JP2021107333A - Oral pharmaceutical composition - Google Patents
Oral pharmaceutical composition Download PDFInfo
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- JP2021107333A JP2021107333A JP2019238439A JP2019238439A JP2021107333A JP 2021107333 A JP2021107333 A JP 2021107333A JP 2019238439 A JP2019238439 A JP 2019238439A JP 2019238439 A JP2019238439 A JP 2019238439A JP 2021107333 A JP2021107333 A JP 2021107333A
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- pharmaceutical composition
- itopride
- salt
- gastrointestinal motility
- component
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- 239000008203 oral pharmaceutical composition Substances 0.000 title claims abstract description 10
- QQQIECGTIMUVDS-UHFFFAOYSA-N N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NCC1=CC=C(OCCN(C)C)C=C1 QQQIECGTIMUVDS-UHFFFAOYSA-N 0.000 claims abstract description 40
- 229960005302 itopride Drugs 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 20
- 229940069428 antacid Drugs 0.000 claims abstract description 18
- 239000003159 antacid agent Substances 0.000 claims abstract description 18
- 230000001458 anti-acid effect Effects 0.000 claims abstract description 17
- 230000005176 gastrointestinal motility Effects 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 230000003213 activating effect Effects 0.000 claims description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 230000002708 enhancing effect Effects 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 230000002496 gastric effect Effects 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 description 12
- 239000002552 dosage form Substances 0.000 description 10
- 230000030136 gastric emptying Effects 0.000 description 10
- ZNIFSRGNXRYGHF-UHFFFAOYSA-N Clonidine hydrochloride Chemical compound Cl.ClC1=CC=CC(Cl)=C1NC1=NCCN1 ZNIFSRGNXRYGHF-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 239000011324 bead Substances 0.000 description 9
- 229960002925 clonidine hydrochloride Drugs 0.000 description 9
- 239000011521 glass Substances 0.000 description 9
- 210000002784 stomach Anatomy 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
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- -1 inorganic acid salts Chemical class 0.000 description 5
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- 230000000052 comparative effect Effects 0.000 description 4
- 201000006549 dyspepsia Diseases 0.000 description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 3
- 229960004373 acetylcholine Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
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- 206010000060 Abdominal distension Diseases 0.000 description 2
- 206010000087 Abdominal pain upper Diseases 0.000 description 2
- 102000015554 Dopamine receptor Human genes 0.000 description 2
- 108050004812 Dopamine receptor Proteins 0.000 description 2
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- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
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- 230000000996 additive effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 229940008027 aluminum hydroxide / magnesium carbonate Drugs 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
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- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- 239000004471 Glycine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- BWZOPYPOZJBVLQ-UHFFFAOYSA-K aluminium glycinate Chemical compound O[Al+]O.NCC([O-])=O BWZOPYPOZJBVLQ-UHFFFAOYSA-K 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 229940043673 aluminum hydroxide / calcium carbonate Drugs 0.000 description 1
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 1
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
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- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical class CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- HUSUHZRVLBSGBO-UHFFFAOYSA-L calcium;dihydrogen phosphate;hydroxide Chemical compound O.[Ca+2].OP([O-])([O-])=O HUSUHZRVLBSGBO-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- 239000000812 cholinergic antagonist Substances 0.000 description 1
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- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
- PGZIKUPSQINGKT-UHFFFAOYSA-N dialuminum;dioxido(oxo)silane Chemical compound [Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O PGZIKUPSQINGKT-UHFFFAOYSA-N 0.000 description 1
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229940124568 digestive agent Drugs 0.000 description 1
- 229940015826 dihydroxyaluminum aminoacetate Drugs 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
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- 238000001647 drug administration Methods 0.000 description 1
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- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
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- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
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- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
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- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、イトプリド及び／又はその塩を含む内服用医薬組成物に関する。より詳細には、本発明は、イトプリド及び／又はその塩の消化管運動賦活作用が増強している内服用医薬組成物に関する。 The present invention relates to an orally-administered pharmaceutical composition containing itopride and / or a salt thereof. More specifically, the present invention relates to an orally-administered pharmaceutical composition in which the gastrointestinal motility activating effect of itopride and / or a salt thereof is enhanced.
イトプリド及びその塩には、ドパミン受容体に対して拮抗作用があり、アセチルコリンを遊離させることによる消化管運動賦活作用を示すので、機能性ディスペプシアや慢性胃炎における消化器症状（腹部膨満感、上腹部痛、食欲不振、胸やけ、悪心、嘔吐等）の改善に使用されている。また、特許文献１には、イトプリド及びその塩には、薬剤投与時における消化管機能異常を治療及び／又は予防する作用があることも報告されている。 Itopride and its salts have an antagonistic effect on dopamine receptors and show gastrointestinal motility activation by releasing acetylcholine. Therefore, gastrointestinal symptoms (abdominal bloating, upper abdomen) in functional dyspepsia and chronic gastritis. It is used to improve pain, loss of appetite, heartburn, nausea, vomiting, etc.). It is also reported in Patent Document 1 that itopride and its salt have an action of treating and / or preventing gastrointestinal dysfunction at the time of drug administration.
しかしながら、消化管運動が低下した状態での内服薬服用（特に小腸から吸収される薬物）において薬物吸収阻害が生じることが一般的に知られており、消化管運動賦活作用が減弱する恐れがある。特に、イトプリド及び／又はその塩の単独投与では、消化管運動賦活作用が十分ではなく、一旦低下した消化管運動を十分に回復できないという欠点がある。そこで、イトプリド及びその塩の消化管運動賦活作用を増強させる製剤の開発が望まれている。 However, it is generally known that drug absorption inhibition occurs when an oral drug is taken in a state where gastrointestinal motility is reduced (particularly, a drug absorbed from the small intestine), and the gastrointestinal motility activating effect may be diminished. In particular, the single administration of itopride and / or a salt thereof has a drawback that the gastrointestinal motility activating effect is not sufficient and the once decreased gastrointestinal motility cannot be sufficiently recovered. Therefore, it is desired to develop a preparation that enhances the gastrointestinal motility activating effect of itopride and its salt.
一方、制酸剤は、胃内の酸を中和して胃内のｐＨを上昇させる薬剤であり、消化管運動に対して抑制的に作用することが知られており（例えば、非特許文献１）、従来、消化管運動賦活薬と制酸剤を併用すると、消化管運動賦活作用が減弱すると考えられている。 On the other hand, an antacid is a drug that neutralizes the acid in the stomach and raises the pH in the stomach, and is known to act suppressively on gastrointestinal motility (for example, non-patent documents). 1) Conventionally, it is considered that the combined use of a gastrointestinal motility activator and an antacid diminishes the gastrointestinal motility activating effect.
本発明は、イトプリド及び／又はその塩の消化管運動賦活作用を増強させた内服用医薬組成物を提供することを目的とする。 An object of the present invention is to provide an orally-administered pharmaceutical composition in which the gastrointestinal motility activating effect of itopride and / or a salt thereof is enhanced.
本発明者は、前記課題を解決すべく鋭意検討を行ったところ、内服用医薬組成物において、イトプリド及び／又はその塩と制酸剤とを組み合わせて使用すると、イトプリド及び／又はその塩の消化管運動賦活作用が飛躍的に増強し得ることを見出した。制酸剤は、消化管運動賦活作用はなく、寧ろ消化管運動に対して抑制的に作用することが知られていることから、制酸剤がイトプリド及び／又はその塩の消化管運動賦活作用を増強させるという知見は、極めて意外といえる。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。 As a result of diligent studies to solve the above problems, the present inventor has found that when an itopride and / or a salt thereof is used in combination with an antacid in an internal medicine composition, the digestion of the itopride and / or the salt thereof is performed. It was found that the tube motility activating effect can be dramatically enhanced. Since it is known that an antacid does not have a gastrointestinal motility activating effect but rather has an inhibitory effect on gastrointestinal motility, the antacid has a gastrointestinal motility activating effect on itopride and / or a salt thereof. It can be said that the finding that it enhances is extremely surprising. The present invention has been completed by further studies based on such findings.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１． (A)イトプリド及び／又はその塩、並びに(B)制酸剤を含有する、内服用医薬組成物。
項２． 前記(A)成分１００重量部当たり、前記(B)成分を総量で１〜５０００重量部含む、項１に記載の内服用医薬組成物。
項３． 前記(B)成分が、炭酸水素ナトリウムである、項１又は２に記載の内服用医薬組成物。
項４． イトプリド及び／又はその塩の消化管運動賦活作用を増強する方法であって、
内服用医薬組成物に、イトプリド及び／又はその塩と共に、制酸剤を配合する、消化管運動賦活作用増強方法。
That is, the present invention provides the inventions of the following aspects.
Item 1. An oral pharmaceutical composition containing (A) itopride and / or a salt thereof, and (B) an antacid.
Item 4. A method for enhancing the gastrointestinal motility-activating effect of itopride and / or a salt thereof.
A method for enhancing gastrointestinal motility activating action, in which an antacid is blended with an oral pharmaceutical composition together with itopride and / or a salt thereof.
本発明の内服用医薬組成物によれば、イトプリド及び／又はその塩と、制酸剤とを併用することによって、イトプリド及び／又はその塩の消化管運動賦活作用を飛躍的に増強させることができる。 According to the pharmaceutical composition for internal use of the present invention, the gastrointestinal motility activating effect of itopride and / or its salt can be dramatically enhanced by using an antacid in combination with itopride and / or its salt. can.
１．内服用医薬組成物
本発明の内服用医薬組成物は、イトプリド及び／又はその塩（「(A)成分」と表記することもある）、並びに制酸剤（「(B)成分」と表記することもある）を含有することを特徴とする。以下、本発明の内服用医薬組成物について詳述する。
1. 1. Oral Pharmaceutical Composition The internal pharmaceutical composition of the present invention includes itopride and / or a salt thereof (sometimes referred to as "(A) component"), and an antacid (referred to as "(B) component"). It is characterized by containing (may be). Hereinafter, the pharmaceutical composition for internal use of the present invention will be described in detail.
［(A)イトプリド及び／又はその塩］
本発明の内服用医薬組成物は、(A)成分として、イトプリド及び／又はその塩を含有する。イトプリドは、ドパミン受容体に作用してアセチルコリンの遊離を促進し、またアセチルコリンの分解を抑制することにより消化管運動を賦活化させることが知られている公知の化合物である。
[(A) Itopride and / or its salt]
The pharmaceutical composition for internal use of the present invention contains itopride and / or a salt thereof as the component (A). Itopride is a known compound known to act on dopamine receptors to promote the release of acetylcholine and to activate gastrointestinal motility by suppressing the degradation of acetylcholine.
イトプリドの塩については、薬学的に許容されることを限度として特に制限されないが、例えば、塩酸塩、臭化水素酸塩、硫酸塩、硝酸塩、燐酸塩等の無機酸塩；酢酸塩、マレイン酸塩、フマル酸塩、リンゴ酸塩、クエン酸塩、シュウ酸塩、乳酸塩、酒石酸塩等の有機酸塩が挙げられる。これらの塩の中でも、好ましくは無機酸塩、より好ましくは塩酸塩が挙げられる。 The salt of itopride is not particularly limited as long as it is pharmaceutically acceptable, but for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; acetate, maleic acid, etc. Examples thereof include organic acid salts such as salts, fumarates, malates, citrates, oxalates, lactates and tartrates. Among these salts, an inorganic acid salt is preferable, and a hydrochloride salt is more preferable.
本発明の内服用医薬組成物では、(A)成分として、イトプリド及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 In the pharmaceutical composition for internal use of the present invention, as the component (A), one of itopride and a salt thereof may be selected and used alone, or two or more thereof may be used in combination.
(A)成分の中でも、好ましくはイトプリドの塩、より好ましくはイトプリド塩酸塩が挙げられる。 Among the components (A), a salt of itopride is preferable, and a salt of itopride hydrochloride is more preferable.
本発明の内服用医薬組成物における(A)成分の含有量については、剤型、投与量等に応じて適宜設定すればよいが、例えば、０．１〜９０重量％、好ましくは１〜３０重量％、より好ましくは２〜１０重量％が挙げられる。 The content of the component (A) in the oral pharmaceutical composition of the present invention may be appropriately set according to the dosage form, dosage and the like, and is, for example, 0.1 to 90% by weight, preferably 1 to 30. By weight%, more preferably 2 to 10% by weight.
［(B)制酸剤］
本発明の内服用医薬組成物は、(B)成分として、制酸剤を含有する。イトプリド及び／又はその塩と制酸剤と併用することによって、イトプリド及び／又はその塩の消化管運動賦活作用を飛躍的に増強させることができる。
[(B) Antacid]
The pharmaceutical composition for internal use of the present invention contains an antacid as the component (B). By using itopride and / or a salt thereof in combination with an antacid, the gastrointestinal motility activating effect of itopride and / or a salt thereof can be dramatically enhanced.
制酸剤とは、胃酸を中和する薬剤である。本発明で使用される制酸剤の種類については、特に制限されないが、例えば、炭酸水素ナトリウム、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、合成ケイ酸アルミニウム、ショ糖硫酸エステルアルミニウム塩、乾燥水酸化アルミニウムゲル、水酸化アルミナマグネシウム、水酸化アルミニウムゲル、水酸化マグネシウム、酸化マグネシウム、炭酸マグネシウム、沈降炭酸カルシウム、無水リン酸水素カルシウム、リン酸水素カルシウム水和物、烏賊骨、石決明、ボレイ、合成ヒドロタルサイト、アミノ酪酸、ジヒドロアルミニウムアミノアセテート、水酸化アルミニウム・炭酸水素ナトリウム共沈生成物、水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲル、水酸化アルミニウム・炭酸マグネシウム・炭酸カルシウム共沈生成物、グリシン、ジヒドロキシアルミニウムアミノアセテート及びロートエキス等が挙げられる。これらの制酸剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 An antacid is a drug that neutralizes stomach acid. The type of the antioxidant used in the present invention is not particularly limited, but for example, sodium hydrogen carbonate, magnesium aluminometasilicate, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, sucrose sulfate ester. Aluminum salt, dried aluminum hydroxide gel, magnesium hydroxide, aluminum hydroxide gel, magnesium hydroxide, magnesium oxide, magnesium carbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, pirate bone, Ishisei, Borei, Synthetic hydrotalcite, Aminobutyric acid, Dihydroaluminum aminoacetate, Aluminum hydroxide / sodium hydrogencarbonate co-precipitated product, Aluminum hydroxide / magnesium carbonate mixed dry gel, Aluminum hydroxide / magnesium carbonate / calcium carbonate Co-precipitation products, glycine, dihydroxyaluminum aminoacetate, funnel extract and the like can be mentioned. These antacids may be used alone or in combination of two or more.
(B)成分の中でも、イトプリド及び／又はその塩の消化管運動賦活作用をより一層効果的に増強させるという観点から、好ましくは炭酸水素ナトリウムが挙げられる。 Among the components (B), sodium hydrogen carbonate is preferably mentioned from the viewpoint of more effectively enhancing the gastrointestinal motility activating effect of itopride and / or a salt thereof.
また、本発明の内服用医薬組成物において、(A)成分と(B)成分の比率としては、例えば、(A)成分１００重量部当たり、(B)成分の総量が１００〜１００００重量部が挙げられる。イトプリド及び／又はその塩の消化管運動賦活作用をより一層増強させるという観点から、(A)成分１００重量部当たり、(B)成分の総量が、好ましくは５００〜５０００重量部、より好ましくは１０００〜３５００重量部が挙げられる。 Further, in the pharmaceutical composition for internal use of the present invention, the ratio of the component (A) to the component (B) is, for example, 100 to 10,000 parts by weight of the total amount of the component (B) per 100 parts by weight of the component (A). Can be mentioned. From the viewpoint of further enhancing the gastrointestinal motility activating effect of itopride and / or a salt thereof, the total amount of the component (B) is preferably 500 to 5000 parts by weight, more preferably 1000 parts by weight per 100 parts by weight of the component (A). ~ 3500 parts by weight can be mentioned.
本発明の内服用医薬組成物における(B)成分の含有量については、前述する(A)成分と(B)成分の比率に応じた範囲内で、使用する(B)成分の種類、剤型、投与量等に応じて適宜設定すればよいが、例えば、１０〜９９．９重量％、好ましくは５０〜９９重量％、より好ましくは７０〜９８重量％が挙げられる。 Regarding the content of the component (B) in the pharmaceutical composition for internal use of the present invention, the type and dosage form of the component (B) to be used within the range corresponding to the ratio of the component (A) and the component (B) described above. It may be appropriately set according to the dosage and the like, and examples thereof include 10 to 99.9% by weight, preferably 50 to 99% by weight, and more preferably 70 to 98% by weight.
［その他の含有成分］
本発明の内服用医薬組成物には、前述する成分以外に、必要に応じて、他の薬理成分を含んでいてもよい。このような薬理成分の種類については、特に制限されないが、例えば、消炎鎮痛剤、消化剤、鎮痙剤、粘膜修復剤、収れん剤、鎮吐剤、鎮咳剤、去痰剤、消炎酵素剤、催眠鎮静剤、抗ヒスタミン剤、強心利尿剤、抗菌剤、血管収縮剤、血管拡張剤、局所麻酔剤、プロトンポンプ阻害薬、生薬、生薬エキス、カフェイン類、メントール類、ポリフェノール等が挙げられる。これらの薬理成分は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。また、これらの薬理成分の含有量については、使用する薬理成分の種類や内服用医薬組成物の剤型等に応じて適宜設定すればよい。
[Other ingredients]
The pharmaceutical composition for internal use of the present invention may contain other pharmacological components in addition to the above-mentioned components, if necessary. The type of such pharmacological component is not particularly limited, but for example, an anti-inflammatory analgesic, a digestive agent, an antispasmodic agent, a mucosal repair agent, an astringent agent, an antiemetic agent, an antitussive agent, a sputum-eliminating agent, an anti-inflammatory enzyme agent, a hypnotic sedative agent, and an antihistamine agent. , Cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, proton pump inhibitors, crude drugs, crude drug extracts, caffeines, menthols, polyphenols and the like. These pharmacological components may be used alone or in combination of two or more. The content of these pharmacological components may be appropriately set according to the type of the pharmacological component used, the dosage form of the pharmaceutical composition for internal use, and the like.
本発明の医薬組成物には、所望の剤型に調製するために、必要に応じて、薬学的に許容される基剤や添加剤等が含まれていてもよい。このような基剤及び添加剤としては、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、等張化剤、可塑剤、分散剤、乳化剤、溶解補助剤、湿潤化剤、安定化剤、懸濁化剤、粘着剤、コーティング剤、光沢化剤、水、油脂類、ロウ類、炭化水素類、脂肪酸類、高級アルコール類、エステル類、水溶性高分子、界面活性剤、低級アルコール類、多価アルコール、ｐＨ調整剤、緩衝剤、酸化防止剤、紫外線防止剤、防腐剤、矯味剤、香料、粉体、増粘剤、色素、キレート剤等が挙げられる。これらの基剤や添加剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。また、これらの基剤や添加剤の含有量については、使用する添加成分の種類や内服用医薬組成物の剤型等に応じて適宜設定すればよい。 The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable base, additives and the like, if necessary, in order to prepare a desired dosage form. Such bases and additives include, for example, excipients, binders, disintegrants, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers. Agents, suspending agents, pressure-sensitive agents, coating agents, brighteners, water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, lower alcohols Types, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, preservatives, flavoring agents, fragrances, powders, thickeners, pigments, chelating agents and the like. These bases and additives may be used alone or in combination of two or more. The content of these bases and additives may be appropriately set according to the type of additive component to be used, the dosage form of the pharmaceutical composition for internal use, and the like.
［剤型］
本発明の内服用医薬組成物の剤型については、特に制限されず、固体状製剤、半固体状製剤、又は液体状製剤のいずれであってもよい。
[Dosage form]
The dosage form of the pharmaceutical composition for internal use of the present invention is not particularly limited, and may be any of a solid-state preparation, a semi-solid-state preparation, and a liquid-state preparation.
固体状製剤としては、具体的には、錠剤、丸剤、カプセル剤（軟カプセル剤、硬カプセル剤）、散剤、顆粒剤（ドライシロップを含む）等が挙げられる。半固体状製剤としては、具体的には、ゼリー剤等が挙げられる。液体状製剤としては、具体的には、液剤、懸濁剤、シロップ剤等が挙げられる。 Specific examples of the solid-state preparation include tablets, pills, capsules (soft capsules, hard capsules), powders, granules (including dry syrup) and the like. Specific examples of the semi-solid preparation include a jelly agent and the like. Specific examples of the liquid preparation include liquid preparations, suspension preparations, syrup preparations and the like.
これらの剤型の中でも、好ましくは固体状製剤が挙げられる。 Among these dosage forms, a solid-state preparation is preferable.
本発明の内服用医薬組成物を前記剤型に調製するには、(A)成分、(B)成分、及び必要に応じて添加される他の薬理成分、基剤、及び添加剤を用いて、医薬分野で採用されている通常の製剤化手法に従って製剤化すればよい。 In order to prepare the pharmaceutical composition for internal use of the present invention in the above-mentioned dosage form, the component (A), the component (B), and other pharmacological components, the base, and the additive added as needed are used. , It may be formulated according to the usual formulation method adopted in the pharmaceutical field.
［用法・用量］
本発明の内服用医薬組成物は、イトプリド及び／又はその塩の消化管運動賦活作用が増強して発揮されるので、消化管運動賦活化によって予防又は改善できる疾患や症状に適用される。このような疾患や症状としては、具体的には、機能性ディスペプシア又は慢性胃炎における消化器症状（腹部膨満感、上腹部痛、食欲不振、胸やけ、悪心、嘔吐等）、胃痛等が挙げられる。
[Dosage and administration]
The pharmaceutical composition for internal use of the present invention is applied to diseases and symptoms that can be prevented or ameliorated by activating gastrointestinal motility because the gastrointestinal motility activating effect of itopride and / or a salt thereof is enhanced and exerted. Specific examples of such diseases and symptoms include gastrointestinal symptoms (abdominal bloating, upper abdominal pain, loss of appetite, heartburn, nausea, vomiting, etc.) in functional dyspepsia or chronic gastritis, stomach pain and the like. ..
本発明の内服用医薬組成物の服用量については、用途、服用者の年齢等に応じて適宜設定すればよいが、例えば、１日当たりのイトプリド及び／又はその塩の服用量が１〜３００ｍｇ程度、好ましくは５０〜１５０ｍｇ程度、より好ましくは１００〜１５０ｍｇ程度となる量で、１日当たり１〜３回程度服用すればよい。 The dose of the pharmaceutical composition for internal use of the present invention may be appropriately set according to the intended use, the age of the user, etc., and for example, the daily dose of itopride and / or a salt thereof is about 1 to 300 mg. It may be taken in an amount of preferably about 50 to 150 mg, more preferably about 100 to 150 mg, about 1 to 3 times a day.
２．消化管運動賦活作用の増強方法
本発明は、更に、イトプリド及び／又はその塩の消化管運動賦活作用を増強する方法であって、内服用医薬組成物に、イトプリド及び／又はその塩と共に、制酸剤を配合することを特徴とする消化管運動賦活作用増強方法を提供する。
2. Method for enhancing gastrointestinal motility activating effect The present invention is a method for further enhancing the gastrointestinal motility activating effect of itopride and / or a salt thereof, which is controlled in an oral pharmaceutical composition together with itopride and / or a salt thereof. Provided is a method for enhancing gastrointestinal motility activating action, which comprises blending an acid agent.
当該消化管運動賦活作用増強方法において、使用される成分の種類、配合量、内服用医薬組成物の剤型等については、前記「１．内服用医薬組成物」の欄に記載の通りである。 The types and amounts of the ingredients used in the method for enhancing the gastrointestinal motility activating effect, the dosage form of the pharmaceutical composition for internal use, etc. are as described in the column of "1. Pharmaceutical composition for internal use". ..
以下、本発明を実施例により具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples.
試験例１：胃排出能の評価
９週齢の雄性ラット（Ｓｌｃ：Ｗｉｓｔａｒ系、日本エスエルシー株式会社）を、無処置群、コントロール群、及び試験群（実施例１及び比較例１〜２）の５群（１群当たり１０〜１３匹）に分けた。各群のラットを５日〜１週間飼育して馴化させた後に以下の条件で試験を行った。
Test Example 1: Evaluation of gastric emptying ability 9-week-old male rats (Slc: Wistar system, Nippon SLC Co., Ltd.) were subjected to an untreated group, a control group, and a test group (Example 1 and Comparative Examples 1 and 2). It was divided into 5 groups (10 to 13 animals per group). Rats in each group were bred for 5 days to 1 week to acclimatize, and then the test was conducted under the following conditions.
・正常群
約２４時間絶食させた後に、生理食塩水（１ｍｌ/ｋｇ）を皮下投与した。生理食塩水投与の１０分後に０．１重量％カルボキシメチルセルロース水溶液（以下、ＣＭＣ液）５ｍｌ／ｋｇ（ラット体重）となる用量で経口投与した。ＣＭＣ液投与の２０分後に、１００個のガラスビーズ（直径７５０〜１０００μｍ）を含む蒸留水１ｍｌを経口投与した。ガラスビーズ投与の６０分後にラットの胃を摘出し、胃内に残存するガラスビーズを計数し、胃排出率を求めた。
-After fasting for about 24 hours in the normal group , physiological saline (1 ml / kg) was subcutaneously administered. Ten minutes after the administration of physiological saline, 0.1 wt% carboxymethyl cellulose aqueous solution (hereinafter referred to as CMC solution) was orally administered at a dose of 5 ml / kg (rat body weight). Twenty minutes after administration of the CMC solution, 1 ml of distilled water containing 100 glass beads (750 to 1000 μm in diameter) was orally administered. 60 minutes after the administration of the glass beads, the rat stomach was removed, and the glass beads remaining in the stomach were counted to determine the gastric emptying rate.
・コントロール群
約２４時間絶食させた後に、消化管運動抑制作用のあるクロニジン塩酸塩（４μｇ／ｋｇ；投与液量は１ｍｌ/ｋｇ）を皮下投与した。クロニジン塩酸塩投与の１０分後にＣＭＣ液５ｍｌ／ｋｇ（ラット体重）となる用量で経口投与した。ＣＭＣ液投与の２０分後に、１００個のガラスビーズ（直径７５０〜１０００μｍ）を含む蒸留水１ｍｌを経口投与した。ガラスビーズ投与の６０分後にラットの胃を摘出し、胃内に残存するガラスビーズを計数し、胃排出率を求めた。
-Control group After fasting for about 24 hours, clonidine hydrochloride (4 μg / kg; dosage: 1 ml / kg) having a gastrointestinal motility inhibitory effect was subcutaneously administered. Ten minutes after the administration of clonidine hydrochloride, the CMC solution was orally administered at a dose of 5 ml / kg (rat body weight). Twenty minutes after administration of the CMC solution, 1 ml of distilled water containing 100 glass beads (750 to 1000 μm in diameter) was orally administered. 60 minutes after the administration of the glass beads, the rat stomach was removed, and the glass beads remaining in the stomach were counted to determine the gastric emptying rate.
・試験群
約２４時間絶食させた後に、消化管運動抑制作用のあるクロニジン塩酸塩（４μｇ／ｋｇ；投与液量は１ｍｌ/ｋｇ）を皮下投与した。クロニジン塩酸塩の投与の１０分後に、表１に示す成分を所定の投与量となるようにＣＭＣ液に添加して作製した試験液を５ｍｌ／ｋｇ（ラット体重）となる用量で経口投与した。試験液投与の２０分後に、１００個のガラスビーズ（直径７５０〜１０００μｍ）を含む蒸留水１ｍｌを経口投与した。ガラスビーズ投与の６０分後にラットの胃を摘出し、胃内に残存するガラスビーズを計数し、胃排出率を求めた。
-Test group After fasting for about 24 hours, clonidine hydrochloride (4 μg / kg; dosage: 1 ml / kg) having a gastrointestinal motility inhibitory effect was subcutaneously administered. Ten minutes after the administration of clonidine hydrochloride, the test solution prepared by adding the components shown in Table 1 to the CMC solution at a predetermined dose was orally administered at a dose of 5 ml / kg (rat body weight). Twenty minutes after administration of the test solution, 1 ml of distilled water containing 100 glass beads (750 to 1000 μm in diameter) was orally administered. 60 minutes after the administration of the glass beads, the rat stomach was removed, and the glass beads remaining in the stomach were counted to determine the gastric emptying rate.
なお、胃排出率は、下記算出式に従って求めた。
結果を図１に示す。クロニジン塩酸塩を投与したコントロール群では、正常群に比べて、胃排出率が著しく低下しており、胃運動が低下した病態を再現できていた。また、クロニジン塩酸塩投与後にイトプリド塩酸塩を単独で投与した比較例１では、コントロール群に比べて、胃排出率が有意に高くなっていた。また、クロニジン塩酸塩投与後に炭酸水素ナトリウムを単独で投与した比較例２では、胃排出率はコントロール群と同等であった。一方、クロニジン塩酸塩投与後にイトプリド塩酸塩及び炭酸水素ナトリウムを投与した実施例１では、比較例１及び２に比べて胃排出率が有意に高くなっており、格段に優れた胃排出能の改善効果が認められた。 The results are shown in FIG. In the control group to which clonidine hydrochloride was administered, the gastric emptying rate was significantly reduced as compared with the normal group, and the pathological condition in which gastric motility was reduced could be reproduced. In addition, in Comparative Example 1 in which itopride hydrochloride was administered alone after the administration of clonidine hydrochloride, the gastric emptying rate was significantly higher than that in the control group. In Comparative Example 2 in which sodium hydrogen carbonate was administered alone after administration of clonidine hydrochloride, the gastric emptying rate was equivalent to that in the control group. On the other hand, in Example 1 in which itopride hydrochloride and sodium hydrogen carbonate were administered after the administration of clonidine hydrochloride, the gastric emptying rate was significantly higher than that in Comparative Examples 1 and 2, and the gastric emptying ability was remarkably improved. The effect was recognized.
製剤例
表２及び３に示す組成の顆粒剤、並びに表４に示す組成の液剤を調製した。これらの製剤は、イトプリド塩酸塩と制酸剤の相乗的作用によって、格段に優れた消化管運動賦活作用を発揮できる。
Pharmaceutical Examples Granules having the compositions shown in Tables 2 and 3 and liquids having the compositions shown in Table 4 were prepared. These preparations can exert a remarkably excellent gastrointestinal motility activating effect by the synergistic action of itopride hydrochloride and an antacid.
Claims (4)
内服用医薬組成物に、イトプリド及び／又はその塩と共に、制酸剤を配合する、消化管運動賦活作用増強方法。 A method for enhancing the gastrointestinal motility-activating effect of itopride and / or a salt thereof.
A method for enhancing gastrointestinal motility activating action, in which an antacid is blended with an oral pharmaceutical composition together with itopride and / or a salt thereof.
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| JPH08259445A (en) * | 1995-01-27 | 1996-10-08 | Takeda Chem Ind Ltd | Medicinal composition for improving gastric emptying performance |
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|---|---|---|---|---|
| JPH08259445A (en) * | 1995-01-27 | 1996-10-08 | Takeda Chem Ind Ltd | Medicinal composition for improving gastric emptying performance |
| WO2006134611A1 (en) * | 2005-06-16 | 2006-12-21 | Hetero Drugs Limited | Compositions of antiulcerative substituted benzimidazoles |
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