WO2004089414A2 - Combinaison de medicaments, association de medicaments et medicament - Google Patents

Combinaison de medicaments, association de medicaments et medicament Download PDF

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Publication number
WO2004089414A2
WO2004089414A2 PCT/BR2004/000046 BR2004000046W WO2004089414A2 WO 2004089414 A2 WO2004089414 A2 WO 2004089414A2 BR 2004000046 W BR2004000046 W BR 2004000046W WO 2004089414 A2 WO2004089414 A2 WO 2004089414A2
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Prior art keywords
drag
drug
units
lansoprazole
bromopride
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PCT/BR2004/000046
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English (en)
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WO2004089414A3 (fr
Inventor
Alexandre FUNARI NEGRÃO
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Medley S.A. Indústria Farmacêutica
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Publication of WO2004089414A2 publication Critical patent/WO2004089414A2/fr
Publication of WO2004089414A3 publication Critical patent/WO2004089414A3/fr

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Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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

Definitions

  • GSD Gastroesophageal reflux disease
  • GFD gastroesophageal reflu ⁇ disease
  • Source Farmacologia Integrada (Integrated Pharmacology) - Page, Curtis, Sutter, Walker & Hoffman - Editora Manole Ltda Ed..
  • Gastroesophageal reflux is the involuntary movement of stomach contents towards the esophagus. In normal individuals, a reflux episode occurs on an hourly basis. How this physiologic process becomes pathological is not well-known. In theory, gastroesophageal reflux disease develops when the exposure to a refluxed harmful material exceeds the protection mechanisms of the esophagus. That is to say, when there is an unbalance between the aggressive and defensive factors. This unbalance produces a wide range of symptoms and abnormalities in the esophagus, including heartburn, esophagitis and ulcers (Stacher G, Lenglinger J, Bergmann H, Schneider C, Hoffman M, Wolfl G, Stacher-Janotta G.
  • GERD gastroesophageal reflux disease
  • drugs - antacids and alginic acid: antacids Mg 2+ and Al 3+ are frequently administered in combination with alginic acid, an inert substance that produces a foam over the gastric acid and colloid (gel) over the stomach contents, thus reducing reflux.
  • the colloidal foam has a high pH, but the greatest benefit of these preparations can result from the antacid contents.
  • H 2 antagonists a study demonstrated that, when the patient does not respond well to the simplest measures, a 12-week course with H 2 antagonists produced healing in up to 75 % of the patients with erosive esophagitis, but this patients did not show any improvement with a longer than 24 week course of treatment. Other studies however, claim that H 2 antagonists are merely symptomatic and do not produce healing. As examples we can mention: ranitidine, farnotidine, nizatidine, cimetidine and famotidine, among others;
  • Proton pump inhibitors are a relatively new class of agents used for the treatment of pathological conditions associated with excessive gastric acid secretion, or excessive exposure to gastric acid, and they also take part as components in the therapeutic regimes used for the treatment of Helicobacter pylori infection. In addition, these agents are more powerful blockers of gastric acid secretion than the older drugs, in which group the histamine H 2 antagonists are included.
  • Proton pump inhibitors differ from antimuscarinics and antihistaminics as to their mechanism of action for they act in the last step of the gastric acid formation process, altering the activity of the H + ,K + ATPase enzyme, therefore presenting greater efficacy (Freston JW.
  • Prokinetic drugs prokinetic drugs are better used as combination therapies with PPI's and H 2 antagonists.
  • Metoclopramide is a type 2 (D 2 ) dopamine receptor antagonist and a 5- hydroxytryptamine (5-HT) receptor stimulant. Its prokinetic effect in the stomach plus the ability to increase lower sphincter tone, probably constitute the beneficial effects mechanism in gastroesophageal reflux diseases. Metoclopramide also presents anticholinergic effects at the central nervous system (CNS) by inhibiting dopamine receptors. Domperidone, a D antagonist that does not cross the blood-brain barrier, can be an appropriate alternative.
  • Cisapride is a benzamide substitute with 5-HT receptors antagonist actions, whilst it stimulates the gastrointestinal motility and increases the lower esophageal sphincter pressure, by way of an mechanism of action that may involve 5-HT receptors.
  • Some patients treated with cisapride present diarrhea, possibly due to this drug's action at the colon.
  • Bromopride is another prokinetic agent, with a better tolerability, that acts at the lower esophageal sphincter, increasing its pressure, also acting on the smooth muscles of the stomach, increasing gastric emptying speed (Kilbinger H & Weihrauch TR. Drugs increasing gastrointestinal motility. Pharmacology 1982. 25: 61-7 ).
  • dyspepsia It is not a symptom, but rather a constellation of symptoms, which is different in each patient. Efforts to define the term are yet more difficult due to the interrelationship of the biological and characteristics variables of personality, life experiences, social aspects and perception, which determine the way in which patients report their symptoms and how physicians interpret them.
  • Classification of patients functional dyspepsia is important in order to identify the baseline illness, thus being a guide to choosing the ideal therapy.
  • the most popular classification divided patients into groups with ulcer-like dyspepsia, poor motility, or reflux (Magalhaes AFN. Dispepsia funcional: conceito e classificacao. In: dispepsias e gastrites, 9-18). Recently, however, reflux-like dyspepsia was excluded for it is associated with gastroesophageal reflux disease without esophagitis (Talley NJ, Weaver AL, Tesmer DL, et al.
  • the most common drug therapy approach to the treatment of the gastroesophageal reflux disease is gastric acid suppression, and unlike peptic ulcer treatment, dosage should be adjusted to each patient. This is an important difference between the two diseases, because even as most of the cases of peptic ulcer are infectious in origin and can be managed with a short term treatment, the gastroesophageal reflux disease is a chronic disorder, and its severity defines the intensity of gastric acid secretion inhibition. Gastric acid secretion blockers
  • Proton pump inhibitors are better as compared to H antagonists, as per clinical trials based on endoscopic observations, thus they should be the first choice of gastric acid secretion inhibitors, either for the healing or maintenance therapy.
  • Prokinetics The theoretical basis for using prokinetics in the treatment of the reflux disease is that these agents would elevate lower esophageal sphincter pressure, enhance gastric emptying, as well as esophageal peristalsis, regulating some of the abnormalities observed in this disorder.
  • Prokinetic drugs in combination with proton pump inhibitors have also been suggested for the treatment of severe or complicated reflux disease.
  • the main objectives of the invention have been: • to facilitate the treatment (for physicians and patients) by providing the use of the
  • a drug comprising drugs that have a synergistic effect, presenting at least two types of drugs: a proton pump inhibitor and a prokinetic.
  • the present invention refers to pharmaceutical drugs easily used for the treatment of disorders associated with functional dyspepsia and gastroesophageal reflux, basically presenting the aforementioned proton pump inhibitor and prokinetic drugs.
  • the invention refers to a drug combination characterized by comprising, individually, and at the same time, jointly:
  • One or more drug units of one or more proton pump inhibitor agents are One or more drug units of one or more proton pump inhibitor agents
  • One or more drug units of one or more prokinetic agents and optionally, other additives or drugs which are well-known to those skilled in the art, within the medium or excipient, also pharmaceutically acceptable.
  • the proton pump inhibitor (PPI) or blocker agents can be selected from the group comprising: lansoprazole, pantoprazole, omeprazole, esomeprazole magnesium, rabeprazole sodium, and others. Lansoprazole is preferably used.
  • Lansoprazole's molecular structure either 2-[[[3-methyl-4-(2,2,2-trifluoro- ethoxy)-2-pyridinyl]methyl]sulfynyl]-lH-benzoimidazole, or 2-(2- benzimidazolylsulfynylmethyl)-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine, consists of a pyridine ring with a trifluoroethoxy group linked to the benzoimidazole ring through a methyl sulfoxide.
  • lansoprazole is formulated as enteric release granules, since an early exposure to the gastric acid would lead to a low bioavailability due to its degradation in acid pH (Chun AHC, Shi
  • Lansoprazole can be administered in capsules, or following dispersion of its enteric granules in some juice or apple puree, with no significant changes in its pharmacokinetics. Maximum plasma concentrations are reached within approximately l,lh to 2,2 h following oral ingestion, and are not dose-dependent.
  • Lansoprazole has a small evident volume of distribution, of about 0,5 L/kg, following 30 mg oral administration. It links to plasma proteins at about 98 %. More than 90 % of the drug is found linked to plasma protein, mainly albumin, and no linkage to red blood cells; there are no data available as to tissue distribution of the drug following intravenous administration. Lansoprazole is rapidly metabolized in the liver, and its main metabolites are
  • 5-hydroxy-lansoprazole formed by CYP2C19 and 3A4, and a sulfone formed by CYP3A4; a sulfonamide is also found, at a lesser amount.
  • the metabolites are also pro-drugs that are converted into active compounds in an acid medium, found in the parietal cells.
  • Lansoprazole presents a elimination half-life varying from l,2h to 2,lh. Metabolites are excreted in the urine and bile, and thus recovered in the feces. Since CYP2C19 is involved in the metabolization of the drug, slow metabolizers of this enzyme present less clearance than fast metabolizers.
  • the prokinetic agents can be selected from the group comprising: bromopride, domperidone, cisapride, alizapride hydrochloride, metoclopramide, and others.
  • Bromopride is preferably used.
  • Drug units are used in one dosage form, preferably bromopride, its derivatives, pharmaceutically acceptable salts or pro-drugs, at the dosage of 10 mg, that will be ingested by the patient at least three times daily, preferably prior to main meals (breakfast, lunch and dinner), during a treatment period of 14 or 28 days, or according to doctor orientation.
  • Bromopride or 4-amino-5-bromo-N-[2-(diethylamino)ethyl]-2- methoxybenzamide, or even 4-amino-5-bromo-N-[2-(diethylamino)ethyl]-o- anisamidam, acts regulating gastric and intestinal (duodenum and jejunum) motility, by restoring muscle tone and normal peristalsis in all cases in which changes to this system occur. It also normalizes the incomplete or delayed emptying of the bile ducts and it has a complete antiemetic effect, acting centrally and peripherally. Bromopride is rapidly absorbed and its plasma half-life (Tl/2) is within approximately 4,9 hours.
  • C max maximum plasma concentration
  • the drug may be presented comprising 28 drug units containing proton pump inhibitors, preferably lansoprazole, and 84 drug units containing a prokinetic agent, preferably bromopride, which corresponds to a 28 day treatment.
  • proton pump inhibitors preferably lansoprazole
  • prokinetic agent preferably bromopride
  • the drug association uses 15 mg or 30 mg dosages for the proton pump inhibitor drug units.
  • Lansoprazole is preferably used, its pharmaceutically acceptable derivatives or salts.
  • the prokinetic agents are used at the dosage of 10 mg per drug unit.
  • Bromopride is preferably used, its pharmaceutically acceptable derivatives or salts.
  • the drug is marketed containing one or more drug units of one or more proton pump inhibitors or blockers, and one or more drag units of one or more prokinetic agents, as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable, jointly but also individually, at the dosages of 15 mg or 30 mg for the proton pump inhibitor drag units, and at the dosage of 10 mg for the prokinetic agent drug units.
  • the drug is marketed containing one or more drug units of lansoprazole, and one or more drag units of bromopride, as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable, jointly but also individually, at the dosages of 15 mg or 30 mg for the lansoprazole drug units, and at the dosage of 10 mg for the bromopride drug units.
  • the drug presented in a facilitated presentation is characterized by comprising one or more drug units of lansoprazole 15 mg or 30 mg to be taken at least once daily, preferably at a fasted state, and one or more drug units of bromopride 10 mg to be taken at least three times daily, preferably prior to main meals (breakfast, lunch and dinner), as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable.
  • Example 1 A 26-year old male patient complaining about heartburn for the past year, mainly following meals, has been presenting a dry cough for the past 60 days, approximately. He also complained about frequent eructation and a "chock-full" sensation. He denied dysphagia, vomiting and epigastric pain. 6 months before, during a physical exam, no abnormalities were detected. In this case, the choice was to apply a "therapeutic test" with the drag Lansoprazole at the dose of 30 mg/day in the morning for 2 weeks. After this period, the patient returned reporting improvement only in the heartburn.
  • bromopride 10 mg before breakfast, lunch and dinner during a period of 30 days.
  • the patient reported significant improvement in the post-prandial gastric fullness sensation and reflux esophagitis.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention concerne une combinaison de médicaments, une association de médicaments, un médicament et un médicament ayant une présentation facilitée, qui comprend séparément et en même temps conjointement: une ou plusieurs unités de médicament renfermant un ou plusieurs agents inhibiteurs de la pompe à protons; une ou plusieurs unités de médicaments renfermant un ou plusieurs agents procinétiques; et éventuellement d'autres additifs ou médicaments qui sont bien connus des spécialistes, mélangés à un milieu ou à un excipient, également acceptable sur le plan pharmaceutique, servant de préférence au traitement de la dyspepsie fonctionnelle et du reflux gastro-oesophagien pathologique.
PCT/BR2004/000046 2003-04-08 2004-03-31 Combinaison de medicaments, association de medicaments et medicament WO2004089414A2 (fr)

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BR0301179 2003-04-08
BRPI0301179-8 2003-04-08

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WO2004089414A2 true WO2004089414A2 (fr) 2004-10-21
WO2004089414A3 WO2004089414A3 (fr) 2004-12-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023306A2 (fr) * 2003-09-05 2005-03-17 Medley S.A. Indústria Farmacêutica Medicament, trousse de medicaments, combinaison de medicaments, association medicinale et medicament ayant une forme de presentation commode

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0803251A1 (fr) * 1996-04-23 1997-10-29 Janssen Pharmaceutica N.V. Formes solides d'administration de cisapride à libération immédiate et indépendente du PH
WO2000051584A2 (fr) * 1999-03-02 2000-09-08 Sepracor Inc. Procedes et compositions destines a l'utilisation de norcisapride (-) en combinaison avec des inhibiteurs de pompes a protons ou des antagonistes du recepteur de h¿2?
WO2003097011A1 (fr) * 2002-05-17 2003-11-27 Eisai Co., Ltd. Compositions et methodes utilisant des inhibiteurs de la pompe a protons

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0803251A1 (fr) * 1996-04-23 1997-10-29 Janssen Pharmaceutica N.V. Formes solides d'administration de cisapride à libération immédiate et indépendente du PH
WO2000051584A2 (fr) * 1999-03-02 2000-09-08 Sepracor Inc. Procedes et compositions destines a l'utilisation de norcisapride (-) en combinaison avec des inhibiteurs de pompes a protons ou des antagonistes du recepteur de h¿2?
WO2003097011A1 (fr) * 2002-05-17 2003-11-27 Eisai Co., Ltd. Compositions et methodes utilisant des inhibiteurs de la pompe a protons

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ANON.: "Refluxkrankheit der Speiseröhre und peptisches Ulkus" FORTSCHRITTE DER MEDIZIN, vol. 116, no. 34, 1998, pages 35-38, XP008037882 *
BEERS ET AL, EDS.: "The Merck Manual of Diagnosis and Therapy" 1999, MERCK RESEARCH LABORATORIES , WHITEHOUSE STATION, NJ, USA , XP002303226 pages 233-237 *
DE MORHAES-FILHO AND CHINZON: "Doença do refluxo gastroesofagico" REV. BRAS. MED., vol. 51, 1994, - 1995 pages 112-124, XP008037884 *
MATHESON AND JARVIS: "Lansoprazole - an update of its place in the management of acid-related disorders" DRUGS, vol. 61, no. 12, 2001, pages 1801-1833, XP008037879 *
MONES ET AL: "Criteria used by general practitioners in prescribing prokinetic or antisecretory drugs in patients with functional dyspepsia" REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS, vol. 93, no. 5, 2001, pages 287-292, XP008037880 *
THJODLEIFSSON: "Treatment of acid-related diseases in the elderly with emphasis on the use of proton pump inhibitors" DRUGS AGING, vol. 19, no. 12, 2002, pages 911-927, XP008037878 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023306A2 (fr) * 2003-09-05 2005-03-17 Medley S.A. Indústria Farmacêutica Medicament, trousse de medicaments, combinaison de medicaments, association medicinale et medicament ayant une forme de presentation commode
WO2005023306A3 (fr) * 2003-09-05 2005-04-21 Medley S A Ind Farmaceutica Medicament, trousse de medicaments, combinaison de medicaments, association medicinale et medicament ayant une forme de presentation commode

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