by polyethylene glycol and acrylic acid, an ester formed by polypropylene glycol and methacrylic acid, an ester formed by polypropylene glycolo and acrylic acid, N-vinylpyrrolidone, and acryloyl morpholine and compounds represented by the general formula H2C=C(Ri)-COOR2, wherein Ri represents a hydrogen atom or a
methyl group, and R2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
According to another embodiment of the present invention, at least one of the polymerizable vinyl monomer is selected from subgroup (1) or subgroup (2) and at least one of the polymerizable vinyl monomer is selected from subgroup (3). According to another embodiment of the present invention the polymerizable vinyl monomers are an acrylic acid or a methacrylic acid and a methyl methacrylate.
There are no particular limitations of the amounts used regarding polyvinyl alcohol or polyvinyl alcohol derivate or a mixture thereof and the polymerizable vinyl monomer(s). However, as a non-limiting example, the amount of acrylic acid or methacrylic acid can be from 5 to 10 wt% of the total amount of the polymerizable vinyl monomers, and the amount of methyl methacrylate can be from 50 to 95 wt% of the total amount of the polymerizable vinyl monomers. According to another non-limiting example, the amount of polyvinyl alcohol or polyvinyl alcohol derivate can be from 20 to 95 wt% and the amount of polymerizable vinyl monomer(s) can be from 5 to 80 wt%. According to another non- limiting example, the amount polyvinyl alcohol or polyvinyl alcohol derivate can be from 50 to 90 wt%, and the amount of polymerizable vinyl monomer(s) can be from 10 to 50 wt%.
In addition to the polyvinyl alcohol or the polyvinyl alcohol derivative or a mixture thereof used in the present invention, a completely hydrolyzed substance, an intermediately hydrolyzed substance or a partially hydrolyzed substance, various modified PVAs such as amine-modified PVA, ethylene-modified PVA and terminal-thiol-modified PVA can also be used.
PVA is a macromolecular compound, and there are various degrees of polymerization known. There are also various methods of manufacturing a capsule comprising polyvinyl alcohol or a polyvinyl alcohol derivate or mixture thereof, and the optimum viscosity varies according to the method used, hence the molecular weight of PVA usable can be selected as appropriate.
Thus, publicly known methods can be used for polymerizing polyvinyl alcohol or a polyvinyl alcohol derivate with the at least at least one polymerizable vinyl monomer. One example of a suitable method is: the polyvinyl alcohol or the polyvinyl alcohol derivate or a mixture thereof is added to water and dissolved by heating, then at least one polymerizable vinyl monomer is added to the solution and polymerization occurs whereupon a resin is obtained. Optionally a polymerization initiator can also be added together or after with the at least one polymerizable vinyl monomer. Suitable polymerization initiator is conventional initiators, such as azo compounds (e.g. 2,2- azobis(2-amidinopropane) hydrochloride), AIBN (azoisobutyronitrile), persulfates (e.g. potassium persulfate, sodium persulfate or ammonium persulfate), organic peroxides (e.g. t-butyl hydroperoxide), or redox initiators (e.g. hydrogen peroxide-tartaric acid or hydrogen peroxide-sodium tartrate).
Manufacturing methods for the capsule can be selected from injection molding method or dipping method, however other methods can also be used, such methods are for example disclosed in EP 1323404, EP 1062274, GB 2357488, US 2003152619, hereby incorporate by reference.
According to the present invention, the capsule material may besides polyvinyl alcohol or a polyvinyl alcohol derivate or a mixture thereof also comprise a setting system (gelling agent) such as disclosed in EP 1062274 and JP 2001170137, which documents are hereby enclosed as a whole as a reference.
A person skilled in the art would recognize that depending on which PVA compositions used for manufacturing the capsule, the obtained capsule will either be soft or hard. When hard capsules comprising PVA are used in the section EXAMPLES below, the capsules comprises capsule material as described hereinabove.
Active substances The proton pump inhibitors suitable for the present invention are selected from the class of potassium competitive acid blockers and /or from the class of acid susceptible proton pump inhibitors. According to one embodiment of the present invention, combinations of two or
more PPIs can be used. Thus, by the term "proton pump inhibitor" is meant that also combinations of two or more PPIs can be used.
The acid susceptible proton pump inhibitors suitable for the present invention are H+K+- ATPase inhibitors and they can be selected from:
omeprazole
esomeprazole
esomeprazole magnesium
lansoprazole
rabeprazole (pariprazole)
leminoprazole
pantoprazole
tenatoprazole
ilaprazole
and
The acid susceptible proton pump inhibitors used in the dosage form of the present invention may be used in their neutral form or in the form of a pharmaceutically acceptable salt such as an alkaline salt selected from any one of their Mg2+, Ca2+, Na+, K+, Li+ or TBA (tert-butyl ammonium) salts. Further a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof, such as for instance hydrates. The above-listed compounds can also be used in their tautomeric form. Also0 included in the present invention are derivatives of the compounds listed above which have the biological function of the compounds listed, such as prodrugs.
Acid susceptible proton pump inhibitors are for example disclosed in EP 0005129, EP 174 726, EP 166 287, GB 2 163 747 and WO 90/06925, WO 91/19711, WO 91/19712,s WO 95/01977, WO 98/54171 and WO 94/27988.
Thus, according to one embodiment of the invention, the acid susceptible PPI is omeprazole or an alkaline salt thereof, such as omeprazole magnesium or a hydrate thereof. According to yet another embodiment of the present invention the acid susceptibleo PPI is esomeprazole, an alkaline salt thereof, such as esomeprazole magnesium, or a hydrate form of any one of them. According to a further embodiment of the present invention the acid susceptible PPI is lansoprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of either one of them. In another embodiment of the present invention the acid susceptible PPI is pantoprazole or a pharmaceutically acceptable salt
thereof or a single enantiomer of either one of them. In yet another embodiment of the present invention, the acid susceptible PPI is rabeprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of either one of them. In a further embodiment of the present invention, the acid susceptible PPI is ilaprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of either one of them. In yet a further embodiment of the present invention, the acid susceptible PPI is tenatoprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of either one of them.
The proton pump inhibitors may also be selected from a potassium competitive acid blocker for example disclosed in WO 99/55706, WO 04/113338, WO 04/113339, WO 04/113340, WO 00/17200, WO 95/19980 and WO 96/05177. These potassium competitive acid blockers may be used in their neutral form or in the form of a pharmaceutically acceptable salt, including pharmaceutically acceptable acid addition salts.
Pharmaceutically acceptable excipient
The used proton pump inhibitor can be filled into the capsule e.g. as a powder or agglomerate, according to this invention without being formulated together with pharmaceutical excipient(s).
More preferably, the proton pump inhibitor is mixed with one or more pharmaceutical excipient to obtain suitable handling and processing properties and a suitable concentration of the proton pump inhibitor in the final preparation. Pharmaceutical excipients such as fillers, binders, lubricants, disintegrating agents, surfactants, alkaline/acidic additives or other pharmaceutically acceptable additives/ingredients alone or in mixtures may be used. The binders are for example polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethylcellulose sodium, polyvinyl pyrrolidone (PVP), or sugars, starches or other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants are found in the groups of pharmaceutically acceptable non-ionic or ionic surfactants, for instance sodium lauryl sulfate.
The mixture may be used for further conventional pharmaceutical processing and for making pellets, granules, agglomerates, beads, mini-/tablets, solid dispersions etc.
Enteric coating layered units
A core material for the individually enteric coating layered units can be constituted according to different principles. Seeds layered with the proton pump inhibitor, optionally mixed with alkaline/acidic substances, can be used in the core material and used for further 5 processing.
The seeds which are to be layered with the proton pump inhibitor may be water insoluble seeds comprising different oxides, celluloses, organic polymers and other materials, alone or in mixtures. The seeds may also be water-soluble seeds comprising different inorganic
IQ salts, sugars, non-pareils and other materials, alone or in mixtures. Further, the seeds may comprise the proton pump inhibitor in the form of crystals, agglomerates, compacts etc. The size of the seeds is not essential for the present invention but may vary from approximately 0.1 to 2 mm. The seeds layered with the proton pump inhibitor are produced either by powder or solution/suspension layering. Granulation or spray coating layering
I5 equipment may be used.
Before the seeds are layered, the proton pump inhibitor may be mixed with further components. Such components can be binders, surfactants, fillers, disintegrating agents, lubricants, alkaline/acidic additives or other pharmaceutically acceptable ingredients alone
2o or in mixtures. The binders are for example polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethylcellulose sodium, polyvinyl pyrrolidone (PVP), or sugars, starches or other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants are found in the groups of pharmaceutically acceptable non-ionic or ionic surfactants, for instance sodium
25 lauryl sulfate.
Alternatively, when the PPI is acid susceptible, the proton pump inhibitor may optionally be mixed with alkaline substances and further mixed with suitable constituents when formulated into a core material. Extrusion/spheronization, balling or compression utilizing 3Q conventional process equipment may produce said core material. The size of the formulated core material is approximately from 0.1 to 4 mm, alternatively from 0.1 to 2
mm. The manufactured core material can further be layered or mixed with additional ingredient(s) with or without comprising a PPI and/or be used for further processing.
Preferably, the proton pump inhibitor is mixed with pharmaceutical excipient(s) to obtain suitable handling and processing properties and a suitable concentration of the PPI in the final preparation. Pharmaceutical excipients such as fillers, binders, lubricants, disintegrating agents, alkaline/acidic additives, surfactants and other pharmaceutically acceptable substances may be used.
When the proton pump inhibitor is mixed with an alkaline substance (or substances), such substances can be chosen among, but are not restricted to, substances as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonate coprecipitate; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as Al2O3.6MgO.CO2.12H2O, (Mg6Al2(OH)i6CO3.4H2O), MgO.Al2O3.2SiO2.nH2O or similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering substances.
Alternatively, the aforementioned core material can be prepared by using spray drying or spray congealing technique.
Enteric coating layer is) Before applying the enteric coating layer(s) onto the core material in the form of individual units, the units may optionally be covered with one or more subcoating layer(s) comprising pharmaceutical excipients optionally including alkaline substances such as pH-buffering substances. This/these subcoating layer(s), separate(s) the core material from the outer layers being enteric coating layer(s). This/these subcoating layer(s) protecting the core material of proton pump inhibitor should be water soluble, water insoluble or rapidly disintegrating in water. If the subcoating layer(s) is water insoluble, the layer(s) should be formulated so as to allow the active substance to be properly released.
The subcoating layer(s) can be applied to the core material by coating or layering procedures in suitable equipments, such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating process. As an alternative, the subcoating layer(s) can be applied to the core material by using powder coating technique. The materials for the subcoating layer(s) are pharmaceutically acceptable substances selected from any one of, but not limited to, sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose sodium, water soluble salts of enteric coating polymers and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents (such as magnesium stearate, titanium dioxide, talc) and other additives may also be included into the subcoating layer(s).
When the optional subcoating layer(s) is applied to the core material, it may constitute a variable thickness. The maximum thickness of the subcoating layer(s) is normally only limited by processing conditions. The subcoating layer(s) may serve as a diffusion barrier and it may also act as a pH-buffering zone. The pH-buffering properties of the separating layer(s) can be further strengthened by introducing into the layer(s) substances chosen from a group of compounds usually used in antacid formulations such as, for instance, magnesium oxide, hydroxide or carbonate, aluminium or calcium hydroxide, carbonate or silicate; composite aluminium/magnesium compounds such as Al2θ3.6MgO.CO2.12H2O, (Mg6Al2(OH)16CO3.4H2O), MgO.Al2O3.2SiO2.nH2O, aluminium hydroxide/sodium bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH- buffering compounds such as, for instance the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids and salts thereof. Talc or other compounds may also be added to improve the function or increase the thickness of the layer(s) and thereby strengthen the diffusion barrier. The optionally applied subcoating layer(s) is not essential for the invention. However, the subcoating layer(s) may improve the chemical stability of the active substance(s) and/or the physical properties of the claimed oral dosage form.
Alternatively, a subcoating layer may be formed in situ by a reaction between enteric coating polymer(s) applied on the core material and alkaline reacting compound(s) in the core material. Thus, the subcoating layer formed comprises a water soluble salt formed between the enteric coating polymer(s) and alkaline reacting compound(s), which is in the position to form a salt.
One or more enteric coating layer(s) are applied onto the core material or onto the core material covered with subcoating layer(s) by using a suitable coating technique. The enteric coating layer material may be dispersed or dissolved in either water or in suitable organic solvents. As enteric coating layer polymers one or more, separately or in combination, of the following can be used, e.g. solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac or other suitable enteric coating polymer(s).
The enteric coating layer(s) may contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layer(s). Such plasticizers are selected from, but not limited to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers.
If present, the amount of plasticizer is optimized for each enteric coating layer formula, in relation to selected enteric coating layer polymer(s), selected plasticizer(s) and the applied amount of said polymer(s), in such a way that the mechanical properties, i.e. flexibility and hardness of the enteric coating layer(s) fulfill the desired requirements, e.g. further processing, stability, dissolution or other properties. If there is a need for a plasticizer, it is usually used in an amount of above 10 percent by weight. Additives such as dispersants, colorants, pigments, polymers e.g. poly(ethylacrylat, methylmethacrylat), anti-tacking and anti-foaming agents may also be included into the enteric coating layer(s). Other substances may be added to increase film thickness and to decrease diffusion of acidic gastric juices into core material that might be acid susceptible. To protect the proton pump
inhibitor that might be an acid susceptible substance, and to obtain an acceptable acid resistance of the dosage form according to the invention, the enteric coating layer(s) constitutes a thickness of approximately at least 10 μm or alternatively at least 20 μm. The maximum thickness of the applied enteric coating is normally only limited by processing s conditions and the desired dissolution profile.
Over-coating layer
Enteric-coated layered units comprising a proton pump inhibitor may further be covered with one or more over-coating layer(s). The over-coating layer(s) can be applied to theo enteric coating layered units by coating or layering procedures in suitable equipments, such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating or layering process. The materials for over-coating layer(s) are chosen among pharmaceutically acceptable substances selected from, but not limited to, any one of sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol,s polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents (such as magnesium stearate, titanium dioxide and talc) and other additives may also be included into the over-coating layer(s). Said over-coating layer may further prevent0 potential agglomeration of enteric coating layered units. The maximum thickness of the applied over-coating layer(s) is normally limited by processing conditions and the desired dissolution profile.
In one embodiment of the present invention the acid susceptible proton pump inhibitor is5 protected by both enteric coating layer(s) and subcoating layer(s) separating the enteric coating from the acid susceptible proton pump inhibitor.
According to another embodiment of the present invention, the oral pharmaceutical dosage form, the capsule, and the pharmaceutical formulation, may contain two portions witho different release profiles of the PPI, i.e. pellets releasing the PPI with a delayed release pulse and pellets releasing the PPI with an immediate release pulse. The PPI is formulated into a core material in the form of units and the units giving the delayed release pulse have
the following layers on the core material in given order: a delay release modifying layer comprising a water soluble or in water swellable polymer(s), talc and a hydrophobizing agent; a lag time controlling layer comprising as essential component a high viscosity water soluble polymer, or a water swellable polymer; an optional subcoating layer; and an outer enteric coating layer; while the units giving an immediate release pulse have the following layer(s) on the core material: an optional subcoating layer; and an optionally outer enteric coating layer.
Other active substances The oral pharmaceutical dosage form, the capsule or the pharmaceutical formulation of the present invention may also comprise other additional pharmaceutical active substances besides the PPI. Examples of such additional active substances include, but are not limited to, anti-bacterial compounds; non-steroidal anti-inflammatory agents (NSAIDs) including acetylsalicylic acid; antacid agents; alginates; prokinetic agents; bisfosfonates; histamine H2-receptor antagonists; and GABAb agonists such as baclofen and those disclosed in WO 01/42252 and WO01/41743.
According to one embodiment of the present invention, the oral pharmaceutical dosage form and the capsule and the pharmaceutical formulation may comprise acetylsalicylic acid (ASA) as the additional pharmaceutically active substance. The acetyl salicylic acid can be selected from its free acid form, derivatives thereof or any other possible forms, for example, but not limiting to scope of the present invention, acetyl salicylic amid or acetyl salicylic complex(s). The ASA can be present in the following forms:
• Powder of ASA (ASA-substance as such); • Agglomerates of ASA;
• Spherical agglomerates of ASA;
• Solid dispersions or solutions of ASA in polymers;
These solid dispersions or solutions of may be accomplished by melting the dispersing/dissolving agent and adding the ASA, or by dissolving the dispersing/dissolving agent and ASA in a common solvent, where after the solvent is evaporated.
• Cyclodextrin complexes of ASA (as powder);
These complexes may comprise α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or derivatives thereof such as e.g. β-hydroxypropyl cyclodextrin. The complexing cyclodextrin may be chosen to affect the release rate, for instance to give extended release (β-hydroxypropyl cyclodextrin) or immediate release (β-cyclodextrin). • Cyclodextrin complexes of AS A granulated together with pharmaceutical excipients;
These complexes may comprise α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or derivatives thereof such as e.g. β-hydroxypropyl cyclodextrin. The complexing cyclodextrin may be chosen to affect the release rate, for instance to give extended release (β-hydroxypropyl cyclodextrin) or immediate release (β-cyclodextrin).
• Units comprising ASA together with pharmaceutical excipient(s) for immediate release;
• Units comprising ASA together with pharmaceutical excipient(s) for extended release. These units may be constructed according to the hydrophilic gel matrix principle, hydrophobic matrix principle or diffusion membrane layered pellets/granules principle;
• Units comprising ASA together with pharmaceutical excipient(s) for enteric release (enteric coated granules or pellets);
• Units comprising ASA together with pharmaceutical excipient(s) for pH- independent time delayed release ((not enteric coated) granules or pellets);
• Units comprising ASA together with effervescent pharmaceutical excipient(s) for immediate release;
• Units comprising ASA layered with an enteric coating layer, such as the enteric coating layer described above; • Mini-/tablets comprising ASA ;
• Coated Mini-/tablets comprising ASA.
The described different forms of ASA are also applicable to the other additional pharmaceutical active substance(s).
Use
The oral pharmaceutical dosage form, the capsule and the pharmaceutical formulation of the present invention are especially advantageous in the prevention and/or reduction of gastrointestinal disorders and/or gastrointestinal complications.
According to one embodiment of the present invention, the oral pharmaceutical dosage form, the capsule and the pharmaceutical formulation have an amount of the proton pump inhibitor in the range of from 5 to 300 mg.
According to yet another embodiment the amount of acid susceptible proton pump inhibitor is in the range of from 10 to 200 mg or from 10 to 100 mg or from 10 to 80 mg. In an alternative embodiment of the present invention the amount of acid susceptible proton pump is selected from about: 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 mg. According to yet another embodiment of the present invention, the amount of acid susceptible proton pump inhibitor is selected from 20, 40 or 80 mg.
The above embodiments related to selected amount of acid susceptible PPI are also relevant for potassium competitive acid blockers
The present invention also relates to a method for the reduction and/or prevention of gastrointestinal disorders and/or gastrointestinal complications in mammals or man by administering to a mammals or man in need thereof a therapeutically effective dose of the oral pharmaceutical dosage form of the present invention or the pharmaceutical formulation of the present invention or the capsule of the present invention. According to further embodiment of the present invention said disorders is reflux oesophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and Zollinger-Ellison syndrom, gastrointestinal complications and/or gastro-oesophageal reflux disease (GORD). According to further embodiments of the present invention said complication is an upper gastrointestinal complication, a peptic ulcer in the stomach or a peptic ulcer in the duodenum.
According to further embodiments of the present invention, the administration is once or twice daily.
The present invention also relates to the use of the oral pharmaceutical dosage form or the capsule or the pharmaceutical formulation for the manufacture of a medicament for the prevention and/or reduction of gastrointestinal disorders and/or gastrointestinal complications. According to further embodiment of the present invention said disorders is reflux oesophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and Zollinger- Ellison syndrom, gastrointestinal complications and/or gastro-oesophageal reflux disease (GORD). According to further embodiments of the present invention, the complication is, as mentioned above, an upper gastrointestinal complication or is a peptic ulcer in the stomach or a peptic ulcer in the duodenum.
The polymer or copolymer comprised in the preparation of the described capsule material can also be used in a film forming composition, which film may be used to coat an oral dosage form, such as a tablet, comprising the pharmaceutically active substances disclosed above.
EXAMPLES
The examples below will further illustrate the present invention. These examples are not intended to limit the scope if the invention as defined hereinabove or as claimed below. The oral pharmaceutical dosage form according to the invention is in the examples devoted as PVA capsule
Example 1: Capsules comprising Omeprazole 10 mg. Comparison of PVA capsule and Gelatin capsule
Hard capsules comprising PVA and hard capsules comprising gelatin, size 3, respectively were filled with enteric coating layered units corresponding to a dose of 10 mg omeprazole. The enteric-coated units were prepared according to the disclosure in EP 0247983, example 2. The prepared capsules were kept in glass bottles without dessicant and stored in accelerated conditions of 500C as well as 400C /75% relative humidity (RH).
The level of degradation products and impurities was measured by means of a liquid chromatographic method and UV detection at 280 nm after extraction from ground pellet powder with mobile phase. The amount of degradation products is expressed as the sum of all degradation product/impurity peak areas in the chromatogram in percent of the total peak area (related to all peaks including the omeprazole peak) (area - %).
Analytical column: Superspher Si 60, 4μm, 125 x 4 mm.
Mobile phase: Dichloromethane with small addition of ammonia and methanol.
Example 2: Capsules comprising Esomeprazole 20 mg and ASA granules 325 mg.
Enteric coating layered units comprising Esomeprazole-Mg trihydrate corresponding to 20 mg Esomeprazole were manufactured and mixed with magnesium stearate. This mixture and ASA (acetyl salicylic acid) granules were filled into hard capsules comprising PVA.
Manufacturing of enteric coated Esomeprazole units
Core material
Sugar_sj)hejejieeds 0.25 to 0.35 mm approx. diameter 300 g
(susj>ensjon_fpr)_ Active, layer
Esomeprazole-Mg trihydrate 445 g Hydroxypropyl methylcellulose 67 g
Polysorbate 80 9 g
Purified water 210O g
(suspension for) Subcoating layer
Hydroxypropyl cellulose 90 g
Talc 340 g Magnesium stearate 22 g
Purified water 3100 g
Enteric coating layer (dispersion for)
Methacrylic acid copolymer type C, 30 % dispersion 1270 g
Tri ethyl citrate 38 g Mono- and diglycerides 19 g
Polysorbate 80 2 g
Purified water 500 g
Esomeprazole-Mg trihydrate was suspended in a water solution containing the dissolved binder hydroxypropyl methylcellulose and the surfactant polysorbate 80. The suspension was sprayed onto sugar sphere seeds in a fluidized bed coating apparatus using bottom spray (Wurster) technique. The prepared core material was covered with the subcoating layer in a fluid bed apparatus by spraying a hydroxypropyl cellulose solution containing suspended talc and magnesium stearate. The enteric coating layer was sprayed as a water dispersion onto the subcoated pellets obtained above, in a fluid bed apparatus.
Mixture of enteric-coated Esomeprazole units and magnesium stearate. Enteric-coated layered units according to above were mixed with magnesium stearate in the proportions given below;
Esomeprazole enteric coated units 100
Magnesium stearate 0.2
Per capsule
Mixture of enteric coated Esomeprazole units and magnesium stearate 86.2 mg
(ace. to above)
ASA granules * 325 mg
Hard capsule comprising PVA, size 0 1 piece
* Rhodine ® 3118 ASA granules, Ba 0407231, from Rhodia France. The majority of the granules passes a sieve having apertures of 1000 micron and is retained on a sieve having apertures of 125 micron.
PVA capsules according to above was placed in plastic (High Density Polyethylene, also referred to as HDPE) bottles with 0.5 g of dessicant, and checked for stability.
Storage condition Time Sum of degradation products,
(%) of Esomeprazole
Start value 0.2
40°C/75% RH 1 months 0.8
25°C/60% RH 1 months 0.2
25°C/60% RH 6 months 0.4
25°C/60% RH* * 6 months* * 0.4**
** test of PVA capsule comprising esomeprazole units (corresponding to 20 mg esomeprazole) and 75 mg ASA granules, placed in bottles without dessicant
Claims
1. An oral pharmaceutical dosage form wherein said dosage form is in the form of a capsule comprising a proton pump inhibitor, which capsule material comprises polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof.
2. An oral pharmaceutical dosage form wherein said dosage form is in the form of a capsule comprising a proton pump inhibitor and a capsule material, which capsule material comprises at least one vinyl monomer and polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof.
3. An oral pharmaceutical dosage form wherein said dosage form is in the form of a capsule comprising a proton pump inhibitor and a capsule material, wherein said capsule material has been obtained by polymerizing at least one polymerizable vinyl monomer in the presence of polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof.
4. An oral pharmaceutical dosage form according to any one of claims 1 to 3, wherein said polyvinyl alcohol or polyvinyl alcohol derivative is a copolymer.
5. An oral pharmaceutical dosage form according to any one of claims 1 to 3, wherein said polyvinyl alcohol or polyvinyl alcohol derivative is a homopolymer.
6. An oral pharmaceutical dosage form according to any one of claims 1 to 5, wherein said dosage form comprises one or more pharmaceutically acceptable excipient.
7. An oral pharmaceutical dosage form according to any one of claims 1 to 6, wherein said dosage form comprises one or more additional pharmaceutically active substance.
8. An oral pharmaceutical dosage form according to any one of claims 1 to 7, wherein said capsule is a hard capsule.
9. An oral pharmaceutical dosage form according to any one of claims 1 to 8, wherein the proton pump inhibitor is protected by enteric coating layer(s).
10. An oral pharmaceutical dosage form according to any one of claims 1 to 9, wherein the proton pump inhibitor is protected by enteric coating layer(s) and subcoating layer(s) separating the enteric coating from the proton pump inhibitor.
5 11. An oral pharmaceutical dosage form according to any one of claims 1 to 10, wherein the proton pump inhibitor is an acid susceptible proton pump inhibitor.
12. An oral pharmaceutical dosage form according to claim 11, wherein the proton pump inhibitor is omeprazole, or an alkaline salt thereof, or a hydrated form thereof. 0
13. An oral pharmaceutical dosage form according to claim 11, wherein the proton pump inhibitor is esomeprazole, or an alkaline salt thereof, or a hydrated form thereof.
14. An oral pharmaceutical dosage form according to claim 11, wherein the proton pumps inhibitor is selected from the group of compounds comprising lansoprazole, pantoprazole, rabeprazole, ilaprazole, tenatoprazole, leminoprazole, or a pharmaceutically acceptable salt thereof, or a single enantiomer of any one of them.
15. An oral pharmaceutical dosage form according to any one of claims 1 to 14, whereino the amount of proton pump inhibitor is in the range of from 5 to 300 mg.
16. An oral pharmaceutical dosage form according to claim 15, wherein the amount of proton pump inhibitor is in the range of from 10 to 200 mg. 5
17. An oral pharmaceutical dosage form according to claim 15, wherein the amount of proton pump inhibitor is selected from 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 mg.
18. An oral pharmaceutical dosage form according to any one of claims 7 to 17, wherein acetyl salicylic acid is the selected additional active substance. 0
19. An oral pharmaceutical dosage form according to claim 18, wherein the amount of acetyl salicylic acid is in the range of from 10 to 500 mg.
20. An oral pharmaceutical dosage form according to any claim 18, wherein the amount of acetyl salicylic acid is in the range of from 25 to 450 mg.
21. An oral pharmaceutical dosage form according to claim 18, wherein the amount of 5 acetyl salicylic acid is in the range of from 50 to 400 mg.
22. An oral pharmaceutical dosage form according to claim 18, wherein the amount of acetyl salicylic acid is in the range of from 60 to 350 mg. o
23. An oral pharmaceutical dosage form according to claim 18, wherein the amount of acetyl salicylic acid is in the range of from 75 to 325 mg.
24. A process for the manufacture of an oral pharmaceutical dosage form according to any one of claims 1 to 23 characterized in that the proton pump inhibitor is filled into a capsules having a capsule material which is obtainable by polymerizing at least one polymerizable vinyl monomer in the presence of polyvinyl alcohol or a polyvinyl alcohol derivative or a mixture thereof.
25. A process for the manufacture of an oral pharmaceutical dosage form according to anyo one of claims 1 to 23 characterized in that i) the proton pump inhibitor; ii) pharmaceutically acceptable excipient(s); iii) optionally additional pharmaceutically active substance(s) are filled into a capsule having a capsule material, which is obtainable by polymerizing at5 least one polymerizable vinyl monomer in the presence of polyvinyl alcohol or a polyvinyl alcohol derivate or a mixture thereof.
26. A process according to claim 24, characterized in that the process includes filling pharmaceutically acceptable excipient(s) into the capsule. 0
27. A process according to any one of claims 24 to 26, characterized in that the process includes filling an additional pharmaceutically active substance into the capsule.
28. A process according to claim 27, wherein said additional pharmaceutically active substance is acetyl salicylic acid.
29. A method for the reduction and/or prevention of gastrointestinal disorders or gastrointestinal complications in mammals or man by administering to a host in need thereof a therapeutically effective dose of a dosage form according to any one of claims 1 to 22.
30. Use of an oral pharmaceutical dosage form according to any one of claims 1 to 22 for the manufacture of a medicament for the prevention and/or reduction of gastrointestinal disorders or gastrointestinal complications.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US83672206P | 2006-08-10 | 2006-08-10 | |
| US60/836,722 | 2006-08-10 | ||
| US86316106P | 2006-10-27 | 2006-10-27 | |
| US60/863,161 | 2006-10-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008018825A1 true WO2008018825A1 (en) | 2008-02-14 |
Family
ID=39033276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE2007/000710 WO2008018825A1 (en) | 2006-08-10 | 2007-08-08 | Oral polyvinyl alcohol capsules comprising proton pump inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2008018825A1 (en) |
Cited By (4)
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| WO2010041276A1 (en) * | 2008-10-06 | 2010-04-15 | Jubilant Organosys Limited | Pharmaceutical compositions comprising amorphous esomeprazole, dosage forms and process thereof |
| CN102319181A (en) * | 2011-09-08 | 2012-01-18 | 广东大华农动物保健品股份有限公司 | Enveloping process for micro-capsule animal medicament |
| CN112168965A (en) * | 2019-07-05 | 2021-01-05 | 中国科学院生物物理研究所 | Use of SRCAP ATPase agonists in the treatment of disorders mediated by the inhibition of intestinal stem cell self-renewal |
| CN111670030B (en) * | 2018-01-29 | 2023-12-08 | 株式会社钟根堂 | Pharmaceutical formulation comprising esomeprazole and sodium bicarbonate |
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| CN111670030B (en) * | 2018-01-29 | 2023-12-08 | 株式会社钟根堂 | Pharmaceutical formulation comprising esomeprazole and sodium bicarbonate |
| CN112168965A (en) * | 2019-07-05 | 2021-01-05 | 中国科学院生物物理研究所 | Use of SRCAP ATPase agonists in the treatment of disorders mediated by the inhibition of intestinal stem cell self-renewal |
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