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WO2019216837A1 - Novel pharmaceutical compositions - Google Patents

Novel pharmaceutical compositions Download PDF

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Publication number
WO2019216837A1
WO2019216837A1 PCT/TR2018/000135 TR2018000135W WO2019216837A1 WO 2019216837 A1 WO2019216837 A1 WO 2019216837A1 TR 2018000135 W TR2018000135 W TR 2018000135W WO 2019216837 A1 WO2019216837 A1 WO 2019216837A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
pharmaceutical composition
composition according
alginic acid
vitamin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/TR2018/000135
Other languages
French (fr)
Inventor
Mahmut Bi̇lgi̇ç
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neutec Ar-Ge Sanayi Ve Ticaret AS
Original Assignee
Neutec Ar-Ge Sanayi Ve Ticaret AS
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Filing date
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Publication of WO2019216837A1 publication Critical patent/WO2019216837A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/734—Alginic acid
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention is related to proton pump inhibitors and alginic acid combinations and the usage of these combinations in treating gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and treating symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain and to pharmaceutical combinations comprising these combinations.
  • GGI gastro gastroesophageal reflux disease
  • peptic ulcer duodenum ulcer
  • Zollinger-Ellison syndrome and treating symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain and to pharmaceutical combinations comprising these combinations.
  • the invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising alginic acid and a proton pump inhibitor selected from rabeprazole or omeprazole or lansoprazole and/or pharmaceutically acceptable derivatives thereof.
  • Rabeprazole is a proton pump inhibitor having a substituted benzimidazole structure which inhibits gastric acid secretion.
  • the chemical name of rabeprazole is 2-[[[4-(3-methoxypropoxy)-3-methyl-2- pridinyl]-methyl]sulfinyl]-lH-benzimidazole and it has been described for the first time in the application numbered EP0268956. It has been described in said document that rabeprazole is effective in treating gastric ulcers.
  • Rabeprazole is marketed as 50 mg capsules, lOmg and 20mg enteric tablet forms.
  • Omeprazole is proton pump inhibitor which reduces gastric acid secretion.
  • the chemical name of omeprazole is 5-Methoxy-2-(4-methoxy-3,5-dimethyl-2-pridinylmethyl-sulfinyl)benzimidazole and it has been described for the first time in the application numbered US4255431. In said document omeprazole has been described to be used in treating ulcer.
  • Lansoprazole is a proton pump inhibitor which inhibits the enzyme system of gastric parietal cells and gastric acid secretion.
  • the chemical name of Lansoprazole is 2-( ⁇ 3-Methyl-4-(2,2,2-trifluoroethoxy)- 2-pridinyl ⁇ sulfinyl benzimidazole, and it has been described for the first time with the application numbered US4628098. It has been described in said document that lansoprazole is effective in treating ulcers.
  • alginic acid is Poly[beta-D-mannopyranosyluronic acid- (1- >4), alpha-L- glucopyranosyluronic acid- (1- >4) and it has been described for the first time with the application numbered US2128551. It has been described in said document that alginic acid is effective in treating pain due to stomach acid and reflux.
  • Alginic acid is marketed as an oral suspension comprising 200mg alginate in combination with carbonated compounds, a chewing tablet and powder form for a 225mg oral solution in combination with magnesium alginate.
  • an unexpected therapeutic benefit particularly a synergistic therapeutic benefit can be obtained by a combination therapy in which an active agent selected from proton pump inhibitors and alginic acid is used in treating gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and treating the symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain. It is possible for said therapeutic benefit to be according to the following, when this combination is used in comparison to what is required when only alginic acid or a proton pump inhibitor is used in treatments;
  • compositions in which alginic acid and an active agent selected from a proton pump inhibitor is used simultaneously or together shows higher therapeutic benefits in comparison to compositions which use these two active agents separately.
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising alginic acid as the active agent and an active agent selected from a proton pump inhibitor or pharmaceutically acceptable derivatives thereof.
  • the combined usage of alginic acid and an active agents selected from a proton pump inhibitor ensures to see the therapeutic effect in a short period of time and ensures that this effect is stronger in comparison to these two active agents being used separately.
  • these positive effects can be seen in combinations when these two active agents are given sequentially and said positive effects can be seen when these two active agents are given inside a dosage form at the same time or inside independent dosage forms simultaneously. High therapeutic benefits can also be observed as long term effects.
  • the present invention is related to pharmaceutical compositions that comprise alginic acid together with rabeprazole, omeprazole, or lansoprazole selected from proton pump inhibitors in order to be used sequentially inside separate dosage forms, simultaneously inside separate dosage forms or simultaneously in the same dosage form.
  • the invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising the following as active agents; a) Alginic acid or pharmaceutically acceptable derivative and
  • the invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising the following as active agents; a) Alginic acid or pharmaceutically acceptable derivative and
  • the invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising the following as active agents; a) Alginic acid or pharmaceutically acceptable derivative and
  • compositions that comprise an active agent selected from proton pump inhibitors a pharmaceutically efficient amount of alginic acid and at least one pharmaceutically acceptable agent.
  • the active agents can be provided as a combination inside a single composition together with at least a pharmaceutically acceptable excipient and they can also be formulized together with at least a pharmaceutically acceptable excipient in which the active agents are separate from each other.
  • the different compositions that have been obtained can be combined in a single dosage form or can be prepared to be in separate dosage forms. If the compositions are in separate dosage forms said dosage forms can be the same as each other or they can be different from each other.
  • the present invention is related to using active agents suitable to the invention in order to prepare a medicine that can be used in combination therapy via being given sequentially or separately or simultaneously to treat gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and to treat symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain.
  • GGID gastro gastroesophageal reflux disease
  • peptic ulcer peptic ulcer
  • duodenum ulcer duodenum ulcer
  • Zollinger-Ellison syndrome peptic ulcer
  • symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain.
  • compositions suitable to the invention means pharmaceutically acceptable salts of the active agents subject to the invention, hydrates, solvates, esters, enantiomers, diastereomers, racemates and/or any polymorphic forms such as amorphous crystals or combinations thereof.
  • compositions according to the invention can be prepared in any form such as tablets, effervescent tablets, effervescent granules, effervescent dry powder, film coated tablet, enteric coated tablet, and double coated tablet, homogenous mixture tablet, dry powder, granule, capsule, micro capsule, pellet, delayed release tablet, modified release tablet, prolonged release tablet, orodispersible tablet or chewing tablets.
  • compositions according to the subject matter of the invention can have any kind of dosage forms together, and said compositions can be in any dosage form if the active agents are stored in dosage forms separate from each other.
  • compositions that comprise combinations suitable to the invention can have any kind of dosage forms mentioned above, or a combination of said dosage forms or a treatment package form formed of said combinations.
  • compositions according to the invention can be in capsule or tablet form.
  • Various active agents can be included in addition to the active agents already available inside the pharmaceutical compositions according to the invention.
  • compositions suitable to the invention additionally comprises at least an excipient selected from the group comprising a dispersant, a diluent, a lubricant, a glidant, a binder, an effervescent pair formed of at least an acidic agent and at least a basic agent, a colorant, a pH adjuster agent, a surfactant, a stabilizer, a sweetener and/or a flavoring agent and an aromatic agent.
  • excipient selected from the group comprising a dispersant, a diluent, a lubricant, a glidant, a binder, an effervescent pair formed of at least an acidic agent and at least a basic agent, a colorant, a pH adjuster agent, a surfactant, a stabilizer, a sweetener and/or a flavoring agent and an aromatic agent.
  • the dispersant that can be used inside the pharmaceutical compositions suitable to the invention can be selected from the group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch and sodium starch glycolate without being limited thereto.
  • the diluent that can be used in the pharmaceutical compositions suitable to the invention can be selected without being limited, from the group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrytalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc and xylitol.
  • the glidant that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauril sulphate, talc, stearic acid and zinc stearate without being limited thereto.
  • the lubricant that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate and talc without being limited thereto.
  • the binder that may be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypermellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone and starch without being limited thereto.
  • the acidic agent that forms the effervescent pair formed of at least an acidic agent and at least a basic agent that can be used inside the pharmaceutical compositions according to the invention can be selected from a group formed of organic acids such as malic acid, citric acid, tartaric acid, fumaric acid and from a group comprising basic agent; sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate without being limited thereto.
  • the pH adjuster agent that can be used inside the pharmaceutical compositions according to the invention can be selected from citrate, phosphate, tartarate, fumarate, acetate and amino acid salts without being limited thereto.
  • the surfactant that can be used inside the pharmaceutical compositions according to the invention can be selected from sodium lauril sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and other similar agents without being limited thereto.
  • the stabilizer that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin without being limited thereto.
  • the sweetener and/or flavoring agent that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharin, saccharin sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol and sodium chloride without being limited thereto.
  • the aromatic agent that can be used inside the pharmaceutical compositions according to the invention can be selected from aromas such as menthol, lemon, orange, vanilla, strawberries, raspberries and caramel without being limited thereto.
  • 0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight rabeprazole or pharmaceutically acceptable derivative thereof can be available inside the pharmaceutical compositions according to the invention.
  • omeprazole or pharmaceutically acceptable derivative thereof can be available inside the pharmaceutical compositions according to the invention.
  • 0.1 to 99% by weight in ratio preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight lansoprazole or pharmaceutically acceptable derivative thereof can be available inside the pharmaceutical compositions according to the invention.
  • compositions according to the invention 0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight alginic acid or pharmaceutically acceptable derivative thereof is available inside the pharmaceutical compositions according to the invention.
  • Rabeprazole or pharmaceutically acceptable derivative that may be present inside the pharmaceutical composition according to the invention i within the range of 2 mg to 100 mg, preferably within the range of 2 mg to 90 mg, especially preferably within the range of 2 mg to 80 mg.
  • Omeprazole or pharmaceutically acceptable derivative that may be present inside the pharmaceutical composition according to the invention is within the range of 1 mg to 100 mg, preferably within the range of 2 mg to 90 mg, especially preferably within the range of 2 mg to 80 mg.
  • Lansoprazole or pharmaceutically acceptable derivateive that may be present inside the pharmaceutical composition according to the invention within the range of 10 mg to 120 mg per unit dosage form, preferably within the range of 10 mg to 100 mg, especially preferably within the range of 10 mg to 80 mg.
  • Alginic acid present inside the pharmaceutical compositions according to the invention is within the range of 10 mg to 1500 mg, preferably within the range of 10 mg to 1200 mg.
  • a third active agent can be optionally included inside the pharmaceutical compositions according to the invention.
  • the third active agent can be selected from anti acid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antioobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibitoci, antiseptic, antiacne, antibacterial, antimicotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic anti-parkinson, antiprotozoal, anthelmintic, antiinflammatory, diuretic, laxative, sulfonamide, imidazole, corticosteroid, thiozolidinedione, biguanide, immunostimulant, immunosuppressant, muscle relaxant, analgesic, psycholeptic, psychoanaleptic peripheral
  • composition according to the invention can be obtained by;
  • the methods mentioned above can be obtained by using the methods separately for the active agent compositions and by combining the resulting compositions or storing them in different dosage forms.
  • the obtained pharmaceutical composition or compositions may be brought into the form of any of the above-mentioned dosage forms.
  • the tablets may be treated with film coating agents, for example, with sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed release coating agents, or coating compositions comprising any of the combinations thereof.
  • Saccharose can be used alone as the sugar based coating agent or it can be used optionally with agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof.
  • agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof.
  • the water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose, synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers and polyvinyl pyrrolidone and polysaccharides such as pullulan or combinations thereof.
  • cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose
  • synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers and polyvinyl pyrrolidone and polysaccharides such as pullulan or combinations thereof.
  • Enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methaciylic acid copolymer S and natural agents such as shellac or combinations thereof.
  • cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate
  • acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methaciylic acid copolymer S
  • natural agents such as shellac or combinations thereof.
  • Delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose, acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsions or combinations thereof.
  • the pharmaceutical composition according to the invention can be used in treating gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and treating and preventing the symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain.
  • GFD gastro gastroesophageal reflux disease
  • peptic ulcer duodenum ulcer
  • Zollinger-Ellison syndrome treating and preventing the symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain.
  • Rabeprazole sodium and sodium alginate active agents are granulized by wet granulation method together with mannitol and a diluent and this mixture is mixed with other excipients.
  • the formulations that are obtained are pressed into tablet form and are coated with coating agents.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention is related to pharmaceutical compositions comprising alginic acid and an active agent selected from proton pump inhibitors that shall be used in treating gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and treating the symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain.

Description

NOVEL PHARMACEUTICAL COMPOSITIONS
The present invention is related to proton pump inhibitors and alginic acid combinations and the usage of these combinations in treating gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and treating symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain and to pharmaceutical combinations comprising these combinations.
Particularly the invention is related to a pharmaceutical composition comprising alginic acid and a proton pump inhibitor selected from rabeprazole or omeprazole or lansoprazole and/or pharmaceutically acceptable derivatives thereof.
Rabeprazole is a proton pump inhibitor having a substituted benzimidazole structure which inhibits gastric acid secretion. The chemical name of rabeprazole is 2-[[[4-(3-methoxypropoxy)-3-methyl-2- pridinyl]-methyl]sulfinyl]-lH-benzimidazole and it has been described for the first time in the application numbered EP0268956. It has been described in said document that rabeprazole is effective in treating gastric ulcers.
Figure imgf000002_0001
Figure 1. Rabeprazole
Rabeprazole is marketed as 50 mg capsules, lOmg and 20mg enteric tablet forms.
Omeprazole is proton pump inhibitor which reduces gastric acid secretion. The chemical name of omeprazole is 5-Methoxy-2-(4-methoxy-3,5-dimethyl-2-pridinylmethyl-sulfinyl)benzimidazole and it has been described for the first time in the application numbered US4255431. In said document omeprazole has been described to be used in treating ulcer.
Figure imgf000003_0001
Figure 2. Omeprazole
Lansoprazole is a proton pump inhibitor which inhibits the enzyme system of gastric parietal cells and gastric acid secretion. The chemical name of Lansoprazole is 2-({3-Methyl-4-(2,2,2-trifluoroethoxy)- 2-pridinyl} sulfinyl benzimidazole, and it has been described for the first time with the application numbered US4628098. It has been described in said document that lansoprazole is effective in treating ulcers.
Figure imgf000003_0002
Figure 3. Lansoprazole The chemical name of alginic acid is Poly[beta-D-mannopyranosyluronic acid- (1- >4), alpha-L- glucopyranosyluronic acid- (1- >4) and it has been described for the first time with the application numbered US2128551. It has been described in said document that alginic acid is effective in treating pain due to stomach acid and reflux.
Figure imgf000003_0003
Figure 4. Alginic acid Alginic acid is marketed as an oral suspension comprising 200mg alginate in combination with carbonated compounds, a chewing tablet and powder form for a 225mg oral solution in combination with magnesium alginate.
It has been surprisingly discovered that an unexpected therapeutic benefit, particularly a synergistic therapeutic benefit can be obtained by a combination therapy in which an active agent selected from proton pump inhibitors and alginic acid is used in treating gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and treating the symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain. It is possible for said therapeutic benefit to be according to the following, when this combination is used in comparison to what is required when only alginic acid or a proton pump inhibitor is used in treatments;
• Reducing the required dosage in order to obtain the required therapeutic effect and/or
• Reducing undesired adverse effects and/or
• Observing therapeutic effect in a short period of time and/or
• Observing therapeutic effect for a long period of time and/or
• Providing a more effective treatment
• Increasing patient compatibility.
In other words it can be said that the pharmaceutical composition in which alginic acid and an active agent selected from a proton pump inhibitor is used simultaneously or together shows higher therapeutic benefits in comparison to compositions which use these two active agents separately.
Accordingly the present invention is a pharmaceutical composition comprising alginic acid as the active agent and an active agent selected from a proton pump inhibitor or pharmaceutically acceptable derivatives thereof.
According to another aspect, the combined usage of alginic acid and an active agents selected from a proton pump inhibitor ensures to see the therapeutic effect in a short period of time and ensures that this effect is stronger in comparison to these two active agents being used separately. By this means it is possible to provide a more effective treatment. Interestingly, these positive effects can be seen in combinations when these two active agents are given sequentially and said positive effects can be seen when these two active agents are given inside a dosage form at the same time or inside independent dosage forms simultaneously. High therapeutic benefits can also be observed as long term effects.
Accordingly the present invention is related to pharmaceutical compositions that comprise alginic acid together with rabeprazole, omeprazole, or lansoprazole selected from proton pump inhibitors in order to be used sequentially inside separate dosage forms, simultaneously inside separate dosage forms or simultaneously in the same dosage form.
On the other hand the invention is related to a pharmaceutical composition comprising the following as active agents; a) Alginic acid or pharmaceutically acceptable derivative and
b) Rabeprazole or pharmaceutically acceptable derivative.
On the other hand the invention is related to a pharmaceutical composition comprising the following as active agents; a) Alginic acid or pharmaceutically acceptable derivative and
b) Omeprazole or pharmaceutically acceptable derivative.
On the other hand the invention is related to a pharmaceutical composition comprising the following as active agents; a) Alginic acid or pharmaceutically acceptable derivative and
b) Lansoprazole or pharmaceutically acceptable derivative.
According to another aspect the present invention is related to pharmaceutical compositions that comprise an active agent selected from proton pump inhibitors a pharmaceutically efficient amount of alginic acid and at least one pharmaceutically acceptable agent.
The active agents can be provided as a combination inside a single composition together with at least a pharmaceutically acceptable excipient and they can also be formulized together with at least a pharmaceutically acceptable excipient in which the active agents are separate from each other. The different compositions that have been obtained can be combined in a single dosage form or can be prepared to be in separate dosage forms. If the compositions are in separate dosage forms said dosage forms can be the same as each other or they can be different from each other.
The present invention is related to using active agents suitable to the invention in order to prepare a medicine that can be used in combination therapy via being given sequentially or separately or simultaneously to treat gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and to treat symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain.
In pharmaceutical compositions suitable to the invention the expression “derivative” means pharmaceutically acceptable salts of the active agents subject to the invention, hydrates, solvates, esters, enantiomers, diastereomers, racemates and/or any polymorphic forms such as amorphous crystals or combinations thereof.
The pharmaceutical compositions according to the invention can be prepared in any form such as tablets, effervescent tablets, effervescent granules, effervescent dry powder, film coated tablet, enteric coated tablet, and double coated tablet, homogenous mixture tablet, dry powder, granule, capsule, micro capsule, pellet, delayed release tablet, modified release tablet, prolonged release tablet, orodispersible tablet or chewing tablets.
The pharmaceutical compositions according to the subject matter of the invention can have any kind of dosage forms together, and said compositions can be in any dosage form if the active agents are stored in dosage forms separate from each other.
In other words, compositions that comprise combinations suitable to the invention can have any kind of dosage forms mentioned above, or a combination of said dosage forms or a treatment package form formed of said combinations.
The pharmaceutical compositions according to the invention can be in capsule or tablet form.
Various active agents can be included in addition to the active agents already available inside the pharmaceutical compositions according to the invention.
The pharmaceutical compositions suitable to the invention additionally comprises at least an excipient selected from the group comprising a dispersant, a diluent, a lubricant, a glidant, a binder, an effervescent pair formed of at least an acidic agent and at least a basic agent, a colorant, a pH adjuster agent, a surfactant, a stabilizer, a sweetener and/or a flavoring agent and an aromatic agent.
The dispersant that can be used inside the pharmaceutical compositions suitable to the invention can be selected from the group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch and sodium starch glycolate without being limited thereto.
The diluent that can be used in the pharmaceutical compositions suitable to the invention can be selected without being limited, from the group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrytalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc and xylitol.
The glidant that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauril sulphate, talc, stearic acid and zinc stearate without being limited thereto.
The lubricant that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate and talc without being limited thereto.
The binder that may be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypermellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone and starch without being limited thereto.
The acidic agent that forms the effervescent pair formed of at least an acidic agent and at least a basic agent that can be used inside the pharmaceutical compositions according to the invention can be selected from a group formed of organic acids such as malic acid, citric acid, tartaric acid, fumaric acid and from a group comprising basic agent; sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate without being limited thereto.
The pH adjuster agent that can be used inside the pharmaceutical compositions according to the invention can be selected from citrate, phosphate, tartarate, fumarate, acetate and amino acid salts without being limited thereto.
The surfactant that can be used inside the pharmaceutical compositions according to the invention can be selected from sodium lauril sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and other similar agents without being limited thereto.
The stabilizer that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin without being limited thereto.
The sweetener and/or flavoring agent that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharin, saccharin sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol and sodium chloride without being limited thereto.
The aromatic agent that can be used inside the pharmaceutical compositions according to the invention can be selected from aromas such as menthol, lemon, orange, vanilla, strawberries, raspberries and caramel without being limited thereto. 0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight rabeprazole or pharmaceutically acceptable derivative thereof can be available inside the pharmaceutical compositions according to the invention.
0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight omeprazole or pharmaceutically acceptable derivative thereof can be available inside the pharmaceutical compositions according to the invention.
0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight lansoprazole or pharmaceutically acceptable derivative thereof can be available inside the pharmaceutical compositions according to the invention.
0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight alginic acid or pharmaceutically acceptable derivative thereof is available inside the pharmaceutical compositions according to the invention.
Rabeprazole or pharmaceutically acceptable derivative that may be present inside the pharmaceutical composition according to the invention i within the range of 2 mg to 100 mg, preferably within the range of 2 mg to 90 mg, especially preferably within the range of 2 mg to 80 mg.
Omeprazole or pharmaceutically acceptable derivative that may be present inside the pharmaceutical composition according to the invention is within the range of 1 mg to 100 mg, preferably within the range of 2 mg to 90 mg, especially preferably within the range of 2 mg to 80 mg.
Lansoprazole or pharmaceutically acceptable derivateive that may be present inside the pharmaceutical composition according to the invention within the range of 10 mg to 120 mg per unit dosage form, preferably within the range of 10 mg to 100 mg, especially preferably within the range of 10 mg to 80 mg.
Alginic acid present inside the pharmaceutical compositions according to the invention is within the range of 10 mg to 1500 mg, preferably within the range of 10 mg to 1200 mg.
A third active agent can be optionally included inside the pharmaceutical compositions according to the invention. The third active agent can be selected from anti acid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antioobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibitoci, antiseptic, antiacne, antibacterial, antimicotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic anti-parkinson, antiprotozoal, anthelmintic, antiinflammatory, diuretic, laxative, sulfonamide, imidazole, corticosteroid, thiozolidinedione, biguanide, immunostimulant, immunosuppressant, muscle relaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldozreductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogs, vitamin Bl, vitamin C, vitamin E, vitamin B6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride and selenium.
The pharmaceutical composition according to the invention can be obtained by;
• Homogeneous mixing of active agents and, if necessary, addition of at least one of the above- mentioned excipients or
• Granulating the active agents with a granulation solution containing at least one of the excipients and then homogeneously mixing with the other excipients or
• Granulating the mixture comprising at least one of the excipients mentioned above and the active agents with a granulation solution and then homogeneously mixing with the other excipients or
• Mixing the active agents with at least one of the excipients mentioned above and granulating it with a granulation solution comprising at least an excipient or
• In the case that the active agents are prepared in two separate compositions, the methods mentioned above can be obtained by using the methods separately for the active agent compositions and by combining the resulting compositions or storing them in different dosage forms.
The obtained pharmaceutical composition or compositions may be brought into the form of any of the above-mentioned dosage forms. In the case that tablet form is obtained, the tablets may be treated with film coating agents, for example, with sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed release coating agents, or coating compositions comprising any of the combinations thereof.
Saccharose can be used alone as the sugar based coating agent or it can be used optionally with agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof.
The water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose, synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers and polyvinyl pyrrolidone and polysaccharides such as pullulan or combinations thereof.
Enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methaciylic acid copolymer S and natural agents such as shellac or combinations thereof.
Delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose, acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsions or combinations thereof.
The pharmaceutical composition according to the invention can be used in treating gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and treating and preventing the symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain. The below mentioned example has been provided in order to describe the combinations subject to the invention and the subject matter of the invention cannot be limited with this example.
EXAMPLE: Tablet Formulation comprising Rabeprazole and Alginic Acid
Rabeprazole sodium and sodium alginate active agents are granulized by wet granulation method together with mannitol and a diluent and this mixture is mixed with other excipients. The formulations that are obtained are pressed into tablet form and are coated with coating agents.
Figure imgf000010_0001

Claims

1. A pharmaceutical composition comprising an active agent or pharmaceutically acceptable derivatives thereof selected from the alginic acid and proton pump inhibitors as active agents.
2. A pharmaceutical composition according to claim 1, characterized by the active agent selected from proton pump inhibitors to be rabeprazole or pharmaceutically acceptable derivative thereof, omeprazole or pharmaceutically acceptable derivatives thereof, lansoprazole or pharmaceutically acceptable derivatives thereof.
3. A pharmaceutical composition according to claim 1 or 2, characterized by comprising rabeprazole or pharmaceutically acceptable derivatives thereof in combination with alginic acid or pharmaceutically acceptable derivatives thereof.
4. A pharmaceutical composition according to claim 3, characterized by comprising rabeprazole or pharmaceutically acceptable derivative thereof in the range of 2-100mg and alginic acid or pharmaceutically acceptable derivative thereof in the range of 10-1500mg.
5. A pharmaceutical composition according to claim 1 or 2, characterized by comprising omeprazole or pharmaceutically acceptable derivatives thereof in combination with alginic acid or pharmaceutically acceptable derivatives thereof.
6. A pharmaceutical composition according to claim 5, characterized by comprising omeprazole or pharmaceutically acceptable derivative thereof in the range of 1-lOOmg and alginic acid or pharmaceutically acceptable derivative thereof in the range of 10-1500mg.
7. A pharmaceutical composition according to claim 1 to 2, characterized by comprising alginic acid or pharmaceutically acceptable derivative thereof in combination with lansoprazole or pharmaceutically acceptable derivatives thereof.
8. A pharmaceutical composition according to claim 7, characterized by comprising lansoprazole or pharmaceutically acceptable derivative thereof in the range of 10-120mg and alginic acid or pharmaceutically acceptable derivative thereof in the range of 10-1500mg.
9. A pharmaceutical composition comprising rabeprazole, omeprazole, or lansoprazole in combination with alginic acid according to claim 1 or 2 characterized in that it is in the form of pharmaceutically acceptable salts of active agents, hydrates, solvates, esters, enantiomers, diastereomers, and/or any of polymorphic forms such as amorphous crystals or combinations thereof.
10. A pharmaceutical composition according claim 1 or 2, characterized by being in any form such as tablets, effervescent tablets, effervescent granules, effervescent dry powder, film coated tablet, enteric coated tablet, double coated tablet, homogenously mixed tablet, dry powder, granule, capsule, micro capsule, pellet, delayed release tablet, modified release tablet, prolonged release tablet, orodispersible tablet, chewing tablets or combination forms thereof.
11. A pharmaceutical composition according to claim 10, characterized by being in capsule form.
12. A pharmaceutical composition according to claim 10, characterized by being in tablet form.
13. A pharmaceutical composition according claims 1 or 2 characterized by comprising at least a pharmaceutically acceptable excipient besides the active agents.
14. A pharmaceutical composition according to claim 13, characterized in that besides the active agents, it comprises at least an excipient selected from the group comprising a dispersant, a diluent, a lubricant, a glidant, a binder, an effervescent pair formed of at least an acidic agent and at least a basic agent, a colorant, a pH adjuster agent, a surfactant, a stabilizer, a sweetener and/or a flavoring agent and an aromatic agent.
15. A pharmaceutical composition according to any of the preceding claims, characterized in that it optionally comprises a third active agent in addition to the active agents it comprises which can be selected from anti acid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antioobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibitoci, antiseptic, antiacne, antibacterid, antimicotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic anti-parkinson, antiprotozoal, anthelmintic, antiinflammatory, diuretic, laxative, sulfonamide, imidazole, corticosteroid, thiozolidinedione, biguanide, immunostimulant, immunosuppressant, muscle relaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha- glucosidase inhibitors, aldozreductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogs, vitamin Bl, vitamin C, vitamin E, vitamin B6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride and selenium.
16. A pharmaceutical composition according to any of the preceding claims, characterized by being used in treating gastro gastroesophageal reflux disease (GERD), peptic ulcer, duodenum ulcer, Zollinger-Ellison syndrome, and treating the symptoms such as pain due to reflux of stomach acid and bile towards the esophagus and acid indigestion, reflux esophagitis, regurgitation and retrosternal pain.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025066A1 (en) * 1996-01-08 1997-07-17 Astra Aktiebolag Oral pharmaceutical dosage forms comprising a proton pump inhibitor and an antacid agent or alginate
WO2010038241A2 (en) * 2008-09-30 2010-04-08 Panacea Biotec Limited Pharmaceutical compositions comprising of proton pump inhibitor, prokinetic agent and alginic acid
US20100160382A1 (en) * 2006-06-05 2010-06-24 Laboratorios Bago S.A. Anti-acid pharmaceutical composition in powder form and process for making it
WO2013141827A1 (en) * 2012-03-21 2013-09-26 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Enteric coated solid pharmaceutical compositions for proton pump inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025066A1 (en) * 1996-01-08 1997-07-17 Astra Aktiebolag Oral pharmaceutical dosage forms comprising a proton pump inhibitor and an antacid agent or alginate
US20100160382A1 (en) * 2006-06-05 2010-06-24 Laboratorios Bago S.A. Anti-acid pharmaceutical composition in powder form and process for making it
WO2010038241A2 (en) * 2008-09-30 2010-04-08 Panacea Biotec Limited Pharmaceutical compositions comprising of proton pump inhibitor, prokinetic agent and alginic acid
WO2013141827A1 (en) * 2012-03-21 2013-09-26 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Enteric coated solid pharmaceutical compositions for proton pump inhibitors

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