WO2016104367A1 - Médicament thérapeutique de la dyspepsie fonctionnelle - Google Patents

Médicament thérapeutique de la dyspepsie fonctionnelle Download PDF

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Publication number
WO2016104367A1
WO2016104367A1 PCT/JP2015/085506 JP2015085506W WO2016104367A1 WO 2016104367 A1 WO2016104367 A1 WO 2016104367A1 JP 2015085506 W JP2015085506 W JP 2015085506W WO 2016104367 A1 WO2016104367 A1 WO 2016104367A1
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Prior art keywords
aldioxa
administration
gastric emptying
compound
functional dyspepsia
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English (en)
Japanese (ja)
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水島　徹
鈴木　秀和
帝太 浅野
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LTT Bio Pharma Co Ltd
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LTT Bio Pharma Co Ltd
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    • 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
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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

Definitions

  • the present invention mainly relates to a therapeutic agent for functional dyspepsia.
  • FD Functional Dyspepsia
  • FD Functional Dyspepsia
  • drugs that improve gastrointestinal motility are used to treat FD.
  • drugs such as mosapride and cisapride, which are 5-HT 4 (serotonin) receptor agonists, and itopride, which is a dopamine receptor antagonist, are used as gastrointestinal motility activators.
  • anti-gastric ulcer drugs that are widely used in clinical practice are rarely used for FD, which is a disease state in which no organic lesion (ulcer) is observed.
  • 5-HT 4 receptor agonists are mainly used in current FD treatment to improve gastric emptying delay. Yes.
  • the effectiveness of these drugs has not been sufficiently confirmed in FD patients (Non-Patent Documents 2 and 3).
  • 5-HT 4 receptor agonists inducing cardiovascular side effects.
  • the 5-HT 4 receptor agonist cisapride has already been withdrawn from the market because it has been reported to induce QT prolongation (cardiotoxicity) (Non-patent Document 4).
  • conventional gastrointestinal motility improving drugs have a problem in that they are poorly effective and can cause side effects.
  • the main object of the present invention is to provide a novel therapeutic agent for functional dyspepsia that is highly effective and safe.
  • the present inventor has intensively studied to solve the above problems, and surprisingly, (i) having an ⁇ 2 antagonistic action and / or (ii) a compound containing aluminum as an active ingredient, It was found that a therapeutic drug for functional dyspepsia can be obtained.
  • the present invention has been completed by making further improvements based on such findings.
  • the present invention includes the following aspects of the invention.
  • a therapeutic agent for functional dyspepsia comprising (i) an ⁇ 2 antagonistic action and / or (ii) an aluminum-containing compound as an active ingredient.
  • the therapeutic agent for functional dyspepsia which comprises (i) an ⁇ 2 antagonistic action and (ii) a compound containing aluminum as an active ingredient.
  • the present invention provides an effective therapeutic agent for functional dyspepsia. Many potential patients with functional dyspepsia can be expected to improve quality of life (QOL).
  • QOL quality of life
  • the therapeutic agent of the present invention is a therapeutic agent provided by drug repositioning that searches for new efficacy of existing pharmaceuticals, it can be expected to suppress R & D costs until market launch and to have a high probability of successful development.
  • the therapeutic agent of the invention can be used as a tool for research on the onset mechanism and treatment method of functional dyspepsia, and is expected to contribute to further improvement of medical technology.
  • Figure 3 shows the effect of aldioxa on clonidine-induced gastric emptying delay.
  • Figure 2 shows the effect of other gastroprotective compounds on clonidine-induced gastric emptying delay.
  • Figure 3 shows the effect of allantoin and aluminum hydroxide on clonidine-induced gastric emptying delay.
  • 2 shows the effect of aldioxa on restraint stress-induced gastric emptying delay and normal gastric emptying.
  • the promotion effect of aldioxa on gastric emptying and the independence of 5-HT 4 receptor and dopamine receptor are shown.
  • the involvement of ⁇ 2 adrenergic receptors in the promoting effect of aldioxa on gastric emptying is shown.
  • the effect of yohimbine on clonidine-induced gastric emptying delay is shown.
  • Figure 3 shows the effect of aldioxa on gastric acceptability in rats.
  • the therapeutic agent for functional dyspepsia of the present invention will be described in detail below.
  • Functional dyspepsia which is a disease targeted by the therapeutic agent of the present invention, is a functional gastrointestinal disorder in which symptoms such as an early feeling of fullness and a feeling of leaning after meal continue chronically even though organic lesions are not observed. It is.
  • Diagnostic criteria for functional dyspepsia are known. For example, diagnosis according to the Rome III diagnostic criteria, diagnosis according to the diagnostic criteria by the Japanese Gastroenterological Association, and the like are exemplified.
  • PDS Postprandial Distress Syndrome
  • EPS Epigastric Pain Syndrome
  • the therapeutic agent of the present invention is provided as a therapeutic agent that improves, among other symptoms of functional dyspepsia, “a feeling of post-meal leanness” and / or “early satiety”.
  • the therapeutic agent of the present invention is A compound having (i) an ⁇ 2 antagonistic action and / or (ii) aluminum is used as an active ingredient.
  • a compound having an ⁇ 2 antagonistic action is preferable as an active ingredient of a therapeutic agent for functional dyspepsia from the viewpoint that it can improve the delay in gastric emptying that causes a feeling of leaning after eating.
  • Having an ⁇ 2 antagonistic action means having an action capable of blocking the function of the adrenergic receptor ⁇ 2 subtype ( ⁇ 2 receptor).
  • ⁇ 2 antagonist can be restated as “ ⁇ 2 blocker”.
  • ⁇ receptors are further classified into ⁇ 1 and ⁇ 2 subtypes. The ⁇ 2 subtype is thought to act in conjunction with the inhibitory trimeric G protein (G i ).
  • the compound having an ⁇ 2 antagonistic action examples include aldioxa, yohimbine, phenoxybenzamine, idazoxan, efaloxane, atipamezole and the like.
  • a compound containing aluminum is preferable as an active ingredient of a therapeutic agent for functional dyspepsia from the viewpoint that early satiety can be improved.
  • “containing aluminum” refers to a compound expressed as a condensate with aluminum hydroxide (Al 2 (OH) 3 ) or a salt of aluminum hydroxide.
  • the compound containing aluminum examples include aldioxa, sucralfate, synthetic hydrotalcite, magnesium aluminate metasilicate, and the like.
  • the therapeutic agent of the present invention comprises A compound having (i) ⁇ 2 antagonistic action and (ii) aluminum is used as an active ingredient.
  • Aldioxa is a compound represented by the following formula (1) and having a structure in which allantoin and aluminum hydroxide are condensed.
  • Aldioxa is thought to be metabolized to allantoin and aluminum hydroxide in the gastric mucosa. From the viewpoint that the allantoin part of aldioxa or its allantoin metabolite contributes to the improvement of gastric emptying delay, and the aluminum hydroxide part or its aluminum hydroxide metabolite contributes to the improvement of premature satiety. Particularly preferred as an active ingredient of a therapeutic agent.
  • the form (administration form) of the therapeutic agent of the present invention is not particularly limited.
  • the active ingredient may be used as it is and is preferably provided as a pharmaceutical composition.
  • the therapeutic agent of the present invention can be formulated by a known technique.
  • Specific examples of the preparation include, but are not limited to, solid preparations such as tablets, capsules, pills, powders, granules, and liquid preparations such as liquids, suspensions, emulsions, injections, and the like.
  • pharmaceutically acceptable carriers and additives can be added as appropriate.
  • the carriers and additives include, but are not limited to, excipients, fillers, binders, wetting agents, fragrances, and coloring agents.
  • the preparation is a liquid preparation
  • a known pharmaceutically acceptable solvent such as physiological saline, a solution having a buffering action, or the like can be used.
  • the therapeutic agent of the present invention is provided as a pharmaceutical composition
  • the content of the active ingredient is not particularly limited, but may be 1 to 90% by weight based on the total weight of the pharmaceutical composition. it can.
  • the administration method of the therapeutic agent of the present invention can be appropriately set by those skilled in the art as long as a therapeutic effect is obtained, and is not particularly limited.
  • Preferred embodiments of the administration method include injection administration (intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, injection into the affected area, etc.), oral administration, suppository administration, transdermal administration (application, etc.) and the like.
  • Oral administration is particularly preferred as an administration method from the viewpoint of ease of administration and less burden on administration subjects, but is not limited thereto.
  • the therapeutic drug of the present invention can be administered to humans, non-human mammals (dogs, cats, mice, rats, hamsters, rabbits, cows, apes, etc.), birds, etc. that require treatment for functional dyspepsia.
  • the administration subject is a human
  • the human subject to be administered can be appropriately selected by those skilled in the art.
  • Suitable humans include patients in need of treatment for functional dyspepsia.
  • Patients in need of treatment for functional dyspepsia include not only patients diagnosed as functional dyspepsia, but also patients with potential functional dyspepsia.
  • weight, age, sex, etc. are not particularly limited.
  • the daily dose of the therapeutic agent of the present invention is not particularly limited.
  • the dosage can be appropriately set according to the symptom, weight, age, sex, etc. of the administration subject (patient), but usually about 0.001 mg to 10 g of active ingredient per day for an adult The degree can be selected from the range of about 0.01 mg to 2 g.
  • the therapeutic agent is not limited to once daily administration, and can be administered in several divided doses.
  • the present invention also provides a method for treating functional dyspepsia.
  • the therapeutic method of the present invention comprises the step (i) of administering an active ingredient which is an ⁇ 2 antagonistic action and / or (ii) a compound containing aluminum to a person in need of treatment for functional dyspepsia.
  • Specific administration forms, administration methods, administration subjects, dosages and the like in the step of administering the above compound can be preferably those described above.
  • the present invention also provides a compound having (i) ⁇ 2 antagonistic action and / or (ii) containing aluminum, which is the aforementioned active ingredient, for use in the treatment of functional dyspepsia.
  • the functional dyspepsia is suppressed or suppressed by using the administration form, administration method, administration subject, dosage, etc. described above to administration subjects such as mammals including humans, birds, etc., in which the functional dyspepsia can progress. Can be prevented.
  • the present invention also provides the use of (i) an ⁇ 2 antagonistic action and / or (ii) an aluminum-containing compound, which is the aforementioned active ingredient, for the manufacture of a medicament for use in the treatment of functional dyspepsia.
  • the medicament may be a pharmaceutical composition, preferably in the aforementioned dosage form.
  • the manufactured medicament is used to treat functional dyspepsia for those who need treatment for the above-mentioned functional dyspepsia, for example, by using it in the above-mentioned dosage form, administration method, administration subject, dosage, etc. Can do.
  • Example 1 Screening of compounds that restore delayed gastric emptying From 209 pharmaceuticals in clinical use, compounds that can restore clonidine-induced gastric emptying were screened.
  • stomach contents collected immediately after intragastric administration was used as a standard sample.
  • Example 2 Evaluation of recovery of delayed gastric emptying by administration of aldioxa (phenol red marker method)
  • Recovery of clonidine-induced gastric emptying delay by aldioxa administration was evaluated by the phenol red marker method.
  • Mice that did not induce clonidine administration and did not induce delayed gastric emptying (Control), mice that received vehicle alone (Vehicle), and mice that received cisapride at a dose of 5 mg / kg (Cisapride) served as control groups.
  • Example 3 Evaluation of recovery of delayed gastric emptying by administration of aldioxa ( 13 C acetic acid breath test method)
  • Recovery of delayed gastric emptying by administration of aldioxa was assessed by 13 C acetic acid breath test.
  • 13 C acetate breath test method was orally administered [13 C] labeled acetic acid is rapidly absorbed in the duodenum rather than the stomach, since it is metabolized to 13 CO 2, temporal profile of the amount of 13 CO 2 in breath Based on the fact that the gastric emptying ability can be estimated by observing.
  • mice Fifteen minutes after clonidine administration, mice were intragastrically administered with racole at a dose of 5 ml / kg, containing [ 13 C] -labeled acetic acid at a dose of 16 mg / kg.
  • mice were intragastrically administered with racole at a dose of 5 ml / kg, containing [ 13 C] -labeled acetic acid at a dose of 16 mg / kg.
  • exhaled air containing 13 CO 2 was collected.
  • the ventilation rate was 50 ml / min.
  • the content of 13 CO2 in the collected exhalation was measured using a POC One analyzer (manufactured by Otsuka Electronics Co., Ltd.). Values for the ratio of 13 CO 2/12 CO 2 ( ⁇ 13 CO 2 ( ⁇ )), shown as the difference between each sample and the standard atmosphere (5% CO 2 and 95% O 2).
  • T 1/2 the gastric half emptying time (the time when half of AUC 90 min was obtained for ⁇ 13 CO 2 ( ⁇ )) was also determined.
  • Example 4 Correlation between gastroprotective action and gastric emptying promoting effect of aldioxa (1)
  • the dose of aldioxa required to exert gastroprotective action was tested.
  • the lesion score (Lesion index (mm 2 ) was calculated by measuring the area of all lesions in square millimeters and calculating the total value of the lesion areas.
  • mice that did not induce indomethacin and did not induce gastric ulcer mice that received only vehicle (Vehicle), mice that received GGA (geranylgeranylacetone (teprenone)) at doses of 50 and 200 mg / kg (GGA)
  • mice administered with sucralfate at doses of 1, 10 and 55.9 mg / kg (Sucralfate) as a control group mice that did not induce indomethacin and did not induce gastric ulcer.
  • FIG. 2A The result is shown in FIG. 2A.
  • administration of aldioxa at a dose of 200 mg / kg restored clonidine-induced gastric emptying delay.
  • FIG. 2A in order to suppress indomethacin-induced gastric ulcer, it was revealed that administration of aldioxa at a dose of 1600 mg / kg was necessary.
  • Example 5 Correlation between gastroprotective action and gastric emptying promoting effect of aldioxa (2)
  • the effect on clonidine-induced gastric emptying delay was evaluated for other gastroprotective compounds.
  • Aldioxa is a dihydroxyaluminum allantoinate that has been reported to be metabolized to allantoin and aluminum hydroxide in the gastric mucosa. Therefore, the effects of allantoin and aluminum hydroxide on clonidine-induced gastric emptying delay were evaluated.
  • Example 7 Effect of administration of aldioxa on restraint stress-induced gastric emptying delay
  • the effect of aldioxa on restraint stress-induced delayed gastric emptying was evaluated.
  • each mouse was individually placed in a 50 ml Falcon tube (Becton Dickinson) for 1 hour to give restraint stress (RS (Restraint Stress)). The tube was small enough to restrain the mouse to the extent that it could breathe but not move freely. Control mice (Control) were allowed to move freely within the cage.
  • RS Restraint Stress
  • Example 8 Effect of aldioxa administration on mice without delayed gastric emptying
  • mice fasted for 18 hours were orally administered with a 1% methylcellulose solution containing a dose of 200 mg / kg aldioxa at a dose of 10 ml / kg.
  • Example 9 Mechanism of action of promoting effect of aldioxa on gastric emptying (1)
  • GR113808 which is a selective antagonist of 5-HT 4 receptor
  • mice administered with vehicle alone (Vehicle) and mice administered with cisapride at a dose of 5 mg / kg (Cisapride) were used as control groups.
  • Mice not administered with GR113808 were similarly tested.
  • Example 10 Mechanism of action of promoting effect of aldioxa on gastric emptying (2)
  • Apomorphine which is an agonist of dopamine receptor, was used instead of clonidine at a dose of 10 mg / kg according to the method described in Example 2.
  • Example 11 Mechanism of action of promoting effect of aldioxa on gastric emptying (3)
  • changes in intracellular cAMP levels (intracellular cAMP levels) by aldioxa administration were evaluated, and the involvement of the adrenergic receptor ⁇ 2 subtype was verified.
  • Example 12 Mechanism of action of promoting effect of aldioxa on gastric emptying (4)
  • the binding affinity between human adrenergic receptor ⁇ 2 subtype and aldioxa was evaluated.
  • ⁇ Method> (Filter binding assay) The filter binding assay was performed according to the method described in the literature: Gavalda A et al. Journal of Pharmacology and Experimental Therapeutics 331: 740-751. Membrane fractions were prepared from CHO-K1 cells expressing the human ⁇ 2 adrenergic receptor. In the PBS buffer in 200 ⁇ l, the membrane fraction with a protein concentration of 10 g per well, 2 nM [ 3 H] -labeled clonidine (85.5 Ci / mmol) and the test compound were incubated at room temperature for 2 hours. . Each test compound was tested in triplicate at concentrations ranging from 10 ⁇ 10 to 3 ⁇ 10 ⁇ 5 M to generate competition curves.
  • Nonspecific binding was measured in the presence of 2.5 ⁇ M atropin.
  • the affinity in the equilibrium state is obtained experimentally by IC 50 value obtained experimentally according to the method described in the literature: Cheng Y and Prusoff WH. Biochem Pharmacol 22: 3099-3108 (1973).
  • the equilibrium antagonist dissociation constant (K i ) was calculated by correcting the K d value of the human ⁇ 2 adrenergic receptor of NMS and the concentration of NMS. K i values were determined from three independent curves. All adjustments were made using Prism (GraphPad Software).
  • Example 13 Mechanism of action of promoting effect of aldioxa on gastric emptying (5)
  • Example 2 The test was conducted according to the description of Example 2 and Example 7 except that yohimbine was administered at a dose of 1 mg / kg and 10 mg / kg instead of aldioxa.
  • Example 14 Evaluation of the effect of aldioxa administration on gastric receptivity
  • gastric acceptability (adaptive relaxation) is an index of fullness.
  • the balloon tube was connected to a pressure regulator Barostat Distender IIR (Starmedical).
  • Barostat Distender IIR Startmedical
  • the pressure inside the balloon (Balloon Pressure) was increased step by step at 1 minute intervals, the volume of the balloon gradually increased with the pressure change and eventually reached a plateau.
  • the increased volume was defined as adaptive relaxation (accomodation).

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Abstract

La présente invention concerne un nouveau médicament thérapeutique de la dyspepsie fonctionnelle. Le composant actif de ce médicament thérapeutique de la dyspepsie fonctionnelle est un composé qui (i) possède une action antagoniste alpha 2 et/ou (ii) contient de l'aluminium.
PCT/JP2015/085506 2014-12-22 2015-12-18 Médicament thérapeutique de la dyspepsie fonctionnelle Ceased WO2016104367A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN107596327A (zh) * 2017-10-26 2018-01-19 忻州市中医医院 一种治疗寒热错杂型功能性消化不良的药物
JP2021113187A (ja) * 2020-01-16 2021-08-05 ライオン株式会社 胃又は十二指腸粘膜下微小炎症改善薬及び胃排出能改善薬
JP2023173771A (ja) * 2022-05-26 2023-12-07 小林製薬株式会社 内服用医薬組成物

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107596327A (zh) * 2017-10-26 2018-01-19 忻州市中医医院 一种治疗寒热错杂型功能性消化不良的药物
JP2021113187A (ja) * 2020-01-16 2021-08-05 ライオン株式会社 胃又は十二指腸粘膜下微小炎症改善薬及び胃排出能改善薬
JP7676152B2 (ja) 2020-01-16 2025-05-14 ライオン株式会社 胃又は十二指腸粘膜下微小炎症改善薬及び胃排出能改善薬
JP2023173771A (ja) * 2022-05-26 2023-12-07 小林製薬株式会社 内服用医薬組成物
JP7759297B2 (ja) 2022-05-26 2025-10-23 小林製薬株式会社 内服用医薬組成物

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