JP2008050324A - Bitter-masking composition - Google Patents
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- 239000000203 mixture Substances 0.000 title claims abstract description 60
- 230000000595 bitter masking effect Effects 0.000 title 1
- 239000000843 powder Substances 0.000 claims abstract description 52
- 239000011248 coating agent Substances 0.000 claims abstract description 36
- 238000000576 coating method Methods 0.000 claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 21
- 235000019640 taste Nutrition 0.000 claims abstract description 19
- 229920003176 water-insoluble polymer Polymers 0.000 claims abstract description 14
- 229920000642 polymer Polymers 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 43
- 239000008187 granular material Substances 0.000 claims description 24
- 235000010355 mannitol Nutrition 0.000 claims description 21
- 239000004503 fine granule Substances 0.000 claims description 18
- ALLWOAVDORUJLA-UHFFFAOYSA-N Rebamipida Chemical group C=1C(=O)NC2=CC=CC=C2C=1CC(C(=O)O)NC(=O)C1=CC=C(Cl)C=C1 ALLWOAVDORUJLA-UHFFFAOYSA-N 0.000 claims description 15
- 229950004535 rebamipide Drugs 0.000 claims description 15
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical group CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 14
- 239000001856 Ethyl cellulose Substances 0.000 claims description 13
- 229920001249 ethyl cellulose Polymers 0.000 claims description 13
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 13
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 12
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 11
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 11
- 239000001069 triethyl citrate Substances 0.000 claims description 10
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 10
- 235000013769 triethyl citrate Nutrition 0.000 claims description 10
- 239000004014 plasticizer Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 2
- 238000010828 elution Methods 0.000 abstract description 5
- 239000010419 fine particle Substances 0.000 abstract description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 20
- 239000007788 liquid Substances 0.000 description 15
- 238000005469 granulation Methods 0.000 description 14
- 230000003179 granulation Effects 0.000 description 14
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 12
- 235000012239 silicon dioxide Nutrition 0.000 description 12
- 235000019658 bitter taste Nutrition 0.000 description 11
- 239000001087 glyceryl triacetate Substances 0.000 description 10
- 235000013773 glyceryl triacetate Nutrition 0.000 description 10
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- 229920002678 cellulose Polymers 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
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- 230000000694 effects Effects 0.000 description 3
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- 150000005846 sugar alcohols Polymers 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 229920003114 HPC-L Polymers 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- -1 and the like Polymers 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000307 polymer substrate Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、医薬の苦味等の不快な味が有効に遮蔽され、かつその溶出性に優れた粉末組成物、製剤化された散剤、細粒剤及び顆粒剤に関する。 The present invention relates to a powder composition, a formulated powder, a fine granule, and a granule that are effectively shielded from unpleasant tastes such as a bitter taste of a medicine and have excellent dissolution properties.
医薬はその適正量を適時に投薬されることによって、予定の効果が期待できる。したがって固形製剤の場合、服用し易い製剤であることが、その薬物コンプライアンスの観点から、重要である。
そこで、例えば錠剤の飲み込みが困難な小児や高齢者に対しては、散剤、細粒剤又は顆粒剤等が提供されている。
しかし、強い苦味等の不快な味を有する医薬を散剤、細粒剤又は顆粒剤とする場合は、不快味遮断のために必要な具体的手段が、しばしば医薬溶出の遅延を招くこととなり、問題となる。
従来より、細粒剤等の主薬の不快味を遮蔽する手段として、主薬含有粉末を種々の高分子基材で被覆する技術が開示されている（特許文献１〜６）。その中には、主薬の苦味の遮蔽とその速放性を両立することを課題とした細粒剤に関するものがある（特許文献１及び２）
A drug can be expected to have a predetermined effect by being dosed in an appropriate amount in a timely manner. Therefore, in the case of a solid preparation, it is important from the viewpoint of drug compliance that the preparation is easy to take.
Therefore, for example, powders, fine granules or granules are provided for children and elderly people who have difficulty swallowing tablets.
However, when a medicine with an unpleasant taste such as a strong bitter taste is used as a powder, fine granule or granule, the specific means necessary for blocking the unpleasant taste often leads to a delay in the dissolution of the medicine. It becomes.
Conventionally, as a means for shielding the unpleasant taste of a main agent such as a fine granule, techniques for coating a main agent-containing powder with various polymer base materials have been disclosed (Patent Documents 1 to 6). Among them, there are those relating to fine granules intended to achieve both the masking of the bitter taste of the active ingredient and its immediate release (Patent Documents 1 and 2).
本発明の課題は、医薬の苦味等の不快な味が有効に遮蔽され、したがって服用し易い組成物であって、かつその溶出性に優れた粉末組成物、製剤化された散剤、細粒剤及び顆粒剤を提供することにある。 An object of the present invention is to provide a powder composition, a formulated powder, and a fine granule which are effective in shielding unpleasant tastes such as a bitter taste of medicine, and thus are easy to take and have excellent dissolution properties. And providing granules.
本発明者らは、前記課題を解決するため、予備的検討として、強力な苦味を有するレバミピド（一般的名称）を用い、従来技術について種々追試をしたところ、苦味の遮蔽効果とその溶出速度の両方において満足と言える結果が得られなかった。
そこで、鋭意検討した結果、レバミピドを含有する粉末組成物に対し、ポリマー基材で三層の皮膜を被覆することにより、前記課題を解決することができることを見出した。
本発明者らは、さらに検討を加え、本発明を完成することができた。
In order to solve the above-mentioned problems, the present inventors conducted a reexamination on the prior art by using rebamipide (generic name) having a strong bitterness as a preliminary study. In both cases, satisfactory results could not be obtained.
Thus, as a result of intensive studies, it was found that the above-mentioned problems can be solved by coating a powder composition containing rebamipide with a three-layer coating with a polymer substrate.
The present inventors have further studied and completed the present invention.
すなわち、本発明によれば、
［１］不快味を有する医薬を含有する微粉末に、三層の皮膜を被覆してなる粉末組成物、
［２］不快味を有する医薬を含有する微粉末に、第一層を水不溶性ポリマー含有組成物、第二層を腸溶性ポリマー含有組成物、第三層を水不溶性ポリマー含有組成物で順次被覆してなる前記［１］に記載の粉末組成物、
［３］第一層及び第三層の水不溶性のポリマーが、エチルセルロースであり、第二層の腸溶性ポリマーがメタクリル酸コポリマーＬＤである前記［２］に記載の粉末組成物、
［４］第一層及び第三層の水不溶性のポリマー含有組成物がエチルセルロース、Ｄ−マンニトール及び可塑剤を含有し、第二層の腸溶性ポリマー含有組成物がメタクリル酸コポリマーＬＤ、Ｄ−マンニトール、滑沢剤及びクエン酸トリエチルを含有する前記［３］に記載の粉末組成物、
［５］前記［１］、［２］、［３］又は［４］に記載の粉末組成物を造粒してなる散剤、細粒剤又は顆粒剤、
［６］医薬がレバミピドである前記［１］、［２］、［３］若しくは［４］に記載の粉末組成物又は前記［５］に記載の散剤、細粒剤若しくは顆粒剤を提供することができる。
That is, according to the present invention,
[1] A powder composition obtained by coating a fine powder containing a medicine having an unpleasant taste with a three-layer coating,
[2] A fine powder containing a pharmaceutical having an unpleasant taste is sequentially coated with a water-insoluble polymer-containing composition as a first layer, an enteric polymer-containing composition as a second layer, and a composition containing a water-insoluble polymer as a third layer. The powder composition according to the above [1],
[3] The powder composition according to the above [2], wherein the water-insoluble polymer of the first layer and the third layer is ethyl cellulose, and the enteric polymer of the second layer is a methacrylic acid copolymer LD,
[4] The water-insoluble polymer-containing composition of the first layer and the third layer contains ethyl cellulose, D-mannitol and a plasticizer, and the enteric polymer-containing composition of the second layer is a methacrylic acid copolymer LD, D-mannitol. A powder composition as described in [3] above, which contains a lubricant and triethyl citrate,
[5] A powder, a fine granule, or a granule formed by granulating the powder composition according to [1], [2], [3], or [4],
[6] To provide the powder composition according to [1], [2], [3] or [4], or the powder, fine granule or granule according to [5], wherein the medicine is rebamipide. Can do.
本発明によれば、不快味を有する医薬の不快味を効果的に遮蔽するとともに、一方でその溶出の遅延を来さない三層被覆粉末組成物を提供することができ、
さらには、これを造粒した服用しやすく、即効性のある不快味医薬含有散剤、細粒剤又は顆粒剤を提供することができる。
According to the present invention, it is possible to provide a three-layer coated powder composition that effectively shields an unpleasant taste of a pharmaceutical having an unpleasant taste, while not causing a delay in elution,
Furthermore, it is possible to provide a powder, fine granule or granule containing an unpleasant tasting medicine which is easy to be taken and granulated.
本発明は、不快味を有する医薬、特に極めて強い苦味を有するレバミピド、レボフロキサシン、ファモチジン等の医薬に対して有効に適用できる。その医薬の好ましい平均粒子径（レーザー回折式粒度分布測定法によるＤ５０値。以下において同じ。）は、１μｍ〜２００μｍ、より好ましくは２μｍ〜５０μｍである。 The present invention can be effectively applied to a medicament having an unpleasant taste, particularly a medicament such as rebamipide, levofloxacin, famotidine and the like having a very strong bitter taste. The preferable average particle diameter (D50 value by laser diffraction particle size distribution measurement method; the same applies hereinafter) of the pharmaceutical is 1 μm to 200 μm, more preferably 2 μm to 50 μm.
三層被覆の芯部を構成する医薬とともに使用してもよい添加剤としては、単なる増量剤として、あるいは皮膜を被覆する際の流動化助剤としての機能を有するものであればよく、例えば、乳糖、Ｄ−マンニトール、結晶セルロース、トウモロコシ澱粉、軽質無水ケイ酸等を挙げることができる。それらの平均粒子径としては、１μｍ〜３００μｍ程度が好ましい。 As an additive that may be used together with the medicine constituting the core of the three-layer coating, any additive may be used as long as it has a function as a mere extender or as a fluidizing aid when coating a film. Examples thereof include lactose, D-mannitol, crystalline cellulose, corn starch, and light anhydrous silicic acid. Their average particle diameter is preferably about 1 μm to 300 μm.
本発明で使用し得る製剤基材と、本発明の粉末組成物又は散剤、細粒剤若しくは顆粒剤中の製剤基材の適正割合は、芯部を構成する医薬の種類、目標とする不快味遮蔽の度合、あるいは溶出制御の度合等によって変動するが、不快味を有する医薬が、レバミピドのように強力な苦味を有する医薬の場合を例に好ましい態様を示せば、以下の如くである。 The appropriate ratio of the pharmaceutical base material that can be used in the present invention and the pharmaceutical composition of the present invention in the powder composition or powder, fine granule, or granule is the type of medicine that constitutes the core, the target unpleasant taste The preferred embodiment of the medicine having an unpleasant taste, such as rebamipide, which has a strong bitter taste, varies depending on the degree of shielding or the degree of elution control, is as follows.
第一層及び第三層の皮膜を構成する水不溶性ポリマーとしては、エチルセルロース、アミノアルキルメタクリレートコポリマーＲＳ、アクリル酸エチル・メタクリル酸メチルコポリマー等が挙げられるが、好ましくはエチルセルロースである。その割合としては、第一層には、粉末組成物重量の５％〜３０％が好ましく、より好ましくは１０％〜２０％である。第三層には、粉末組成物重量の１％〜２０％が好ましく、より好ましくは２％〜１０％である。 Examples of the water-insoluble polymer constituting the coating of the first layer and the third layer include ethyl cellulose, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer, and the like, preferably ethyl cellulose. As the proportion thereof, 5% to 30% of the weight of the powder composition is preferable in the first layer, and more preferably 10% to 20%. In the third layer, 1% to 20% of the weight of the powder composition is preferable, and more preferably 2% to 10%.
第一層及び第三層の構成成分である水不溶性ポリマーとともに使用してもよい可塑剤としては、トリアセチン、ステアリン酸、ポリエチレングリコール、クエン酸トリエチル等が挙げられるが、中でもトリアセチンが好ましい。その割合として、第一層には、粉末組成物重量の１％〜１０％が好ましく、より好ましくは２％〜６％である。第三層には、粉末組成物重量の０．１％〜５％が好ましく、より好ましくは０．５％〜３％である。
第一層及び第三層の構成成分である水不溶性ポリマーとともに使用してもよいその他の成分としては、Ｄ−マンニトール、キシリトール、エリスリトール等の多価アルコール類が挙げられるが、中でもＤ−マンニトールが好ましい。その割合としては、第一層には、粉末組成物重量の０％〜３０％が好ましく、より好ましくは５％〜１５％である。第三層には、粉末組成物重量の０％〜２０％が好ましく、より好ましくは０％〜５％である。
Examples of the plasticizer that may be used together with the water-insoluble polymer that is a constituent of the first layer and the third layer include triacetin, stearic acid, polyethylene glycol, triethyl citrate, and the like, among which triacetin is preferable. As the ratio, 1% to 10% of the weight of the powder composition is preferable in the first layer, and more preferably 2% to 6%. For the third layer, 0.1% to 5% of the weight of the powder composition is preferable, and more preferably 0.5% to 3%.
Other components that may be used together with the water-insoluble polymer that is a component of the first layer and the third layer include polyhydric alcohols such as D-mannitol, xylitol, and erythritol. preferable. As the ratio, 0% to 30% of the weight of the powder composition is preferable in the first layer, and more preferably 5% to 15%. In the third layer, 0% to 20% of the weight of the powder composition is preferable, and more preferably 0% to 5%.
第二層の皮膜を構成する腸溶性ポリマーとしては、メタクリル酸コポリマーＬＤ、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート等が挙げられるが、好ましくはメタクリル酸コポリマーＬＤである。その割合としては、粉末組成物重量の１％〜２０％がこのましく、より好ましくは５％〜１５％である。
第二層の構成成分である腸溶性ポリマーとともに使用してもよい可塑剤としては、クエン酸トリエチル、ポリエチレングリコール等が挙げられるが、中でもクエン酸トリエチルが好ましい。その割合としては、粉末組成物重量の０．１％〜５％が好ましく、より好ましくは０．５％〜１．５％である。
第二層の構成成分である腸溶性ポリマーとともに使用してもよい他の成分としてタルク、軽質無水ケイ酸等が挙げられるが、中でもタルクが好ましく、その割合としては、粉末組成物重量の０．１％〜１５％が好ましく、より好ましくは１％〜１０％である。また、前記例示の多価アルコール類も使用でき、中でもＤ−マンニトールが好ましい。その割合として、粉末組成物重量の０．１％〜１５％が好ましく、より好ましくは１％〜１０％である。
Examples of the enteric polymer constituting the coating of the second layer include methacrylic acid copolymer LD, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and the like, and methacrylic acid copolymer LD is preferable. The proportion is preferably 1% to 20% of the weight of the powder composition, more preferably 5% to 15%.
Examples of the plasticizer that may be used together with the enteric polymer that is a component of the second layer include triethyl citrate, polyethylene glycol, and the like, among which triethyl citrate is preferable. The proportion is preferably from 0.1% to 5%, more preferably from 0.5% to 1.5% of the weight of the powder composition.
Examples of other components that may be used together with the enteric polymer that is a constituent of the second layer include talc and light anhydrous silicic acid. Among these, talc is preferable, and the ratio thereof is about 0.00% of the weight of the powder composition. It is preferably 1% to 15%, more preferably 1% to 10%. The exemplified polyhydric alcohols can also be used, and D-mannitol is particularly preferable. The proportion is preferably 0.1% to 15%, more preferably 1% to 10% of the weight of the powder composition.
第一層の皮膜重量としては、本発明粉末組成物重量の１０％〜５０％が好ましく、第二層の皮膜重量としては、本発明粉末組成物重量の５％〜３０％が好ましく、第三層の皮膜重量としては、本発明粉末組成物重量の１％〜２０％が好ましい。 The film weight of the first layer is preferably 10% to 50% of the weight of the powder composition of the present invention, and the film weight of the second layer is preferably 5% to 30% of the weight of the powder composition of the present invention. The film weight of the layer is preferably 1% to 20% of the weight of the powder composition of the present invention.
第一層、第二層及び第三層を構成する水不溶性ポリマー又は腸溶性ポリマーとともに使用してもよい前記例示の添加剤の使用重量は、合せて皮膜重量の６０％程度までが好ましい。 The total weight of the exemplified additives that may be used together with the water-insoluble polymer or enteric polymer constituting the first layer, the second layer, and the third layer is preferably up to about 60% of the coating weight.
前記例示の皮膜組成物は、例えば水に分散させて使用することができる。 The exemplified coating composition can be used by being dispersed in water, for example.
本発明組成物にＤ−マンニトール等の多価アルコール、結晶セルロース、乳糖、軽質無水ケイ酸等の賦形剤やヒドロキシプロピルセルロース等の結合剤を用いて造粒し、散剤、細粒剤又は顆粒剤とすることができる。
これらの製剤は、必要に応じ、着色剤、矯味剤等の製剤上の添加物を使用して製造してもよい。
The composition of the present invention is granulated using a polyhydric alcohol such as D-mannitol, an excipient such as crystalline cellulose, lactose or light anhydrous silicic acid, or a binder such as hydroxypropylcellulose, and then a powder, fine granule or granule It can be used as an agent.
These preparations may be produced using additives on the preparation such as coloring agents and flavoring agents as necessary.
本発明の組成物、散剤、細粒剤及び顆粒剤は、通常の方法、例えば第十五改正日本薬局方の製剤総則に記載されている方法により、容易に製造をすることができる。 The composition, powder, fine granule, and granule of the present invention can be easily produced by an ordinary method, for example, a method described in the general formulation of the 15th revision Japanese Pharmacopoeia.
以下に不快味を有する医薬として強い苦味を有するレバミピド（一般名：胃炎・胃潰瘍治療薬）を使用した実施例により本発明をさらに詳しく説明するが、本発明はこれらに限定されるものではない。
なお、以下の実施例及び参考例の製剤基材として下記（市販品）を使用した。
乳糖（ファーマトース４５０Ｍ：五協産業）、軽質無水ケイ酸（アドソリダー１０１：ワイ・ケー・エフ）、３０％エチルセルロース水分散液（アクアコート：大日本製薬）、Ｄ−マンニトール（マンニットＰ：東和化成工業）、トリアセチン（トリアセチン：有機合成薬品工業）、メタクリル酸コポリマーＬＤ（オイドラギットＬ３０Ｄ５５：デグサジャパン）、タルク（クラウンタルク：松村産業）、クエン酸トリエチル（シトロフレックス２ＳＣ−６０：森村商事）、結晶セルロース（セオラスＫＧ８０２：旭化成ケミカルズ）、ヒドロキシプロピルセルロース（ＨＰＣ−Ｌ：日本曹達）
Hereinafter, the present invention will be described in more detail by way of examples using rebamipide (generic name: gastritis / gastric ulcer therapeutic agent) having a strong bitter taste as a pharmaceutical having an unpleasant taste, but the present invention is not limited thereto.
In addition, the following (commercial product) was used as a formulation base material in the following Examples and Reference Examples.
Lactose (Pharmacose 450M: Gokyo Sangyo), light anhydrous silicic acid (ADSOLIDER 101: WKF), 30% ethylcellulose aqueous dispersion (Aqua Coat: Dainippon Pharmaceutical), D-mannitol (Mannit P: Towa Kasei Kogyo), Triacetin (Triacetin: Organic Synthetic Chemical Industry), Methacrylic Acid Copolymer LD (Eudragit L30D55: Degussa Japan), Talc (Crown Talc: Matsumura Sangyo), Triethyl Citrate (Citroflex 2SC-60: Morimura Shoji), Crystal Cellulose (Theorus KG802: Asahi Kasei Chemicals), Hydroxypropylcellulose (HPC-L: Nippon Soda)
実施例１
１．コーティング液及び造粒液の調製
常法に従って下記組成からなるコーティング液及び造粒液を調製した。
（１）コーティング液Ａ
３０％エチルセルロース水分散液 ２７０ｇ
Ｄ−マンニトール ６０ｇ
トリアセチン ２７ｇ
水 ４８０ｇ
（２）コーティング液Ｂ
３０％メタクリル酸コポリマーＬＤ １６０ｇ
Ｄ−マンニトール ２４ｇ
タルク ２４ｇ
クエン酸トリエチル ５ｇ
水 ３００ｇ
（３）コーティング液Ｃ
３０％エチルセルロース水分散液 ９０ｇ
トリアセチン ９ｇ
水 ８０ｇ
（４）造粒液Ｘ
ヒドロキシプロピルセルロース ３０ｇ
水 ５７０ｇ
（５）造粒液Ｙ
ヒドロキシプロピルセルロース ５ｇ
軽質無水ケイ酸 ２８ｇ
水 １７５ｇ
Example 1
1. Preparation of Coating Solution and Granulation Solution A coating solution and a granulation solution having the following composition were prepared according to a conventional method.
(1) Coating liquid A
270 g of 30% ethylcellulose aqueous dispersion
D-mannitol 60g
Triacetin 27g
480g of water
(2) Coating liquid B
30% methacrylic acid copolymer LD 160g
D-mannitol 24g
Talc 24g
5g triethyl citrate
300 g of water
(3) Coating liquid C
90 g of 30% ethylcellulose aqueous dispersion
Triacetin 9g
80g of water
(4) Granulation liquid X
Hydroxypropylcellulose 30g
570 g of water
(5) Granulation liquid Y
Hydroxypropylcellulose 5g
Light anhydrous silicic acid 28g
175 g of water
２．三層被膜を施した細粒剤の製造
レバミピド２００ｇ（平均粒子径：約５μｍ）、乳糖６０ｇ及び軽質無水ケイ酸１２ｇを流動層造粒乾燥・コーティング機（パウレック製：ＭＰ０１−ＳＰＣ型）に投入し、この混合物を流動させながら、予め調製した前記コーティング液Ａを噴霧して第一層皮膜を施し、次いで前記コーティング液Ｂを用いて第二層皮膜を施し、さらに前記コーティング液Ｃを用いて第三層皮膜を施して乾燥させた。ここで得られた細粒を流動層造粒乾燥・コーティング機（パウレック製：ＭＰ０１）に移し、Ｄ−マンニトール２９０ｇ及び結晶セルロース７０ｇを加え、これら混合物を流動させながら、前記造粒液Ｘ及び造粒液Ｙを順次用いて造粒し、下記組成の細粒剤を得た。
［成 分］ ［細粒剤１０００ｍｇ当たりの重量（ｍｇ）］
核部分
レバミピド ２００
乳糖 ６０
軽質無水ケイ酸 １２
第一層
エチルセルロース ８１
Ｄ−マンニトール ６０
トリアセチン ２７
第二層
メタクリル酸コポリマーＬＤ ４８
Ｄ−マンニトール ２４
タルク ２４
クエン酸トリエチル ５
第三層
エチルセルロース ２７
トリアセチン ９
造粒層
Ｄ−マンニトール ２９０
結晶セルロース ７０
ヒドロキシプロピルセルロース ３５
軽質無水ケイ酸 ２８
2. Manufacture of fine granules with a three-layer coating Rebamipide 200g (average particle size: about 5μm), lactose 60g and light anhydrous silicic acid 12g are put into a fluidized bed granulation drying and coating machine (Powrec: MP01-SPC type) Then, while the mixture is flowing, the coating liquid A prepared in advance is sprayed to apply the first layer film, then the coating liquid B is used to apply the second layer film, and further the coating liquid C is used. A third layer coating was applied and dried. The fine particles obtained here are transferred to a fluidized bed granulation drying / coating machine (manufactured by POWREC: MP01), 290 g of D-mannitol and 70 g of crystalline cellulose are added, and the mixture is allowed to flow, Granules Y were sequentially used for granulation to obtain fine granules having the following composition.
[Components] [Weight per mg of fine granules (mg)]
Core rebamipide 200
Lactose 60
Light anhydrous silicic acid 12
First layer ethylcellulose 81
D-mannitol 60
Triacetin 27
Second layer Methacrylic acid copolymer LD 48
D-mannitol 24
Talc 24
Triethyl citrate 5
3rd layer ethyl cellulose 27
Triacetin 9
Granulated layer D-mannitol 290
Crystalline cellulose 70
Hydroxypropylcellulose 35
Light anhydrous silicic acid 28
参考例１
１．コーティング液及び造粒液の調製
常法に従って下記組成からなるコーティング液及び造粒液を調製した。
（１）コーティング液Ｄ
３０％エチルセルロース水分散液 ３６０ｇ
Ｄ−マンニトール ６０ｇ
トリアセチン ３６ｇ
水 ５６０ｇ
（２）コーティング液Ｂ（前記と同じ）
３０％メタクリル酸コポリマーＬＤ １６０ｇ
Ｄ−マンニトール ２４ｇ
タルク ２４ｇ
クエン酸トリエチル ５ｇ
水 ３００ｇ
（４）造粒液Ｘ（前記と同じ）
ヒドロキシプロピルセルロース ３０ｇ
水 ５７０ｇ
（５）造粒液Ｙ（前記と同じ）
ヒドロキシプロピルセルロース ５ｇ
軽質無水ケイ酸 ２８ｇ
水 １７５ｇ
Reference example 1
1. Preparation of Coating Solution and Granulation Solution A coating solution and a granulation solution having the following composition were prepared according to a conventional method.
(1) Coating liquid D
30% ethylcellulose aqueous dispersion 360g
D-mannitol 60g
Triacetin 36g
560g of water
(2) Coating liquid B (same as above)
30% methacrylic acid copolymer LD 160g
D-mannitol 24g
Talc 24g
5g triethyl citrate
300 g of water
(4) Granulation liquid X (same as above)
Hydroxypropylcellulose 30g
570 g of water
(5) Granulation liquid Y (same as above)
Hydroxypropylcellulose 5g
Light anhydrous silicic acid 28g
175 g of water
２．二層被膜を施した細粒剤の製造
レバミピド２００ｇ（平均粒子径：約５μｍ）、乳糖６０ｇ及び軽質無水ケイ酸１２ｇを流動層造粒乾燥・コーティング機（パウレック製：ＭＰ０１−ＳＰＣ型）に投入し、この混合物を流動させながら、予め調製した前記コーティング液Ｄを噴霧して第一層皮膜を施し、次いで前記コーティング液Ｂを用いて第二層皮膜を施して乾燥させた。ここで得られた細粒を流動層造粒乾燥・コーティング機（パウレック製：ＭＰ０１）に移し、Ｄ−マンニトール２９０ｇ及び結晶セルロース７０ｇを加え、これら混合物を流動させながら、前記造粒液Ｘ及び造粒液Ｙを順次用いて造粒し、下記組成の細粒剤を得た。
［成 分］ ［細粒剤１０００ｍｇ当たりの重量（ｍｇ）］
核部分
レバミピド ２００
乳糖 ６０
軽質無水ケイ酸 １２
第一層
エチルセルロース １０８
Ｄ−マンニトール ６０
トリアセチン ３６
第二層
メタクリル酸コポリマーＬＤ ４８
Ｄ−マンニトール ２４
タルク ２４
クエン酸トリエチル ５
造粒層
Ｄ−マンニトール ２９０
結晶セルロース ７０
ヒドロキシプロピルセルロース ３５
軽質無水ケイ酸 ２８
2. Manufacture of fine granules with double-layer coating Rebamipide 200g (average particle size: approx. 5μm), lactose 60g and light anhydrous silicic acid 12g are put into a fluidized bed granulation drying and coating machine (Pauleck: MP01-SPC type) While the mixture was flowing, the coating liquid D prepared in advance was sprayed to give the first layer film, and then the coating liquid B was used to apply the second layer film and dried. The fine particles obtained here are transferred to a fluidized bed granulation drying / coating machine (manufactured by POWREC: MP01), 290 g of D-mannitol and 70 g of crystalline cellulose are added, and the mixture is allowed to flow, Granules Y were sequentially used for granulation to obtain fine granules having the following composition.
[Components] [Weight per mg of fine granules (mg)]
Core rebamipide 200
Lactose 60
Light anhydrous silicic acid 12
1st layer ethylcellulose 108
D-mannitol 60
Triacetin 36
Second layer Methacrylic acid copolymer LD 48
D-mannitol 24
Talc 24
Triethyl citrate 5
Granulated layer D-mannitol 290
Crystalline cellulose 70
Hydroxypropylcellulose 35
Light anhydrous silicic acid 28
試験例１ 溶出試験
実施例１の細粒剤及び比較例１の細粒剤について、各５００ｍｇ（レバミピド１００ｍｇ）を試料とし、試験液に薄めたｐＨ６．０のリン酸二水素ナトリウム・クエン酸緩衝液（１ → ４）９００ｍｌを用い、日本薬局方溶出試験第２法により、毎分５０回転、６０分間、の条件にて試験した。その結果、下記の溶出率を得た。
レバミピド溶出率（％）
実施例１ ８１．７
比較例１ ８２．０
Test Example 1 Dissolution Test About the fine granule of Example 1 and the fine granule of Comparative Example 1, 500 mg (100 mg of rebamipide) was used as a sample, and the solution was diluted to pH 6.0 with sodium dihydrogen phosphate / citrate buffer. Using 900 ml of the liquid (1 → 4), the test was conducted under the conditions of 50 revolutions per minute and 60 minutes according to the second method of the Japanese Pharmacopoeia dissolution test. As a result, the following elution rate was obtained.
Rebamipide dissolution rate (%)
Example 1 81.7
Comparative Example 1 82.0
試験例２ 苦味遮蔽効果
試験は、実施例１の細粒剤及び比較例１の細粒剤について、被験者７名に対し実施した。試験方法は、舌に各試料５００ｍｇ（レバミピド１００ｍｇ）を乗せ、口内で細粒剤を崩壊させ苦味を感じるまでの時間を測定し、下記の結果を得た。
苦味の発現時間（秒）
実施例１ ２５±７
比較例１ １５±４
以上より、本発明の細粒剤は、レバミピドの速い溶出を保持しつつ、苦味遮蔽効果が顕著に改善されたことが判る。
Test Example 2 Bitter taste shielding effect The test was performed on 7 subjects with respect to the fine granule of Example 1 and the fine granule of Comparative Example 1. In the test method, 500 mg of each sample (100 mg of rebamipide) was placed on the tongue, and the time until the fine granules were disintegrated and bitterness was felt in the mouth was measured, and the following results were obtained.
Bitterness onset time (seconds)
Example 1 25 ± 7
Comparative Example 1 15 ± 4
From the above, it can be seen that the fine granule of the present invention has remarkably improved the bitterness-shielding effect while maintaining the rapid dissolution of rebamipide.
本発明によれば、医薬の不快味を効果的に遮蔽した服用しやすく、溶出性に優れた粉末組成物、散剤、細粒剤あるいは顆粒剤を医療産業又は医療現場に提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, the powder composition, powder, fine granule, or granule which was easy to take which shielded the unpleasant taste of the medicine effectively, and was excellent in the elution property can be provided to the medical industry or a medical field.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006230552A JP2008050324A (en) | 2006-08-28 | 2006-08-28 | Bitter-masking composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006230552A JP2008050324A (en) | 2006-08-28 | 2006-08-28 | Bitter-masking composition |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012005365A1 (en) * | 2010-07-09 | 2012-01-12 | 帝人ファーマ株式会社 | Particle coating preparation |
| JPWO2012029348A1 (en) * | 2010-08-31 | 2013-10-28 | 協和発酵キリン株式会社 | Granules and orally disintegrating tablets containing a bitter-tasting drug |
| JP2022546120A (en) * | 2019-09-03 | 2022-11-02 | スクエア パワー リミテッド | Rebamipide for use in the prevention and treatment of celiac disease |
-
2006
- 2006-08-28 JP JP2006230552A patent/JP2008050324A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012005365A1 (en) * | 2010-07-09 | 2012-01-12 | 帝人ファーマ株式会社 | Particle coating preparation |
| JP5000017B2 (en) * | 2010-07-09 | 2012-08-15 | 帝人ファーマ株式会社 | Fine particle coating formulation |
| CN102958522A (en) * | 2010-07-09 | 2013-03-06 | 帝人制药株式会社 | Particle coating preparation |
| CN102958522B (en) * | 2010-07-09 | 2015-12-16 | 帝人制药株式会社 | Microgranule coated preparation |
| JPWO2012029348A1 (en) * | 2010-08-31 | 2013-10-28 | 協和発酵キリン株式会社 | Granules and orally disintegrating tablets containing a bitter-tasting drug |
| EP2614816A4 (en) * | 2010-08-31 | 2014-06-25 | Kyowa Hakko Kirin Co Ltd | Granules containing bitter drug and orally disintegrating tablet |
| JP2022546120A (en) * | 2019-09-03 | 2022-11-02 | スクエア パワー リミテッド | Rebamipide for use in the prevention and treatment of celiac disease |
| JP7649296B2 (en) | 2019-09-03 | 2025-03-19 | スクエア パワー リミテッド | Pharmaceutical composition containing rebamipide for use in the prevention and treatment of celiac disease |
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