WO2012162777A1 - Oral pharmaceutical composition comprising a proton pump inhibitor and a prokinetic agent that can be used in excess stomach acid disorders - Google Patents

Oral pharmaceutical composition comprising a proton pump inhibitor and a prokinetic agent that can be used in excess stomach acid disorders Download PDF

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Publication number
WO2012162777A1
WO2012162777A1 PCT/BR2012/000168 BR2012000168W WO2012162777A1 WO 2012162777 A1 WO2012162777 A1 WO 2012162777A1 BR 2012000168 W BR2012000168 W BR 2012000168W WO 2012162777 A1 WO2012162777 A1 WO 2012162777A1
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pharmaceutical composition
oral pharmaceutical
composition according
agents
gastric acid
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PCT/BR2012/000168
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French (fr)
Portuguese (pt)
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WO2012162777A9 (en
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Maurizio BILLI
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Eurofarma Laboratórios S.A
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    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/33—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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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

Definitions

  • An oral pharmaceutical composition comprising a proton pump inhibitor and a prokinetic agent for use in gastric acid excess disorders.
  • the present invention relates to an oral pharmaceutical composition containing at least one gastric acid suppressing agent, particularly a proton pump inhibitor (PPI), and a prokinetic agent (PA), intended for use in excess acid related disorders.
  • gastric disease for example, gastroesophageal reflux disease.
  • Gastric acid-related disorders including gastroesophageal reflux disease, reflux esophagitis, peptic ulcer, gastric ulcer, have pathogenesis related to gastric motility and excessive emission of gastric acid.
  • Such disorders are typically treated with gastric acid inhibitors such as ranitidine and omeprazole, which are acid suppressing agents.
  • Prokinetic agents including bromopride, cisapride, alizapride, clebopride, domperidone, and metoclopramide have been known to increase gastrointestinal motility, preventing duodenogastric reflux, which is known to treat gastroesophageal reflux disease.
  • Proton pump inhibitors including omeprazole, lansoprazole and pantoprazole, have rapidly replaced H2 receptor antagonists in the treatment of esophageal reflux because they are highly effective, with better resolution of symptoms.
  • Combination therapy of a prokinetic agent and a gastric acid lowering agent has already been shown to be more effective than proton pump inhibitor monotherapy.
  • Administration of cisapride and ranitidine has been shown to decrease esophageal exposure to acidity (Inauen W. et al., Gut. 1993; 34: 1025-1031).
  • Such therapy has also been shown to improve the speed of healing (de Boer WA et al., Alimeht Pharmacol. Ther. 1994; 8: 147-157).
  • PI 9607344-6 discloses a fixed unit dosage form, tablet or capsule, in pellet form enteric coating.
  • PI 0401556-8 relates to a combination of PPI and prokinetic agent, particularly lanzoprazole + bromopride.
  • PI 0506704-9 mentions a delayed release composition, bimodal prokinetic release agent.
  • the present invention relates to a pharmaceutical composition containing one or more gastric acid suppressing agents, particularly a proton pump inhibitor, one or more prokinetic agents, and pharmaceutically acceptable excipients.
  • gastric acid suppressing agents particularly a proton pump inhibitor
  • prokinetic agents particularly a proton pump inhibitor
  • pharmaceutically acceptable excipients such as heartburn, gastroesophageal reflux disease, reflux esophagitis, peptic ulcer, gastric ulcer, and the like.
  • composition refers to either mixing all components together in a unit dosage form or to two or more individual and autonomous component formulations within a unit dosage form, e.g. a gelatin capsule, hydroxypropyl methyl cellulose (HPMC) capsule and the like.
  • a gelatin capsule e.g. a gelatin capsule, hydroxypropyl methyl cellulose (HPMC) capsule and the like.
  • HPMC hydroxypropyl methyl cellulose
  • one capsule contains a PPI and excipients
  • another capsule contains a PA and excipients
  • such two capsules in turn are contained in a single capsule
  • a capsule contains a PPI and excipients
  • a tablet contains a PA and excipients
  • said capsule and said tablet are both contained in a single capsule.
  • the capsule may contain a PA and the tablet may contain a PPI;
  • one tablet contains a PPI and excipients
  • another tablet contains a PA and excipients, and such two tablets are contained in a single capsule; .
  • a two layer tablet one layer containing a PPI and another layer containing a PA.
  • the invention relates to an oral composition, characterized in that it comprises in a single unit dosage form, particularly in a capsule, tablets distinct from (a) one or more slurry pump inhibitors. protons chosen from omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole, with their respective excipients and (b) one or more prokinetic agents chosen from bromopride, cisapride, alizapride, clebopride, domperidone, and metoclopramide, with their excipients.
  • protons chosen from omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole, with their respective excipients
  • prokinetic agents chosen from bromopride, cisapride, alizapride, clebopride, domperidone, and metoclopramide, with their excipients.
  • Such a particular configuration provides:
  • proton pump inhibitors are known to be unstable in acidic medium and therefore subject to degradation and may be protected by specific coating;
  • each tablet may have specific, same or distinct characteristics as:
  • release rate (immediate, slow, delayed, controlled, and the like);
  • Proton pump inhibitors present in the dosage forms of the invention may be used in neutral or alkaline salt form, for example as magnesium, calcium, sodium, potassium or lithium salts. Where applicable, proton pump inhibitors may be used in racemic form as pure enantiomer or alkaline salts of enantiomers.
  • the preferred proton pump inhibitor is chosen from pantoprazole, its salts, esters, hydrates, derivatives, prodrugs or metabolites in any polymorphic form. More particularly, pantoprazole sodium is used sesquihydrate.
  • the preferred prokinetic agent is chosen from domperidone, its salts, esters, hydrates, derivatives, prodrugs or metabolites in any polymorphic form.
  • composition of the invention in its broad sense, and particularly in the realization of two separate tablets contained in a gelatin capsule, hydroxypropyl methylcellulose (HPMC) capsules and the like, contains pharmaceutically acceptable excipients such as diluents, binders, disintegrants, colorants, nonstick, lubricants, plasticizers, sequestrants, coating agents, antioxidants, opacifiers, flavorings, sweeteners, and the like, used alone or in combination with each other.
  • pharmaceutically acceptable excipients for man is in the book "Remington's Pharmaceutical Sciences” 18th Edition, (1990), Mack Publishing Co., USA.
  • diluents suitable for the invention are chosen from microcrystalline cellulose, lactose monohydrate or anhydrous, dibasic calcium phosphate, saccharides such as mannitol, sorbitol, sucrose and glucose,
  • alkalinizing agents suitable for the invention are selected from magnesium oxide, sodium hydroxide, sodium bicarbonate, sodium carbonate and mixtures thereof.
  • Suitable binding agents for without excluding any others, are chosen from povidone, crospovidone and hydroxypropylcellulose.
  • disintegrants suitable for the invention are selected from cross-linked polyvinylpyrrolidone, starch (corn, potato, and the like), modified starches, croscarmellose, croscarmellose sodium, sodium starch glycolate, hydroxypropyl methylcellulose, hydroxypropylcellulose low substitution, and mixtures thereof.
  • lubricants suitable for the invention are colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures thereof.
  • Examples suitable for the invention of coating materials and their supplements for tablets, without excluding any others, are hydroxypropyl methylcellulose, Eudragit (manufactured by Evonik), Opadry (manufactured by Colorcon), triethylcitrate, propylene glycol and the like.
  • the amounts of the actives in the compositions of the invention in their free form are:
  • domperidone 10mg.
  • the invention relates to the use of the composition described above in the manufacture of a medicament used in the treatment of disorders caused by gastric acid, particularly heartburn, reflux disease. gastroesophageal, reflux esophagitis, peptic ulcer, gastric ulcer.

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Abstract

The present invention relates to an oral pharmaceutical composition containing at least one stomach acid suppressant, particularly a proton pump inhibitor (PPI), and a prokinetic agent (PA), designed to treat disorders related to excess stomach acid, for example gastro-oesophageal reflux disease.

Description

Composição farmacêutica oral compreendendo um inibidor de bomba de prótons e um agente procinético para uso em transtornos de excesso de ácido gástrico  An oral pharmaceutical composition comprising a proton pump inhibitor and a prokinetic agent for use in gastric acid excess disorders.
CAMPO DA INVENÇÃO FIELD OF INVENTION
A presente invenção diz respeito a uma composição farmacêutica oral contendo ao menos um agente de supressão de ácido gástrico, particularmente um inibidor da bomba de prótons (PPI), e um agente procinético (PA), voltada ao uso em transtornos relacionados ao excesso de ácido gástrico, por exemplo, a doença de refluxo gastroesofágico .  The present invention relates to an oral pharmaceutical composition containing at least one gastric acid suppressing agent, particularly a proton pump inhibitor (PPI), and a prokinetic agent (PA), intended for use in excess acid related disorders. gastric disease, for example, gastroesophageal reflux disease.
ANTECEDENTES DA INVENÇÃO  BACKGROUND OF THE INVENTION
Os distúrbios relacionados ao ácido gástrico, entre os quais, a doença de refluxo gastroesofágico, esofagite de refluxo, úlcera péptica, úlcera gástrica, têm patogenia relacionada à motilidade gástrica e emissão excessiva de ácido gástrico. Tais distúrbios são tipicamente tratados com inibidores de ácido gástrico, como ranitidina e omeprazol, que são agentes de supressão de ácido.  Gastric acid-related disorders, including gastroesophageal reflux disease, reflux esophagitis, peptic ulcer, gastric ulcer, have pathogenesis related to gastric motility and excessive emission of gastric acid. Such disorders are typically treated with gastric acid inhibitors such as ranitidine and omeprazole, which are acid suppressing agents.
Há publicações que propõem acelerar a cicatrização de úlcera gástrica por estimulação da motilidade gástrica. Agentes pró-cinéticos, entre os quais bromoprida, cisaprida, alizaprida, cleboprida, domperidona, e metoclopramida têm conhecida ação no aumento da motilidade gastrintestinais, evitando refluxo duodenogástricô, com uso conhecido para tratar a doença de refluxo gastroesofágico .  There are publications that propose to accelerate the healing of gastric ulcer by stimulation of gastric motility. Prokinetic agents, including bromopride, cisapride, alizapride, clebopride, domperidone, and metoclopramide have been known to increase gastrointestinal motility, preventing duodenogastric reflux, which is known to treat gastroesophageal reflux disease.
Inibidores da bomba de prótons, entre eles omeprazol, lansoprazol e pantoprazol, tem rapidamente substituído os antagonistas de receptores H2 no tratamento de refluxo esofágico, pois apresentam grande eficácia, com melhor resolução de sintomas. Proton pump inhibitors, including omeprazole, lansoprazole and pantoprazole, have rapidly replaced H2 receptor antagonists in the treatment of esophageal reflux because they are highly effective, with better resolution of symptoms.
Uma terapia combinada de um agente pró-cinético e um agente de diminuição de ácido gástrico já demonstrou mais efetividade do que a monoterapia com inibidores da bomba de prótons . A administração de cisaprida e ranitidina mostrou diminuir a exposição do esôfago a acidez (Inauen W. et al., Gut. 1993; 34:1025-1031). Tal terapia mostrou também melhora na rapidez da cura (de Boer WA et al . , Alimeht Pharmacol. Ther. 1994; 8: 147-157) .  Combination therapy of a prokinetic agent and a gastric acid lowering agent has already been shown to be more effective than proton pump inhibitor monotherapy. Administration of cisapride and ranitidine has been shown to decrease esophageal exposure to acidity (Inauen W. et al., Gut. 1993; 34: 1025-1031). Such therapy has also been shown to improve the speed of healing (de Boer WA et al., Alimeht Pharmacol. Ther. 1994; 8: 147-157).
No estado da técnica, podemos destacar: US In the state of the art, we can highlight: US
4.786.505 (omeprazol com revestimento entérico); WO 9501803 (agente pró-cinético); EP 247.983, WO 9427988, US 5.330.982, US 6.046.183 e US 6.521.255. 4,786,505 (enteric coated omeprazole); WO 9501803 (prokinetic agent); EP 247,983, WO 9427988, US 5,330,982, US 6,046,183 and US 6,521,255.
O PI 9607344-6 descreve uma forma de dosagem unitária fixada, tablete ou cápsula, em revestimento entérico na forma de pellets.  PI 9607344-6 discloses a fixed unit dosage form, tablet or capsule, in pellet form enteric coating.
O PI 0401556-8 refere-se a uma combinação de PPI e agente pró-cinético, particularmente lanzoprazol + bromoprida .  PI 0401556-8 relates to a combination of PPI and prokinetic agent, particularly lanzoprazole + bromopride.
O PI 0506704-9 menciona uma composição de liberação retardada, agente pró-cinético de liberação bimodal .  PI 0506704-9 mentions a delayed release composition, bimodal prokinetic release agent.
O pedido internacional, WO 2004071374, revela uma composição de dose única onde o PPI é de liberação retardada e o agente pró-cinético de liberação imediata e/ou sustentada .  International application WO 2004071374 discloses a single dose composition wherein the PPI is delayed release and the prokinetic immediate and / or sustained release agent.
O pedido internacional, WO 2005117870, destaca uma composição de PPI, agente de tamponamento e agente pró- cinético . International application, WO 2005117870, highlights a composition of PPI, buffering agent and pro-active agent. kinetic.
Entretanto, ainda existe a busca por uma medicação para distúrbios relacionados ao ácido gástrico, agindo também sobre náuseas e vómito que podem ocorrer em paralelo, e que permitam alta adesão do paciente ao tratamento.  However, there is still a search for a medication for gastric acid-related disorders, also acting on nausea and vomiting that may occur in parallel, and that allow high adherence of the patient to treatment.
DESCRIÇÃO DA INVENÇÃO  DESCRIPTION OF THE INVENTION
Em vista das deficiências do estado da técnica, a presente invenção refere-se a uma composição farmacêutica contendo um ou mais agentes de supressão de ácido gástrico, particularmente um inibidor da bomba de prótons, um ou mais agentes pró-cinéticos, e excipientes farmaceuticamente aceitáveis. Tal composição é útil no tratamento de distúrbios relacionados ao ácido gástrico, como azia, doença de refluxo gastroesofágico, esofagite de refluxo, úlcera péptica, úlcera gástrica, e similares.  In view of prior art deficiencies, the present invention relates to a pharmaceutical composition containing one or more gastric acid suppressing agents, particularly a proton pump inhibitor, one or more prokinetic agents, and pharmaceutically acceptable excipients. . Such a composition is useful in the treatment of gastric acid related disorders such as heartburn, gastroesophageal reflux disease, reflux esophagitis, peptic ulcer, gastric ulcer, and the like.
Conforme utilizado aqui, "composição" refere-se tanto à mistura de todos os componentes entre si, numa forma de dosagem unitária, quanto a duas ou mais formulações individuais e autónomas de componentes, inseridas dentro de uma forma de dosagem unitária, por exemplo, uma cápsula de gelatina, cápsula de hidroxipropilmetil celulose (HPMC) e similares. Estão cobertas pela invenção concretizações em que :  As used herein, "composition" refers to either mixing all components together in a unit dosage form or to two or more individual and autonomous component formulations within a unit dosage form, e.g. a gelatin capsule, hydroxypropyl methyl cellulose (HPMC) capsule and the like. Embodiments are covered by the invention in which:
- uma cápsula contém um PPI e excipientes, outra cápsula contém um PA e excipientes, e tais duas cápsulas por sua vez estão contidas em uma única cápsula;  - one capsule contains a PPI and excipients, another capsule contains a PA and excipients, and such two capsules in turn are contained in a single capsule;
- uma cápsula contém um PPI e excipientes, e um comprimido contém um PA e excipientes, e dita cápsula e dito comprimido estão ambos contidos em uma única cápsula. De forma alternativa, a cápsula pode conter um PA e o comprimido pode conter um PPI; - a capsule contains a PPI and excipients, and a tablet contains a PA and excipients, and said capsule and said tablet are both contained in a single capsule. Alternatively, the capsule may contain a PA and the tablet may contain a PPI;
- um comprimido contém um PPI e excipientes, e outro comprimido contém um PA e excipientes, e tais dois comprimidos estão contidos em uma única cápsula; .  - one tablet contains a PPI and excipients, and another tablet contains a PA and excipients, and such two tablets are contained in a single capsule; .
um comprimido com duas camadas, uma camada contendo um PPI e outra camada contendo um PA.  a two layer tablet, one layer containing a PPI and another layer containing a PA.
De forma preferencial, sem excluir qualquer outra, a invenção refere-se a uma composição oral, caracterizada pelo fato de compreender em uma única forma de dosagem unitária, particularmente em uma cápsula, comprimidos distintos de (a) um ou mais inibidores da bomba de prótons escolhidos entre omeprazol, esomeprazol, pantoprazol, lansoprazol e rabeprazol, com os respectivos excipientes e (b) um ou mais agentes pró-cinéticos escolhidos entre bromoprida, cisaprida, alizaprida, cleboprida, domperidona, e metoclopramida, com os respectivos excipientes.  Preferably, without excluding any other, the invention relates to an oral composition, characterized in that it comprises in a single unit dosage form, particularly in a capsule, tablets distinct from (a) one or more slurry pump inhibitors. protons chosen from omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole, with their respective excipients and (b) one or more prokinetic agents chosen from bromopride, cisapride, alizapride, clebopride, domperidone, and metoclopramide, with their excipients.
Tal configuração particular propicia:  Such a particular configuration provides:
- a preparação autónoma de comprimidos que levam em conta as características particulares tanto dos inibidores da bomba de prótons quanto dos agentes pró- cinético. Por exemplo, sabe-se que inibidores da bomba de prótons são instáveis em meio ácido, sendo, portanto sujeitos a degradação, podendo ser protegidos por revestimento específico;  - the autonomous preparation of tablets which take into account the particular characteristics of both proton pump inhibitors and prokinetic agents. For example, proton pump inhibitors are known to be unstable in acidic medium and therefore subject to degradation and may be protected by specific coating;
- a separação entre tais princípios ativos, em virtude da característica individual de sítio de liberação no organismo, - the separation between such active principles by virtue of the individual release site characteristic in the body,
a utilização independente, se desejada, dos comprimidos isoladamente um do outro;  the independent use, if desired, of the tablets alone from one another;
a facilitação da adesão ao tratamento, por tratar-se de uma única unidade de administração contendo os dois princípios ativos.  facilitating adherence to treatment as it is a single administration unit containing both active ingredients.
Dentro dessa configuração preferencial da composição da invenção, com características versáteis quanto à forma de dosagem unitária, cada comprimido pode apresentar características específicas, iguais ou distintas entre si, como :  Within this preferred embodiment of the composition of the invention, having versatile unit dosage characteristics, each tablet may have specific, same or distinct characteristics as:
- revestimento entérico;  - enteric coating;
velocidade de liberação (imediata, lenta, adiada, controlada, e similares) ;  release rate (immediate, slow, delayed, controlled, and the like);
- mistura individual de cada ativo com outros princípios ativos ou ingredientes de atividades específicas.  - mixing each asset individually with other active ingredients or activity-specific ingredients.
Inibidores da bomba de prótons presentes nas formas de dosagem da invenção podem ser utilizados na forma neutra ou na forma de sal alcalino, por exemplo, como sais de magnésio, cálcio, sódio, potássio ou lítio. Onde aplicável, os inibidores da bomba de prótons, podem ser utilizados na forma racêmica, na forma de enantiômero puro, ou sais alcalinos de enantiômeros .  Proton pump inhibitors present in the dosage forms of the invention may be used in neutral or alkaline salt form, for example as magnesium, calcium, sodium, potassium or lithium salts. Where applicable, proton pump inhibitors may be used in racemic form as pure enantiomer or alkaline salts of enantiomers.
Dentro de uma realização particular da invenção, o inibidor da bomba de prótons preferido é escolhido entre o pantoprazol, seus sais, ésteres, hidratos, derivados, pró- drogas ou metabólitos, sob qualquer forma polimórfica. Mais particularmente, utiliza-se pantoprazol sódico sesquiidratado . Within a particular embodiment of the invention, the preferred proton pump inhibitor is chosen from pantoprazole, its salts, esters, hydrates, derivatives, prodrugs or metabolites in any polymorphic form. More particularly, pantoprazole sodium is used sesquihydrate.
Dentro de uma realização particular da invenção, o agente pró-cinético preferido é escolhido entre a domperidona, seus sais, ésteres, hidratos, derivados, pró- drogas ou metabólitos, sob qualquer forma polimórfica.  Within a particular embodiment of the invention, the preferred prokinetic agent is chosen from domperidone, its salts, esters, hydrates, derivatives, prodrugs or metabolites in any polymorphic form.
A composição da invenção em sua acepção ampla, e particularmente na realização de dois comprimidos distintos contidos em uma cápsula de gelatina, cápsulas de hidroxipropilmetil celulose (HPMC) e similares, contém excipientes farmaceuticamente aceitáveis, como diluentes, aglutinantes, desintegrantes, corantes, antiaderentes, lubrificantes, plastificantes, sequestrantes, agentes de revestimento, antioxidantes, opacificantes, aromatizantes, edulcorantes, e similares, utilizados sós ou em combinações entre si. Uma referência conhecida do homem da técnica sobre excipientes farmaceuticamente aceitáveis é no livro "Remington's Pharmaceutical Sciences", 18a edição, (1990), Mack Publishing Co., USA. The composition of the invention in its broad sense, and particularly in the realization of two separate tablets contained in a gelatin capsule, hydroxypropyl methylcellulose (HPMC) capsules and the like, contains pharmaceutically acceptable excipients such as diluents, binders, disintegrants, colorants, nonstick, lubricants, plasticizers, sequestrants, coating agents, antioxidants, opacifiers, flavorings, sweeteners, and the like, used alone or in combination with each other. A known technique reference pharmaceutically acceptable excipients for man is in the book "Remington's Pharmaceutical Sciences" 18th Edition, (1990), Mack Publishing Co., USA.
Exemplos de diluentes adequados à invenção, sem excluir quaisquer outros, são escolhidos entre celulose microcristalina, lactose monoidratada ou anidra, fosfato dibásico de cálcio, sacarideos como manitol, sorbitol, sacarose e glicose,  Examples of diluents suitable for the invention, without excluding others, are chosen from microcrystalline cellulose, lactose monohydrate or anhydrous, dibasic calcium phosphate, saccharides such as mannitol, sorbitol, sucrose and glucose,
Exemplos de agentes alcalinizantes adequados à invenção, sem excluir quaisquer outros, são escolhidos entre óxido de magnésio, hidróxido de sódio, bicarbonato de sódio, carbonato de sódio e suas misturas.  Examples of alkalinizing agents suitable for the invention, without excluding any others, are selected from magnesium oxide, sodium hydroxide, sodium bicarbonate, sodium carbonate and mixtures thereof.
Exemplos de agentes aglutinantes adequados à invenção, sem excluir quaisquer outros, são escolhidos entre povidona, crospovidona e hidroxipropilcelulose. Examples of suitable binding agents for without excluding any others, are chosen from povidone, crospovidone and hydroxypropylcellulose.
Exemplos de desintegrantes adequados à invenção, sem excluir quaisquer outros, são selecionados entre polivinilpirrolidona, reticulados ou não, amido (de milho, de batata, e similares) , amidos modificados, croscarmelose, croscarmelose sódica, amido glicolato de sódio, hidroxipropilmetil celulose, hidroxipropilcelulose de baixa substituição, e misturas destes.  Examples of disintegrants suitable for the invention, without excluding any others, are selected from cross-linked polyvinylpyrrolidone, starch (corn, potato, and the like), modified starches, croscarmellose, croscarmellose sodium, sodium starch glycolate, hydroxypropyl methylcellulose, hydroxypropylcellulose low substitution, and mixtures thereof.
Exemplos de lubrificantes adequados à invenção, sem excluir quaisquer outros, são dióxido de silício coloidal, talco, ácido esteárico, estearato de magnésio, estearato de cálcio, estearato de zinco, fumarato de sódio estearila, e misturas destes.  Examples of lubricants suitable for the invention, without excluding any others, are colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures thereof.
Exemplos adequados à invenção de materiais de revestimentos e seus complementares, para comprimidos, sem excluir quaisquer outros, são, hidroxipropilmetil celulose, Eudragit (fabricado por Evonik) , Opadry (fabricado por Colorcon) , trietilcitrato, propileno glicol e similares.  Examples suitable for the invention of coating materials and their supplements for tablets, without excluding any others, are hydroxypropyl methylcellulose, Eudragit (manufactured by Evonik), Opadry (manufactured by Colorcon), triethylcitrate, propylene glycol and the like.
Dentro de realizações preferenciais, as quantidades dos ativos nas composições da invenção, na sua forma livre, são de:  Within preferred embodiments, the amounts of the actives in the compositions of the invention in their free form are:
- pantoprazol: 20 ou 40mg.  - pantoprazole: 20 or 40mg.
- domperidona: lOmg.  domperidone: 10mg.
Dentro de outro aspecto, a invenção refere-se ao uso da composição descrita anteriormente na manufatura de um medicamento utilizado no tratamento dos distúrbios causados por ácido gástrico, particularmente azia, doença de refluxo gastroesofágico, esofagite de refluxo, úlcera péptica, úlcera gástrica. Within another aspect, the invention relates to the use of the composition described above in the manufacture of a medicament used in the treatment of disorders caused by gastric acid, particularly heartburn, reflux disease. gastroesophageal, reflux esophagitis, peptic ulcer, gastric ulcer.
EXEMPLO  EXAMPLE
Os exemplos dados a seguir devem ser entendidos como concretizações particulares da invenção, sem por esse motivo imporem restrição de qualquer forma ou natureza, além do conteúdo das reivindicações apresentadas mais adiante.  The following examples are to be understood as particular embodiments of the invention without, therefore, imposing any restriction of any form or nature beyond the content of the claims set forth below.
TABELA 1  TABLE 1
PANTOPRAZOL 20MG COMPRIMIDO REVESTIDO PANTOPRAZOL 20MG COATED TABLET
Ingrediente Quantidade Ingredient Quantity
Pantoprazol sódio sesquiidratado 21, 140mg  Pantoprazole sodium sesquihydrate 21,140mg
Manitol 29, 032mg  Mannitol 29, 032mg
Povidona K90 1, 995mg  Povidone K90 1,995mg
Carbonato sódio 11, 243mg  Sodium carbonate 11, 243mg
Povidona reticulada 12, 500mg  Reticulated Povidone 12, 500mg
Água deionizada NA  NA deionized water
Estearato cálcio 1, 600mg  Calcium Stearate 1, 600mg
Hidroxipropilmetil celulose 91% + 6, 362mg  Hydroxypropylmethylcellulose 91% + 6,362mg
Polietileno Glicol 9%  Polyethylene Glycol 9%
Hidroxipropilcelulose 0, 078mg  Hydroxypropylcellulose 0.078mg
Povidona K30 0, lOOmg  Povidone K30 0,000mg
Dióxido de titânio 0, 088mg  Titanium Dioxide 0.088mg
Propilenoglicol 1, 114mg  Propylene Glycol 1, 114mg
Oxido ferro amarelo 0, 009mg  Yellow Iron Oxide 0.009mg
Álcool etílico absoluto NA  Absolute ethyl alcohol NA
Eudragit L 30 D 55 27, 384mg  Eudragit L 30 D 55 27, 384mg
Polissorbato 80 0, 292mg  Polysorbate 80 0, 292mg
Trietileitrato 0, 782mg Simeticona USP 0, 077mgTrietileitrate 0, 782mg Simethicone USP 0, 077mg
Talco 3, 844mgTalc 3, 844mg
Hidróxido de sódio qs pHSodium hydroxide qs pH
Água deionizada NA NA deionized water
TABELA 2  TABLE 2
PANTOPRAZOL 40MG COMPRIMIDO REVESTIDO  40MG COATED PANTOPRAZOL COATED
Ingrediente Quantidade Ingredient Quantity
Pantoprazol sódio sesquiidratado 42,280mgPantoprazole sodium sesquihydrate 42,280mg
Manitol 58, 065mgMannitol 58.065mg
Povidona K90 3, 99mgPovidone K90 3, 99mg
Carbonato sódio 22, 85mgSodium carbonate 22, 85mg
Povidona reticulada 25, OOOmgReticulated Povidone 25, OOOmg
Água deionizada NANA deionized water
Estearato cálcio 3, 20mgCalcium Stearate 3, 20mg
Hidroxipropilmetil celulose 91% + 10, 171mg Polietileno Glicol 9 Hydroxypropylmethylcellulose 91% + 10,171mg Polyethylene Glycol 9
Hidroxipropilcelulose 0, 124mg Hydroxypropylcellulose 0.124mg
Povidona K30 0, 160mgPovidone K30 0, 160mg
Dióxido de titânio 0, 140mgTitanium Dioxide 0, 140mg
Propilenoglicol 1, 780mgPropylene Glycol 1, 780mg
Oxido ferro amarelo 0, 015mgYellow Iron Oxide 0.015mg
Álcool etílico absoluto NAAbsolute ethyl alcohol NA
Eudragit L 30 D 55 51, 874Eudragit L 30 D 55 51,874
Polissorbato 80 0, 557mgPolysorbate 80 0, 557mg
Trietilcitrato 1, 491mgTriethylcitrate 1, 491mg
Simeticona USP 0,148mgSimethicone USP 0.148mg
Talco 7, 354mgTalc 7, 354mg
Hidróxido de sódio qs pH Água deionizada NA Sodium hydroxide qs pH NA deionized water
TABELA 3  TABLE 3
DOMPERIDONA 10MG COMPRIMIDO  DOMPERIDONE 10MG COMPRESSED
Figure imgf000011_0001
Figure imgf000011_0001
Apesar do homem da técnica, com o auxílio dos ensinamentos aqui apresentados, serem capaz de concretizar de formas não expressamente divulgadas aqui, mas com as mesmas funções em busca do mesmo resultado, tais realizações equivalentes também estão protegidas nas reivindicações a seguir .  Although the man of the art, with the help of the teachings herein, is capable of realizing in ways not expressly disclosed herein, but with the same functions in pursuit of the same result, such equivalent embodiments are also protected in the following claims.

Claims

REIVINDICAÇÕES
1. COMPOSIÇÃO FARMACÊUTICA ORAL, caracterizada pelo fato de compreender um ou mais agentes de supressão de ácido gástrico, um ou mais agentes pró-cinéticos, e excipientes farmaceuticamente aceitáveis.  ORAL PHARMACEUTICAL COMPOSITION, characterized in that it comprises one or more gastric acid suppressing agents, one or more prokinetic agents, and pharmaceutically acceptable excipients.
2. COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com a reivindicação 1, caracterizada pelo fato de que ditos agentes de supressão de ácido gástrico são inibidores da bomba de prótons .  ORAL PHARMACEUTICAL COMPOSITION according to claim 1, characterized in that said gastric acid suppressing agents are proton pump inhibitors.
3. COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com a reivindicação 1, caracterizada pelo fato de que ditos agentes de supressão de ácido gástrico são inibidores da bomba de prótons, preferencialmente escolhidos dentre omeprazol, esomeprazol, pantoprazol, lansoprazol e rabeprazol.  ORAL PHARMACEUTICAL COMPOSITION according to claim 1, characterized in that said gastric acid suppressing agents are proton pump inhibitors, preferably chosen from omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole.
4. COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com a reivindicação 1, caracterizada pelo fato de que ditos agentes de supressão de ácido gástrico são preferencialmente escolhidos entre o pantoprazol, seus sais, ésteres, hidratos, derivados, pró-drogas ou metabólitos, sob qualquer forma polimórfica.  ORAL PHARMACEUTICAL COMPOSITION according to claim 1, characterized in that said gastric acid suppressing agents are preferably chosen from pantoprazole, its salts, esters, hydrates, derivatives, prodrugs or metabolites in any form. polymorphic.
5. COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com a reivindicação 1, caracterizada pelo fato de que um dos ditos agentes de supressão de ácido gástrico é preferencialmente pantoprazol sódico sesquiidratado .  ORAL PHARMACEUTICAL COMPOSITION according to claim 1, characterized in that one of said gastric acid suppressing agents is preferably pantoprazole sodium sesquihydrate.
6. COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com a reivindicação 1, caracterizada pelo fato de que ditos agentes pró-cinéticos são preferencialmente escolhidos entre bromoprida, cisaprida, alizaprida, cleboprida, domperidona, e metoclopramida. ORAL PHARMACEUTICAL COMPOSITION according to claim 1, characterized in that said prokinetic agents are preferably chosen from bromopride, cisapride, alizapride, clebopride, domperidone, and metoclopramide.
7. COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com a reivindicação 1, caracterizada pelo fato de que ditos agentes pró-cinéticos são preferencialmente escolhidos entre domperidona, seus sais, ésteres, hidratos, derivados, pró- drogas ou metabólitos, sob qualquer forma polimórfica.  ORAL PHARMACEUTICAL COMPOSITION according to claim 1, characterized in that said prokinetic agents are preferably chosen from domperidone, its salts, esters, hydrates, derivatives, prodrugs or metabolites in any polymorphic form.
8. COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com a reivindicação 1, caracterizada pelo fato de dita composição oral compreender, em uma única forma de dosagem unitária, particularmente uma cápsula, comprimidos distintos de (a) um ou mais inibidores da bomba de prótons, particularmente pantoprazol, e excipientes farmaceuticamente aceitáveis e (b) um ou mais agentes pró-cinéticos, particularmente domperidona, e excipientes farmaceuticamente aceitáveis.  ORAL PHARMACEUTICAL COMPOSITION according to claim 1, characterized in that said oral composition comprises, in a single unit dosage form, particularly a capsule, tablets distinct from (a) one or more proton pump inhibitors, particularly pantoprazole, and pharmaceutically acceptable excipients and (b) one or more prokinetic agents, particularly domperidone, and pharmaceutically acceptable excipients.
9. COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com a reivindicação 1, caracterizada pelo fato de que ditos excipientes farmaceuticamente aceitáveis são escolhidos entre diluentes, ligantes, desintegrantes, corantes, antiaderentes, lubrificantes, plastificantes, sequestrantes, agentes de revestimento, antioxidantes, opacificantes, aromatizantes e edulcorantes .  ORAL PHARMACEUTICAL COMPOSITION according to claim 1, characterized in that said pharmaceutically acceptable excipients are chosen from diluents, binders, disintegrants, colorants, non-stickers, lubricants, plasticizers, sequestrants, coating agents, antioxidants, opacifiers, flavorants. and sweeteners.
10. COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com a reivindicação 1, caracterizada pelo fato de que compreende 20 ou 40mg de pantoprazol em sua forma livre, e lOmg de domperidona, em sua forma livre.  ORAL PHARMACEUTICAL COMPOSITION according to claim 1, characterized in that it comprises 20 or 40 mg of pantoprazole in its free form and 10 mg of domperidone in its free form.
11. USO DA COMPOSIÇÃO FARMACÊUTICA ORAL, de acordo com uma qualquer das reivindicações 1 a 10, caracterizada pelo fato de ser na manufatura de um medicamento útil no tratamento dos distúrbios causados por ácido gástrico, particularmente azia, doença de refluxo gastroesofágico, esofagite de refluxo, úlcera péptica, úlcera gástrica. Use of the oral pharmaceutical composition according to any one of Claims 1 to 10, characterized in because it is in the manufacture of a drug useful in the treatment of disorders caused by gastric acid, particularly heartburn, gastroesophageal reflux disease, reflux esophagitis, peptic ulcer, gastric ulcer.
PCT/BR2012/000168 2011-06-03 2012-05-29 Oral pharmaceutical composition comprising a proton pump inhibitor and a prokinetic agent that can be used in excess stomach acid disorders WO2012162777A1 (en)

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