JP7515253B2 - Solid pharmaceutical preparations - Google Patents
Solid pharmaceutical preparations Download PDFInfo
- Publication number
- JP7515253B2 JP7515253B2 JP2019238556A JP2019238556A JP7515253B2 JP 7515253 B2 JP7515253 B2 JP 7515253B2 JP 2019238556 A JP2019238556 A JP 2019238556A JP 2019238556 A JP2019238556 A JP 2019238556A JP 7515253 B2 JP7515253 B2 JP 7515253B2
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- JP
- Japan
- Prior art keywords
- component
- group
- particle group
- pharmaceutical formulation
- oral pharmaceutical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000007787 solid Substances 0.000 title claims description 48
- 239000000825 pharmaceutical preparation Substances 0.000 title description 14
- 239000002245 particle Substances 0.000 claims description 122
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- 239000011361 granulated particle Substances 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 24
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 22
- 229960001929 meloxicam Drugs 0.000 claims description 21
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 17
- 229940069428 antacid Drugs 0.000 claims description 17
- 239000003159 antacid agent Substances 0.000 claims description 17
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 14
- 230000001458 anti-acid effect Effects 0.000 claims description 14
- 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 claims description 12
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- 239000000395 magnesium oxide Substances 0.000 claims description 7
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 7
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 7
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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 claims description 6
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- 150000001875 compounds Chemical class 0.000 description 4
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- FBOUIAKEJMZPQG-AWNIVKPZSA-N (1E)-1-(2,4-dichlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)pent-1-en-3-ol Chemical compound C1=NC=NN1/C(C(O)C(C)(C)C)=C/C1=CC=C(Cl)C=C1Cl FBOUIAKEJMZPQG-AWNIVKPZSA-N 0.000 description 2
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- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
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- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229930189914 platycodon Natural products 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910052700 potassium Chemical group 0.000 description 1
- 239000011591 potassium Chemical group 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- KDPUQELWHOMNPN-UHFFFAOYSA-M potassium;dihydrogen phosphate;dihydrate Chemical compound O.O.[K+].OP(O)([O-])=O KDPUQELWHOMNPN-UHFFFAOYSA-M 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229940048730 senega Drugs 0.000 description 1
- 229950000112 serrapeptase Drugs 0.000 description 1
- 108010038132 serratiopeptidase Proteins 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- JWBPVFVNISJVEM-UHFFFAOYSA-M sodium caffeine benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1.CN1C(=O)N(C)C(=O)C2=C1N=CN2C JWBPVFVNISJVEM-UHFFFAOYSA-M 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 150000005846 sugar alcohols Chemical group 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 229960004636 thonzylamine hydrochloride Drugs 0.000 description 1
- HTJXMOGUGMSZOG-UHFFFAOYSA-N tiaramide Chemical compound C1CN(CCO)CCN1C(=O)CN1C(=O)SC2=CC=C(Cl)C=C21 HTJXMOGUGMSZOG-UHFFFAOYSA-N 0.000 description 1
- 229950010302 tiaramide Drugs 0.000 description 1
- 229960000896 tipepidine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960000732 tripelennamine hydrochloride Drugs 0.000 description 1
- 229960001593 triprolidine hydrochloride Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 229930195727 α-lactose Natural products 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、内服医薬製剤及び固形医薬製剤に関する。 The present invention relates to oral pharmaceutical preparations and solid pharmaceutical preparations.
解熱鎮痛薬等の内服医薬製剤は、非ステロイド性抗炎症剤（ＮＳＡＩＤｓ）等が解熱鎮痛成分として汎用されている。ＮＳＡＩＤｓの中でも、メロキシカム又はその医薬的に許容可能な塩（以下、「メロキシカム（塩）」ということがある）は、鎮痛作用を長時間にわたって示す鎮痛成分として知られている。
メロキシカム（塩）は、副作用として胃障害を有することが知られている。胃障害の抑制を図るために、制酸剤を配合した内服医薬製剤が知られている。
例えば、特許文献１には、メロキシカム（塩）と制酸剤との組み合わせからなる配合物が開示されている。
In oral pharmaceutical preparations such as antipyretic analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as antipyretic and analgesic ingredients. Among NSAIDs, meloxicam or a pharma- ceutical acceptable salt thereof (hereinafter, sometimes referred to as "meloxicam (salt)") is known as an analgesic ingredient that exhibits an analgesic effect for a long period of time.
Meloxicam (salt) is known to have a side effect of causing stomach disorders, and oral pharmaceutical preparations containing antacids to suppress stomach disorders are known.
For example, Patent Document 1 discloses a formulation comprising a combination of meloxicam (salt) and an antacid.
制酸剤としては、乾燥水酸化アルミニウムゲル、グリシン、ケイ酸マグネシウム、水酸化アルミニウムゲル、水酸化アルミニウム－炭酸マグネシウム共乾燥ゲル、水酸化アルミニウム－重炭酸ナトリウム共沈殿物、水酸化アルミニウム－炭酸カルシウム－炭酸マグネシウム共沈殿物、水酸化マグネシウム－硫酸アルミニウムカリウム共沈殿物及び炭酸マグネシウム等が知られている。本発明者は、制酸剤の中でも、マグネシウム原子を含有する制酸剤を用いることで、溶出性を高められるという知見を得た。即ち、マグネシウム原子を含有する制酸剤を用いることで、服用後に、メロキシカム（塩）を早期に溶出させて、即効性を高められる。
しかしながら、マグネシウム原子を含有する化合物を制酸剤として用いると、経時的に内服医薬製剤が変色するという問題がある。
そこで、本発明は、メロキシカム（塩）と制酸剤とを組み合わせる配合剤において、マグネシウム原子を含有する化合物を制酸剤として含有しても、変色を抑制できる内服医薬製剤を目的とする。
Known antacids include dried aluminum hydroxide gel, glycine, magnesium silicate, aluminum hydroxide gel, aluminum hydroxide-magnesium carbonate co-dried gel, aluminum hydroxide-sodium bicarbonate co-precipitate, aluminum hydroxide-calcium carbonate-magnesium carbonate co-precipitate, magnesium hydroxide-aluminum potassium sulfate co-precipitate, and magnesium carbonate. The present inventor has found that, among antacids, the use of an antacid containing a magnesium atom can enhance dissolution. That is, the use of an antacid containing a magnesium atom can allow meloxicam (salt) to be dissolved early after administration, enhancing the immediate effect.
However, when a compound containing a magnesium atom is used as an antacid, there is a problem that the oral pharmaceutical preparation discolors over time.
Therefore, the present invention aims to provide an oral pharmaceutical preparation that can suppress discoloration in a combination drug that combines meloxicam (salt) with an antacid, even when the combination drug contains a compound containing a magnesium atom as an antacid.
本発明は以下の態様を有する。
＜１＞
メロキシカム及びその医薬的に許容可能な塩から選ばれる少なくとも１種（Ａ）と、
マグネシウム原子を含有する制酸剤（Ｂ）と、
乳糖、結晶セルロース、トウモロコシデンプン、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、Ｄ－マンニトール、ポビドン及びクロスポビドンからなる群から選ばれる少なくとも１種（Ｃ）と、
を含有する、内服医薬製剤。
＜２＞
前記（Ｂ）成分は、酸化マグネシウム（Ｂ－１）、炭酸マグネシウム（Ｂ－２）及びメタケイ酸アルミン酸マグネシウム（Ｂ－３）からなる群から選ばれる１種以上である、＜１＞に記載の内服医薬製剤。
＜３＞
前記（Ｃ）成分／前記（Ｂ）成分で表される質量比は、０．０１～１２である＜１＞又は＜２＞に記載の内服医薬製剤。
＜４＞
錠剤である、＜１＞～＜３＞のいずれかに記載の内服医薬製剤。
The present invention has the following aspects.
＜1＞
At least one member (A) selected from meloxicam and a pharma- ceutical acceptable salt thereof;
an antacid containing a magnesium atom (B);
At least one selected from the group consisting of lactose, crystalline cellulose, corn starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, D-mannitol, povidone, and crospovidone (C);
An oral medicinal formulation comprising:
＜2＞
The oral pharmaceutical formulation according to <1>, wherein the component (B) is at least one selected from the group consisting of magnesium oxide (B-1), magnesium carbonate (B-2) and magnesium aluminometasilicate (B-3).
＜3＞
The oral pharmaceutical formulation according to <1> or <2>, wherein the mass ratio of the (C) component/the (B) component is 0.01 to 12.
＜4＞
The oral pharmaceutical formulation according to any one of <1> to <3>, which is a tablet.
＜５＞
メロキシカム及びその医薬的に許容可能な塩から選ばれる少なくとも１種（Ａ）を含有し、かつ、マグネシウム原子を含有する制酸剤（Ｂ）を実質的に含有しない粒子の群（α１）と、
前記（Ｂ）成分を含有し、前記（Ａ）成分を実質的に含有しない粒子の群（β１）と、
を有し、
前記粒子の群（α１）及び前記粒子の群（β１）の少なくとも一方は、造粒粒子の群である、固形医薬製剤。
＜６＞
前記（Ｂ）成分は、酸化マグネシウム（Ｂ－１）、炭酸マグネシウム（Ｂ－２）及びメタケイ酸アルミン酸マグネシウム（Ｂ－３）からなる群から選ばれる１種以上である、＜５＞に記載の固形医薬製剤。
＜７＞
前記粒子の群（α１）及び前記粒子の群（β１）の少なくとも一方に、乳糖、結晶セルロース、トウモロコシデンプン、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、Ｄ－マンニトール、ポビドン及びクロスポビドンからなる群から選ばれる少なくとも１種（Ｃ）をさらに含有する、＜５＞又は＜６＞に記載の固形医薬製剤。
＜８＞
前記（Ｃ）成分／前記（Ｂ）成分で表される質量比は、０．０１～１２である、＜７＞に記載の固形医薬製剤。
＜９＞
錠剤である、＜５＞～＜８＞のいずれかに記載の固形医薬製剤。
＜5＞
A group (α1) of particles containing at least one kind (A) selected from meloxicam and a pharma- ceutically acceptable salt thereof and substantially not containing an antacid (B) containing a magnesium atom;
A group (β1) of particles containing the component (B) and substantially not containing the component (A);
having
At least one of the particle group (α1) and the particle group (β1) is a group of granulated particles.
＜6＞
The solid pharmaceutical formulation according to <5>, wherein the component (B) is at least one selected from the group consisting of magnesium oxide (B-1), magnesium carbonate (B-2) and magnesium aluminometasilicate (B-3).
＜７＞
The solid pharmaceutical formulation according to <5> or <6>, further comprising at least one kind (C) selected from the group consisting of lactose, crystalline cellulose, corn starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, D-mannitol, povidone and crospovidone in at least one of the particle group (α1) and the particle group (β1).
＜8＞
The solid pharmaceutical formulation according to <7>, wherein the mass ratio of the (C) component/the (B) component is 0.01 to 12.
＜9＞
The solid pharmaceutical formulation according to any one of <5> to <8>, which is a tablet.
本発明の内服医薬製剤によれば、メロキシカム（塩）と制酸剤とを組み合わせる配合剤において、マグネシウム原子を含有する化合物を制酸剤として含有しても、変色を抑制できる。 According to the oral pharmaceutical preparation of the present invention, discoloration can be suppressed even when a compound containing a magnesium atom is contained as an antacid in a combination drug that combines meloxicam (salt) and an antacid.
本発明の内服医薬製剤は、メロキシカム及びその医薬的に許容可能な塩から選ばれる少なくとも１種（Ａ）（（Ａ）成分）と、マグネシウム原子を含有する制酸剤（Ｂ）（（Ｂ）成分）と、を含有する。
内服医薬製剤の剤形としては、錠剤（フィルムコーティング錠、口腔内崩壊錠等）、カプセル剤、マイクロカプセル剤、顆粒剤、細粒剤、散剤等の固形医薬製剤等が挙げられる。
本発明の内服医薬製剤としては、中でも、錠剤、カプセル剤等がより好ましい。錠剤としては、単層錠でもよいし、二層以上の多層錠でもよい。また、錠剤は、素錠でもよいし、コーティング錠でもよい。カプセル剤としては、例えば、軟質カプセルやマイクロカプセルに封入した錠剤でもよい。
The oral pharmaceutical formulation of the present invention contains at least one type (A) selected from meloxicam and a pharma- ceutical acceptable salt thereof (component (A)), and an antacid (B) containing a magnesium atom (component (B)).
Dosage forms of oral pharmaceutical preparations include solid pharmaceutical preparations such as tablets (film-coated tablets, orally disintegrating tablets, etc.), capsules, microcapsules, granules, fine granules, and powders.
As the oral pharmaceutical preparation of the present invention, tablets, capsules, etc. are more preferable. The tablets may be single-layer tablets or multi-layer tablets of two or more layers. The tablets may be plain tablets or coated tablets. The capsules may be tablets enclosed in soft capsules or microcapsules.
本発明の内服医薬製剤が錠剤の場合、錠剤の形状によって、本発明の効果は大きく変化しない。錠剤の寸法は、本発明の効果の点では特に限定されないが、錠剤の取り扱いやすさと嚥下性の点から、錠剤の直径φは、例えば、６～１４ｍｍが好ましい。
錠剤の取り扱いやすさと嚥下性の点から、錠剤の形状は、円柱部及び前記円柱部の上下の端面から膨出する膨出部とを有する形状が好ましい。前記の円柱部及び膨出部を有する形状の錠剤としては、Ｒ錠（標準Ｒ錠、糖衣Ｒ錠等）、２段Ｒ錠、スミ角平錠、スミ丸平錠等が挙げられる。これらの錠剤の膨出部は上下非対称であってもよいが、上下対称であることが好ましい。
When the oral pharmaceutical preparation of the present invention is a tablet, the effect of the present invention does not change significantly depending on the shape of the tablet. The size of the tablet is not particularly limited in terms of the effect of the present invention, but the diameter φ of the tablet is preferably, for example, 6 to 14 mm in terms of ease of handling and swallowing.
From the viewpoint of ease of handling and swallowability, the shape of the tablet is preferably a shape having a cylindrical portion and a bulging portion bulging from the upper and lower end faces of the cylindrical portion. Examples of the tablet having the cylindrical portion and the bulging portion include R tablets (standard R tablets, sugar-coated R tablets, etc.), two-stage R tablets, Sumi square flat tablets, Sumi round flat tablets, etc. The bulging portions of these tablets may be asymmetrical from top to bottom, but are preferably symmetrical from top to bottom.
内服医薬製剤が顆粒剤、細粒剤又は散剤である場合、内服医薬製剤の平均粒子径は、１０～７００μｍが好ましく、５０～５００μｍがより好ましい。平均粒子径は、レーザー回折式粒度分布測定法に準じて測定される、重量平均粒子径（Ｄ５０）である。 When the oral pharmaceutical preparation is a granule, fine granule, or powder, the average particle size of the oral pharmaceutical preparation is preferably 10 to 700 μm, more preferably 50 to 500 μm. The average particle size is the weight-average particle size (D50) measured according to a laser diffraction particle size distribution measurement method.
（第一の実施形態）
＜内服医薬製剤＞
本発明の第一の実施形態に係る内服医薬製剤について、説明する。
本実施形態の内服医薬製剤は、（Ａ）成分と、（Ｂ）成分と、特定の（Ｃ）成分とを併有する。
本実施形態の内服医薬製剤としては、単層錠、丸剤、（Ａ）～（Ｃ）成分を共に造粒した顆粒剤、粉体混合された散剤や細粒剤等が挙げられる。また、本実施形態の内服医薬製剤としては、（Ａ）～（Ｃ）成分を併有する層を有する多層錠が挙げられる。即ち、本実施形態の内服医薬製剤は、（Ａ）～（Ｃ）成分が共存する剤形である。
(First embodiment)
<Oral medicinal preparations>
The oral pharmaceutical formulation according to the first embodiment of the present invention will be described.
The oral pharmaceutical formulation of this embodiment contains component (A), component (B), and specific component (C).
The oral pharmaceutical formulation of this embodiment may be a single-layer tablet, a pill, a granule in which the components (A) to (C) are granulated together, a powder or fine granule in which the powders are mixed, etc. In addition, the oral pharmaceutical formulation of this embodiment may be a multi-layer tablet having a layer in which the components (A) to (C) are both present. That is, the oral pharmaceutical formulation of this embodiment is a dosage form in which the components (A) to (C) coexist.
≪（Ａ）成分≫
（Ａ）成分は、メロキシカム（化学名：４－ヒドロキシ－２－メチル－Ｎ－（５－メチル－２－チアゾリル）－２Ｈ－１，２－ベンゾチアジン－３－カルボキサミド－１，１－ジオキシド）及びその医薬的に許容可能な塩から選ばれる少なくとも１種である。メロキシカムの医薬的に許容可能な塩としては、例えば、欧州特許第２，４８２Ｂ１号明細書、米国特許第４，２３３，２９９号明細書及び国際公開第９９／４９８６７号に記載されているものが挙げられる。許容可能な塩としては、ナトリウム塩、カリウム塩、アンモニウム塩、メグルミン塩、トリス塩等が挙げられる。
（Ａ）成分は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。
<Component (A)>
Component (A) is at least one selected from meloxicam (chemical name: 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) and pharma-ceutically acceptable salts thereof. Examples of pharma-ceutically acceptable salts of meloxicam include those described in European Patent No. 2,482 B1, U.S. Patent No. 4,233,299, and International Publication No. WO 99/49867. Acceptable salts include sodium salts, potassium salts, ammonium salts, meglumine salts, tris salts, etc.
The component (A) may be used alone or in combination of two or more types.
内服医薬製剤中の（Ａ）成分の含有量は、服用１回当たりの（Ａ）成分としては、０．５～７０ｍｇが好ましく、２～５０ｍｇがより好ましく、２．５～２０ｍｇがさらに好ましく、５～１５ｍｇが特に好ましい。（Ａ）成分の含有量が上記下限値以上であれば、内服医薬製剤の薬理効果をより高められる。（Ａ）成分の含有量が上記上限値以下であれば、錠剤製造時の障害（例えば、打錠機の盤や杵に対する内服医薬製剤の付着等）を生じにくい。また、（Ａ）成分の含有量が上記上限値以下であれば、胃障害をより軽減できる。
なお、内服医薬製剤が錠剤の場合、下記の（Ａ）成分の含有量は、１錠に含まれていてもよいし、１回に服用する錠剤数の総量でもよい。
The content of the (A) component in the oral pharmaceutical preparation is preferably 0.5 to 70 mg, more preferably 2 to 50 mg, even more preferably 2.5 to 20 mg, and particularly preferably 5 to 15 mg per dose of the (A) component. If the content of the (A) component is equal to or greater than the lower limit, the pharmacological effect of the oral pharmaceutical preparation can be further enhanced. If the content of the (A) component is equal to or less than the upper limit, problems during tablet production (e.g., adhesion of the oral pharmaceutical preparation to the disks and punches of a tablet press) are less likely to occur. In addition, if the content of the (A) component is equal to or less than the upper limit, stomach problems can be further reduced.
When the oral pharmaceutical preparation is a tablet, the content of the following component (A) may be contained in one tablet or may be the total amount of the tablets taken at one time.
内服医薬製剤が錠剤やカプセル剤の場合、錠剤１錠（又は１カプセル）当たりの（Ａ）成分の含有量は、服用１回当たりの錠剤数（又はカプセル数）を勘案して適宜決定される。 When the oral pharmaceutical preparation is a tablet or capsule, the content of component (A) per tablet (or capsule) is appropriately determined taking into account the number of tablets (or capsules) per dose.
内服医薬製剤中の（Ａ）成分の含有割合は、例えば、内服医薬製剤の総質量に対して、０．１～２０質量％が好ましく、０．５～１０質量％がより好ましく、１．０～５．０質量％がさらに好ましい。（Ａ）成分の含有割合が上記下限値以上であれば、内服医薬製剤の薬理効果をより高められる。（Ａ）成分の含有割合が上記上限値以下であれば、錠剤製造時の障害（例えば、打錠機の盤や杵に対する内服医薬製剤の付着等）を生じにくい。また、（Ａ）成分の含有割合が上記上限値以下であれば、胃障害をより軽減できる。 The content of component (A) in the oral pharmaceutical formulation is, for example, preferably 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, and even more preferably 1.0 to 5.0% by mass, based on the total mass of the oral pharmaceutical formulation. If the content of component (A) is equal to or greater than the lower limit, the pharmacological effect of the oral pharmaceutical formulation can be further improved. If the content of component (A) is equal to or less than the upper limit, problems during tablet production (for example, adhesion of the oral pharmaceutical formulation to the plates and punches of a tablet press) are less likely to occur. Furthermore, if the content of component (A) is equal to or less than the upper limit, stomach problems can be further reduced.
≪（Ｂ）成分≫
（Ｂ）成分は、マグネシウム原子を含有する制酸剤である。本実施形態の内服医薬製剤は、（Ｂ）成分を含有することで、（Ａ）成分による胃障害を軽減できる。
（Ｂ）成分は、いわゆるマグネシウム系制酸剤であり、分子中にマグネシウム原子を有するアルカリ性化合物である。（Ｂ）成分は、マグネシウム原子の他に、ナトリウム、カリウム等のアルカリ金属原子、アルミニウム、ケイ素等の金属原子を含んでもよい。（Ｂ）成分の総質量に対するマグネシウム原子の含有割合は、１質量％以上である。本発明の課題に対する効果の顕著性から、（Ｂ）成分の総質量に対するマグネシウム原子の含有割合は、１０質量％以上が好ましい。（Ｂ）成分中のマグネシウム原子の含有割合は、化学式から算出される質量比により求められる値である。
<Component (B)>
The component (B) is an antacid containing a magnesium atom. By containing the component (B), the oral pharmaceutical preparation of the present embodiment can reduce stomach disorders caused by the component (A).
The (B) component is a so-called magnesium-based antacid, and is an alkaline compound having magnesium atoms in the molecule. In addition to magnesium atoms, the (B) component may contain alkali metal atoms such as sodium and potassium, and metal atoms such as aluminum and silicon. The content ratio of magnesium atoms to the total mass of the (B) component is 1 mass% or more. In view of the remarkable effect on the problem of the present invention, the content ratio of magnesium atoms to the total mass of the (B) component is preferably 10 mass% or more. The content ratio of magnesium atoms in the (B) component is a value obtained by a mass ratio calculated from a chemical formula.
（Ｂ）成分としては、例えば、酸化マグネシウム（以下、（Ｂ－１）成分ということがある）、炭酸マグネシウム（以下、（Ｂ－２）成分ということがある）及びメタケイ酸アルミン酸マグネシウム（以下、（Ｂ－３）成分ということがある）が好ましい。これらの（Ｂ）成分を含有することで、（Ａ）成分の溶出性の向上が図れる。
これらの（Ｂ）成分は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。
As the component (B), for example, magnesium oxide (hereinafter, sometimes referred to as the component (B-1)), magnesium carbonate (hereinafter, sometimes referred to as the component (B-2)), and magnesium aluminometasilicate (hereinafter, sometimes referred to as the component (B-3)) are preferable. By including these components (B), the elution property of the component (A) can be improved.
These components (B) may be used alone or in combination of two or more.
内服医薬製剤中の（Ｂ）成分の含有量は、服用１回当たりの（Ｂ）成分として、６８～７００ｍｇが好ましい。（Ｂ）成分の含有量が上記下限値以上であれば、（Ａ）成分による胃障害をより軽減でき、（Ａ）成分の溶出性の向上が図れる。（Ｂ）成分の含有量が上記上限値以下であれば、内服医薬製剤の変色のさらなる抑制が図れる。 The content of component (B) in the oral pharmaceutical formulation is preferably 68 to 700 mg per dose of component (B). If the content of component (B) is equal to or greater than the lower limit above, gastric disorders caused by component (A) can be further reduced, and the dissolution of component (A) can be improved. If the content of component (B) is equal to or less than the upper limit above, discoloration of the oral pharmaceutical formulation can be further suppressed.
医薬製剤中の（Ｂ）成分が、（Ｂ－１）酸化マグネシウムの場合、服用１回当たりの（Ｂ）成分の量は、６８～７００ｍｇが好ましく、７０～６００ｍｇがより好ましく、１００～５００ｍｇがさらに好ましい。（Ｂ）成分の含有量が上記下限値以上であれば、（Ａ）成分による胃障害をより軽減できる。（Ｂ）成分の含有量が上記上限値以下であれば、内服医薬製剤の変色のさらなる抑制が図れる。
医薬製剤中の（Ｂ）成分が、（Ｂ－２）炭酸マグネシウムまたは（Ｂ－３）メタケイ酸アルミン酸マグネシウムの場合、服用１回当たりの（Ｂ）成分の量は、６８～７００ｍｇが好ましく、１１０～７００ｍｇがより好ましく、１８０～６００ｍｇがさらに好ましく、２７０～５００ｍｇとなる量が最も好ましい。（Ｂ）成分の含有量が上記下限値以上であれば、（Ａ）成分による胃障害をより軽減できる。（Ｂ）成分の含有量が上記上限値以下であれば、内服医薬製剤の変色のさらなる抑制が図れる。
When the component (B) in the pharmaceutical preparation is magnesium oxide (B-1), the amount of the component (B) per dose is preferably 68 to 700 mg, more preferably 70 to 600 mg, and even more preferably 100 to 500 mg. If the content of the component (B) is equal to or greater than the lower limit, gastric disorders caused by the component (A) can be further reduced. If the content of the component (B) is equal to or less than the upper limit, discoloration of the oral pharmaceutical preparation can be further suppressed.
When the (B) component in the pharmaceutical preparation is (B-2) magnesium carbonate or (B-3) magnesium aluminometasilicate, the amount of (B) component per dose is preferably 68 to 700 mg, more preferably 110 to 700 mg, even more preferably 180 to 600 mg, and most preferably 270 to 500 mg. If the content of (B) component is equal to or greater than the above lower limit, gastric disorders caused by (A) component can be further alleviated. If the content of (B) component is equal to or less than the above upper limit, discoloration of the oral pharmaceutical preparation can be further suppressed.
内服医薬製剤中の（Ｂ）成分の含有割合は、内服医薬製剤の総質量に対して、４～９０質量％が好ましく、７～８５質量％がより好ましい。（Ｂ）成分の含有割合が上記下限値以上であれば、（Ａ）成分による胃障害をより軽減でき、（Ａ）成分の溶出性の向上が図れる。（Ｂ）成分の含有割合が上記上限値以下であれば、内服医薬製剤の変色のさらなる抑制が図れる。 The content of component (B) in the oral pharmaceutical formulation is preferably 4 to 90% by mass, more preferably 7 to 85% by mass, based on the total mass of the oral pharmaceutical formulation. If the content of component (B) is equal to or greater than the lower limit above, gastric disorders caused by component (A) can be further reduced, and the dissolution of component (A) can be improved. If the content of component (B) is equal to or less than the upper limit above, discoloration of the oral pharmaceutical formulation can be further suppressed.
医薬組成物中、（Ａ）成分／（Ｂ）成分で表される質量比（Ａ／Ｂ比）は、０．００５～１．０が好ましく、０．０１～０．５がより好ましい。Ａ／Ｂ比が上記下限値以上であれば、服用性をより高められる。Ａ／Ｂ比が上記上限値以下であれば、胃障害をより低減できる。 In the pharmaceutical composition, the mass ratio (A/B ratio) of component (A) to component (B) is preferably 0.005 to 1.0, and more preferably 0.01 to 0.5. If the A/B ratio is equal to or greater than the lower limit, the intake can be improved. If the A/B ratio is equal to or less than the upper limit, gastric disorders can be reduced.
≪（Ｃ）成分≫
内服医薬製剤は、乳糖（乳糖造粒物、無水乳糖を含む）、結晶セルロース（微結晶セルロースを含む）、トウモロコシデンプン（トウモロコシデンプン造粒物を含む）、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、Ｄ－マンニトール、ポビドン及びクロスポビドンからなる群から選ばれる少なくとも１種（Ｃ）（（Ｃ）成分）を含有する。本実施形態の内服医薬製剤は、（Ｃ）成分を含有することで、内服医薬製剤の変色を抑制できる。
<Component (C)>
The oral pharmaceutical formulation contains at least one component (C) (component (C)) selected from the group consisting of lactose (including lactose granules and anhydrous lactose), crystalline cellulose (including microcrystalline cellulose), corn starch (including corn starch granules), hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, D-mannitol, povidone, and crospovidone. By containing component (C), the oral pharmaceutical formulation of this embodiment can suppress discoloration of the oral pharmaceutical formulation.
（Ｃ）成分としては、乳糖（（Ｃ－１）成分）、トウモロコシデンプン（（Ｃ－３）成分）、低置換度ヒドロキシプロピルセルロース（（Ｃ－４）成分）、結晶セルロース（（Ｃ－５）成分）、マンニトール（（Ｃ－６）成分）、クロスポビドン（（Ｃ－７）成分）が好ましい。（Ｃ－１）成分は、乳糖造粒物（（Ｃ－２）成分）でもよい。これらの（Ｃ）成分であれば、変色のさらなる抑制が図れる。
これらの（Ｃ）成分は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。
As the component (C), lactose (component (C-1)), corn starch (component (C-3)), low-substituted hydroxypropyl cellulose (component (C-4)), crystalline cellulose (component (C-5)), mannitol (component (C-6)), and crospovidone (component (C-7)) are preferred. The component (C-1) may also be lactose granules (component (C-2)). With these components (C), discoloration can be further suppressed.
These components (C) may be used alone or in combination of two or more.
（Ｃ－１）成分は、乳から得られる天然の二糖類で、１個のグルコース単位と１個のガラクトース単位からなる。
（Ｃ－２）成分は、乳糖が主成分であり、ヒドロキシプロピルセルロース等で造粒した造粒物である。
（Ｃ－３）成分は、成熟したトウモロコシの種子から得たでんぷんである。
（Ｃ－４）成分は、セルロースの低置換度ヒドロキシプロピルエーテルである。
（Ｃ－５）成分は、繊維性植物からパルプとして得たα－セルロースを酸で部分的に解重合し、精製したものである。
（Ｃ－６）成分は、ヘキソースに分類される糖アルコールである。
（Ｃ－７）成分は、１－ビニル－２－ピロリドンの架橋重合物である。
無水乳糖は、β－乳糖又はβ－乳糖とα－乳糖の混合物である。（Ｃ－１）成分や（Ｃ－２）成分が水分を３～６質量％含有するのに対し、無水乳糖の水分量は１．０質量％以下である。上記水分量は、カールフィッシャー水分で測定できる。
微結晶セルロースは、一般のセルロース（パルプ等）を加水分解し、結晶領域のみを残してこれを磨砕、精製、乾燥したものであり、平均粒子径が１～２００μｍの粒子である。上記平均粒子径の測定方法は、レーザー回折散乱法によって行う。
トウモロコシデンプン造粒物は、日本薬局方トウモロコシデンプンを温湯に懸濁し、噴霧乾燥造粒することにより顆粒状に製したものであり、平均粒子径が３～３５μｍの球形又は多角形の粒子である。上記平均粒子径の測定方法は、鏡検によって行う。
The (C-1) component is a natural disaccharide obtained from milk and consists of one glucose unit and one galactose unit.
The component (C-2) is a granulated product whose main component is lactose and which is granulated with hydroxypropyl cellulose or the like.
The (C-3) component is starch obtained from mature corn seeds.
The component (C-4) is a low-substituted hydroxypropyl ether of cellulose.
The component (C-5) is obtained by partially depolymerizing α-cellulose obtained as pulp from fibrous plants with an acid and purifying it.
The (C-6) component is a sugar alcohol classified as a hexose.
The component (C-7) is a crosslinked polymer of 1-vinyl-2-pyrrolidone.
Anhydrous lactose is β-lactose or a mixture of β-lactose and α-lactose. While components (C-1) and (C-2) contain 3 to 6% water by mass, the water content of anhydrous lactose is 1.0% by mass or less. The water content can be measured by Karl Fischer moisture content.
Microcrystalline cellulose is produced by hydrolyzing ordinary cellulose (such as pulp) and grinding, purifying, and drying the crystalline regions, and has an average particle size of 1 to 200 μm. The average particle size is measured by a laser diffraction scattering method.
The corn starch granules are produced by suspending corn starch according to the Japanese Pharmacopoeia in hot water, followed by spray-drying and granulation to produce granules, and are spherical or polygonal particles with an average particle size of 3 to 35 μm. The average particle size is measured by microscopic examination.
内服医薬製剤中の（Ｃ）成分の下限値は、服用１回当たりの（Ｃ）成分の量として、１ｍｇ以上が好ましく、６ｍｇ以上がより好ましい。（Ｃ）成分の含有量が上記下限値以上であれば、内服医薬製剤中で（Ｃ）成分が均一に分布し、内服医薬製剤の変色のさらなる抑制が図れる。
内服医薬製剤中の（Ｃ）成分の上限値は、服用１回当たりの（Ｃ）成分の量として、１２００ｍｇ以下が好ましく、８４０ｍｇ以下がより好ましい。（Ｃ）成分の含有量が上記上限値以下であれば、（Ａ）成分の溶出性をより高められる。
服用１回当たりの内服医薬製剤中の（Ｃ）成分の含有量の好適な範囲は、１～１２００ｍｇが好ましく、６～８４０ｍｇがより好ましく、２５～６４０ｍｇがさらに好ましい。
なお、内服医薬製剤が錠剤の場合、上記の（Ｃ）成分の含有量は、１錠に含まれていてもよいし、１回に服用する錠剤数の総量でもよい。
The lower limit of the amount of component (C) in the oral pharmaceutical preparation is preferably 1 mg or more, more preferably 6 mg or more, per dose of component (C). If the content of component (C) is equal to or more than the lower limit, component (C) is uniformly distributed in the oral pharmaceutical preparation, and discoloration of the oral pharmaceutical preparation can be further suppressed.
The upper limit of the amount of component (C) in the oral pharmaceutical preparation is preferably 1200 mg or less, more preferably 840 mg or less, per dose of component (C). If the content of component (C) is equal to or less than the upper limit, the dissolution of component (A) can be further improved.
The preferred range of the content of component (C) in the oral pharmaceutical preparation per dose is 1 to 1200 mg, more preferably 6 to 840 mg, and even more preferably 25 to 640 mg.
When the oral pharmaceutical preparation is a tablet, the content of the above component (C) may be contained in one tablet or may be the total amount of the tablets taken at one time.
内服医薬製剤中の（Ｃ）成分の含有割合は、内服医薬製剤の総質量に対して、１～９５質量％が好ましく、３～９１質量％がより好ましい。（Ｃ）成分の含有割合が上記下限値以上であれば、（Ａ）成分の溶出性が高められた内服医薬製剤の変色のさらなる抑制が図れる。（Ｃ）成分の含有割合が上記上限値以下であれば、内服医薬製剤を錠剤とした場合に、（Ａ）成分の溶出性をより高められる。 The content of component (C) in the oral pharmaceutical formulation is preferably 1 to 95% by mass, more preferably 3 to 91% by mass, based on the total mass of the oral pharmaceutical formulation. If the content of component (C) is equal to or greater than the lower limit, discoloration of the oral pharmaceutical formulation having enhanced dissolution of component (A) can be further suppressed. If the content of component (C) is equal to or less than the upper limit, the dissolution of component (A) can be further enhanced when the oral pharmaceutical formulation is made into a tablet.
内服医薬製剤中、（Ｃ）成分／（Ｂ）成分で表される質量比（Ｃ／Ｂ比）の下限値は、０．０１以上が好ましく、０．０３以上がより好ましく、０．０６以上がさらに好ましい。Ｃ／Ｂ比の上限値は、１２以下が好ましく、４以下がより好ましく、１以下がさらに好ましい。例えば、Ｃ／Ｂ比は、０．０１～１２が好ましく、０．０３～４がより好ましく、０．０６～１がさらに好ましい。Ｃ／Ｂ比が上記下限値以上であれば、内服医薬製剤の変色のさらなる抑制が図れる。Ｃ／Ｂ比が上記上限値以下であれば、内服医薬製剤を錠剤とした場合に、摩損が生じにくい硬度を維持しつつ、（Ａ）成分の溶出性をより高められる。 In the oral pharmaceutical preparation, the lower limit of the mass ratio (C/B ratio) of the (C) component to the (B) component is preferably 0.01 or more, more preferably 0.03 or more, and even more preferably 0.06 or more. The upper limit of the C/B ratio is preferably 12 or less, more preferably 4 or less, and even more preferably 1 or less. For example, the C/B ratio is preferably 0.01 to 12, more preferably 0.03 to 4, and even more preferably 0.06 to 1. If the C/B ratio is equal to or greater than the lower limit, discoloration of the oral pharmaceutical preparation can be further suppressed. If the C/B ratio is equal to or less than the upper limit, when the oral pharmaceutical preparation is made into a tablet, the dissolution of the (A) component can be further improved while maintaining a hardness that is resistant to wear.
≪任意成分≫
内服医薬製剤は、必要に応じて、本発明の効果を損なわない範囲で、（Ａ）～（Ｃ）成分以外の他の成分（任意成分）をさらに含有してもよい。
任意成分としては、生理活性成分、添加剤（但し、（Ａ）～（Ｃ）成分を除く）等が挙げられる。
Optional Ingredients
The oral pharmaceutical preparation may further contain other components (optional components) other than the components (A) to (C) as necessary, within the scope of not impairing the effects of the present invention.
The optional components include physiologically active components, additives (excluding components (A) to (C)), and the like.
生理活性成分の例としては、解熱鎮痛成分（但し、（Ａ）成分を除く。）（例えばピロキシカム、アンピロキシカム、セロコキシブ、ロフェコキシブ、チアラミド、ロキソプロフェンナトリウム、エテンザミド、スルピリン、アセトアミノフェン、アセチルサリチル酸等）、鎮静催眠成分（例えば、アリルイソプロピルアセチル尿素、ブロムワレリル尿素等）、抗ヒスタミン成分（例えば、塩酸イソチペンジル、塩酸ジフェニルピラリン、塩酸ジフェンヒドラミン、塩酸ジフェテロール、塩酸トリプロリジン、塩酸トリペレナミン、塩酸トンジルアミン、塩酸フェネタジン、塩酸メトジラジン、サリチル酸ジフェンヒドラミン、ジフェニルジスルホン酸カルビノキサミン、酒石酸アリメマジン、タンニン酸ジフェンヒドラミン、テオクル酸ジフェニルピラリン、ナパジシル酸メブヒドロリン、プロメタジンメチレン二サリチル酸塩、マレイン酸カルビノキサミン、ｄｌ－マレイン酸クロルフェニラミン、ｄ－マレイン酸クロルフェニラミン、リン酸ジフェテロール等）、中枢興奮成分（例えば、安息香酸ナトリウムカフェイン、カフェイン、無水カフェイン等）、鎮咳去痰成分（コデインリン酸塩、デキストロメトルファン臭化水素酸塩、ジメモルファンリン酸塩、チペピジンヒベンズ酸塩、メトキシフェナミン塩酸塩、トリメトキノール塩酸塩、カルボシステイン、アセチルシステイン、エチルシステイン、ｄｌ－メチルエフェドリン、ブロムヘキシン塩酸塩、セラペプターゼ、塩化リゾチーム、アンブロキソール、テオフィリン、アミノフィリン）、ビタミン成分（例えば、ビタミンＢ１及びその誘導体並びにそれらの塩類、ビタミンＢ２及びその誘導体並びにそれらの塩類、ビタミンＢ６及びその誘導体並びにそれらの塩類、ビタミンＢ１２及びその誘導体並びにそれらの塩類、ビタミンＣ及びその誘導体並びにそれらの塩類、ビタミンＤ及びその誘導体並びにそれらの塩類、ビタミンＥ及びその誘導体並びにそれらの塩類、ヘスペリジン及びその誘導体並びにそれらの塩類等）、生薬（イレイセン、エンゴサク、オウゴン、ガイハク、カンゾウ、キキョウ、シャクヤク、セネガ等、第十七改正日本薬局方 医薬品各条「生薬等」に収載の成分）等が挙げられる。これらの生理活性成分は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。
内服医薬製剤中の上記生理活性成分の配合割合は、特に限定されないが、内服医薬製剤の総質量に対して、１～４０質量％が好ましく、３～３０質量％がより好ましい。
Examples of the physiologically active ingredient include antipyretic and analgesic ingredients (excluding ingredient (A)) (e.g., piroxicam, ampiroxicam, cerocoxib, rofecoxib, tiaramide, loxoprofen sodium, ethenzamide, sulpyrine, acetaminophen, acetylsalicylic acid, etc.), sedative and hypnotic ingredients (e.g., allylisopropylacetylurea, bromvalerylurea, etc.), antihistamine ingredients (e.g., isothipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenetheoclate Nylpyraline, mebhydroline napadisalicylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, difeterol phosphate, etc.), central stimulants (e.g., sodium caffeine benzoate, caffeine, anhydrous caffeine, etc.), antitussive and expectorant ingredients (codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, tipepidine hibenzate, methoxyphenamine hydrochloride, trimetoquinol hydrochloride, carbocysteine, acetylcysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline), vitamin ingredients (e.g., vitamin B Vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin B6 and its derivatives and their salts, vitamin B12 and its derivatives and their salts, vitamin C and its derivatives and their salts, vitamin D and its derivatives and their salts, vitamin E and its derivatives and their salts, hesperidin and its derivatives and their salts, etc.), herbal medicines (Irei Sen, Corydalis Root, Scutellaria Root, Gaihaku, Licorice, Platycodon Root, Peony Root, Senega, etc., ingredients listed in the 17th Revised Japanese Pharmacopoeia, each article on pharmaceuticals, "Herbal Medicines, etc."), etc. These physiologically active ingredients may be used alone or in combination of two or more.
The blending ratio of the physiologically active ingredient in the oral pharmaceutical preparation is not particularly limited, but is preferably 1 to 40% by mass, more preferably 3 to 30% by mass, based on the total mass of the oral pharmaceutical preparation.
添加剤の例としては、結合剤、賦形剤、崩壊剤、滑沢剤、香料、色素、基剤、甘味剤、酸味剤等が挙げられる。
結合剤としては、ショ糖、ゼラチン、アラビアゴム末、ポリビニルピロリドン、プルラン、デキストリン等が挙げられる。
賦形剤としては、従来公知の賦形剤の内、（Ｃ）成分を除く賦形剤が挙げられ、例えば、粉糖、Ｌ－システイン等が挙げられる。
崩壊剤としては、従来公知の賦形剤の内、（Ｃ）成分を除く崩壊剤が挙げられ、例えば、クロスカルメロースナトリウム等が挙げられる。
滑沢剤としては、ステアリン酸マグネシウム、フマル酸ステアリルナトリウム、ショ糖脂肪酸エステル、軽質無水ケイ酸等が挙げられる。
香料としては、メントール、リモネン、植物精油（ハッカ油、ミント油、ライチ油、オレンジ油、レモン油等）等が挙げられる。
色素としては、三二酸化鉄等が挙げられる。
基剤としては、水、エタノール等が挙げられる。
甘味剤としては、サッカリンナトリウム、アスパルテーム、ステビア、グリチルリチン酸二カリウム、アセスルファムカリウム、ソーマチン、スクラロース等が挙げられる。
酸味剤としては、クエン酸、酒石酸、リンゴ酸、コハク酸、フマル酸、乳酸及びそれらの塩等が挙げられる。
これらの添加剤は、１種単独で用いられてもよいし、２種以上が組み合わされて用いられてもよい。
内服医薬製剤中の添加剤の含有割合は、特に限定されないが、内服医薬製剤の総質量に対して、１～８０質量％が好ましく、２～６０質量％がより好ましい。上記任意成分の内、賦形剤及び崩壊剤（但し、（Ｃ）成分を除く）を含有する場合、その合計量は、内服医薬製剤の総質量に対して、２０質量％以下が好ましく、１５質量％以下がより好ましく、１０質量％以下がさらに好ましい。賦形剤及び崩壊剤の合計量が上記上限値以下であれば、内服医薬製剤の変色のさらなる抑制が図れる。
なお、（Ａ）～（Ｃ）成分及び任意成分の合計は、１００質量％を超えない。
Examples of the additives include binders, excipients, disintegrants, lubricants, flavors, colorants, bases, sweeteners, and acidulants.
Examples of binders include sucrose, gelatin, powdered gum arabic, polyvinylpyrrolidone, pullulan, and dextrin.
The excipient may be any of the conventionally known excipients other than component (C), such as powdered sugar, L-cysteine, etc.
The disintegrant may be any of the conventionally known excipients other than component (C), such as croscarmellose sodium.
Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid esters, light anhydrous silicic acid, and the like.
Examples of the fragrance include menthol, limonene, and plant essential oils (peppermint oil, mint oil, lychee oil, orange oil, lemon oil, etc.).
The pigment may be ferric oxide or the like.
The base includes water, ethanol, and the like.
Sweeteners include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, and sucralose.
The acidulant includes citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.
These additives may be used alone or in combination of two or more.
The content ratio of the additive in the oral pharmaceutical formulation is not particularly limited, but is preferably 1 to 80% by mass, more preferably 2 to 60% by mass, based on the total mass of the oral pharmaceutical formulation. When the optional components include an excipient and a disintegrant (excluding component (C)), the total amount thereof is preferably 20% by mass or less, more preferably 15% by mass or less, and even more preferably 10% by mass or less, based on the total mass of the oral pharmaceutical formulation. If the total amount of the excipient and disintegrant is equal to or less than the upper limit, discoloration of the oral pharmaceutical formulation can be further suppressed.
The total amount of components (A) to (C) and any optional components does not exceed 100% by mass.
＜製造方法＞
本実施形態の内服医薬製剤の製造方法は、（Ａ）～（Ｃ）成分が共存できるものであれば、特に限定されない。
内服医薬製剤が単層錠である場合、（Ａ）～（Ｃ）成分及び必要に応じて任意成分を粉体混合し、得られた粉体混合物を打錠する製造方法が挙げられる。
また、例えば、（Ａ）～（Ｃ）成分及び必要に応じて任意成分を粉体混合し、得られた粉体混合物を造粒して造粒粒子の群とし、これを顆粒剤とする製造方法が挙げられる。得られた粒子群をカプセルに封入してカプセル剤としてもよいし、得られた粒子群を打錠して錠剤としてもよい。
<Production Method>
The method for producing the oral pharmaceutical formulation of the present embodiment is not particularly limited as long as the components (A) to (C) can coexist.
When the oral pharmaceutical preparation is a single-layer tablet, the preparation may be produced by powder-mixing the components (A) to (C) and, if necessary, any optional components, and compressing the resulting powder mixture into tablets.
In addition, for example, the components (A) to (C) and any optional components as required are powder-mixed, the resulting powder mixture is granulated to form a group of granulated particles, and the resulting group of particles is made into a granule. The resulting group of particles may be encapsulated to form a capsule, or the resulting group of particles may be compressed to form a tablet.
以下、顆粒剤の造粒方法について説明する。
造粒方法としては、乾式造粒法、湿式造粒法等が挙げられる。湿式造粒法としては、流動層造粒法、攪拌造粒法、転動造粒法、押し出し造粒法等が挙げられる。
造粒方法としては、製造性の点から、湿式造粒法が好ましい。中でも、（Ａ）～（Ｃ）成分を効率良く接触可能なこと、操作性、生産性の観点から、流動層造粒法及び攪拌造粒法が好ましい。
造粒条件は、造粒方法に応じて適宜選定できる。例えば、流動層造粒法にて造粒を行う場合は、給気温度６０～１００℃、給気風量１．０～４．０ｍ３／分で造粒を行うことができる。攪拌造粒法にて造粒を行う場合は、チョッパー回転速度５００～３０００ｒｐｍ、アジテーター回転速度１００～５００ｒｐｍにて造粒を行うことできる。
The granulation method for the granules will be described below.
Examples of the granulation method include a dry granulation method, a wet granulation method, etc. Examples of the wet granulation method include a fluidized bed granulation method, an agitation granulation method, a rolling granulation method, an extrusion granulation method, etc.
As the granulation method, a wet granulation method is preferred from the viewpoint of manufacturability. Among them, a fluidized bed granulation method and an agitation granulation method are preferred from the viewpoints of efficient contact of the components (A) to (C), operability, and productivity.
Granulation conditions can be appropriately selected depending on the granulation method. For example, when granulation is performed by a fluidized bed granulation method, granulation can be performed at an inlet air temperature of 60 to 100° C. and an inlet air volume of 1.0 to 4.0 m 3 /min. When granulation is performed by an agitation granulation method, granulation can be performed at a chopper rotation speed of 500 to 3000 rpm and an agitator rotation speed of 100 to 500 rpm.
製造上問題ない液体を噴霧しながら造粒を行ってもよい。このような液体としては、水、エタノール等が挙げられる。
一般的に湿式造粒法では、水溶性高分子や水不溶性アクリル酸重合体等の結合剤を水に分散又は溶解させた結合液を噴霧しながら造粒を行う。本態様の造粒工程においても、結合液を噴霧しながら造粒を行ってよい。この場合、得られる粒子群（Ｘ）を構成する粒子（ｘ）は結合剤を含む。
結合剤が水溶性高分子を含む場合、崩壊性を良好に保つ点から、粒子（ｘ）は、結合剤の含有量が少ないことが好ましい。具体的には、結合液の噴霧量は、水溶性高分子の含有量が、粒子（ｘ）の総質量に対し、５質量％以下となる量が好ましい。
Granulation may be carried out while spraying a liquid that does not cause problems in manufacturing, such as water, ethanol, etc.
In general, in the wet granulation method, granulation is performed while spraying a binder liquid in which a binder such as a water-soluble polymer or a water-insoluble acrylic acid polymer is dispersed or dissolved in water. In the granulation step of this embodiment, granulation may be performed while spraying a binder liquid. In this case, the particles (x) constituting the obtained particle group (X) contain a binder.
When the binder contains a water-soluble polymer, the particles (x) preferably have a small binder content in order to maintain good disintegrability. Specifically, the amount of the binder solution sprayed is preferably such that the content of the water-soluble polymer is 5% by mass or less relative to the total mass of the particles (x).
造粒後、必要に応じて、水分率の調整等を目的とし、得られた造粒粒子を乾燥する。
乾燥方法としては、特に限定されないが、流動層造粒機又は箱式通気型式乾燥機等の乾燥機を使用して棚乾燥することが好ましい。
乾燥条件は、乾燥方法に応じて適宜選定できる。例えば、流動層造粒機を用いて乾燥を行う場合は、給気温度６０～１００℃、乾燥時間１０～９０分間、給気風量１．０～４．０ｍ３／分で乾燥させることができる。箱式通気型式乾燥機を用いて乾燥を行う場合は、乾燥温度４０～９０℃、乾燥時間１５～１３０分間で乾燥させることができる。
After granulation, the resulting granulated particles are dried, if necessary, for the purpose of adjusting the moisture content, etc.
The drying method is not particularly limited, but shelf drying using a dryer such as a fluidized bed granulator or a box-type ventilation dryer is preferred.
Drying conditions can be appropriately selected depending on the drying method. For example, when drying is performed using a fluidized bed granulator, drying can be performed at an intake air temperature of 60 to 100°C, a drying time of 10 to 90 minutes, and an intake air volume of 1.0 to 4.0 m3/min. When drying is performed using a box-type ventilation dryer, drying can be performed at a drying temperature of 40 to 90°C, and a drying time of 15 to 130 minutes.
以上、粉体混合工程と造粒工程とを有する態様の製造方法について説明したが、粒子群（Ｘ）の製造方法はこの態様の製造方法に限定されるものではない。
例えば、造粒工程を有し、粉体混合工程を有しない製造方法により粒子群（Ｘ）を製造してもよい。この場合、造粒工程では、造粒する各成分（（Ａ）～（Ｃ）成分等）を、粉体等の固体の状態で接触させてもよく、液状媒体に溶解又は分散された状態で接触させてもよい。
Although the manufacturing method having the powder mixing step and the granulation step has been described above, the manufacturing method of the particle group (X) is not limited to this embodiment.
For example, the particle group (X) may be produced by a production method having a granulation step but not having a powder mixing step. In this case, in the granulation step, the components to be granulated (e.g., components (A) to (C)) may be contacted in a solid state such as powder, or in a state dissolved or dispersed in a liquid medium.
粉体混合工程を経ずに造粒工程を行う場合、（Ａ）～（Ｃ）成分の造粒機への投入順序は、製造上問題なければ特に限定されない。例えば、（Ａ）成分を投入し、造粒した後、造粒機に（Ｂ）成分及び（Ｃ）を投入し、さらに造粒を行ってもよく、（Ａ）成分と（Ｂ）成分の投入順序を逆にしてもよい。粒子（ｘ）がより均一になりやすく、さらに工程の煩雑化を避けることができる点では、（Ａ）～（Ｃ）成分を同時に又は予め造粒機に投入して造粒を行うことが好ましい。 When the granulation step is performed without going through the powder mixing step, the order in which components (A) to (C) are fed into the granulator is not particularly limited as long as it does not cause any problems in terms of production. For example, component (A) may be fed and granulated, and then components (B) and (C) may be fed into the granulator and further granulated, or the order in which components (A) and (B) are fed may be reversed. In terms of making the particles (x) more uniform and avoiding the process becoming complicated, it is preferable to feed components (A) to (C) into the granulator simultaneously or in advance and perform granulation.
＜使用方法＞
本実施形態の内服医薬製剤の使用方法は、剤形に応じて適宜決定される。即ち、（Ａ）～（Ｃ）成分が所望の服用量となるように、内服医薬製剤を経口で摂取する。
<How to use>
The method of use of the oral pharmaceutical preparation of this embodiment is appropriately determined depending on the dosage form. That is, the oral pharmaceutical preparation is orally taken so that the components (A) to (C) are administered in the desired dose.
本実施形態の内服医薬製剤によれば、（Ａ）成分と（Ｂ）成分とを併有するため、（Ａ）成分の薬効を発揮しつつ、（Ａ）成分による胃障害を軽減できる。ここで、（Ａ）成分と（Ｂ）成分とが共存すると、内服医薬製剤は経時的に変色する。しかしながら、本実施形態の内服医薬製剤によれば、（Ｃ）成分を含有するため、（Ａ）成分と（Ｂ）成分とが共存しても、内服医薬製剤の変色を抑制できる。 The oral pharmaceutical formulation of this embodiment contains both component (A) and component (B), and therefore can reduce stomach damage caused by component (A) while exerting the medicinal effect of component (A). Here, when components (A) and (B) coexist, the oral pharmaceutical formulation discolors over time. However, the oral pharmaceutical formulation of this embodiment contains component (C), and therefore discoloration of the oral pharmaceutical formulation can be suppressed even when components (A) and (B) coexist.
（Ａ）成分と（Ｂ）成分とが共存する剤形（単層錠、（Ａ）成分と（Ｂ）成分とが同一層に含まれる多層錠、カプセル剤、マイクロカプセル剤、顆粒剤、細粒剤、散剤等）においては、本発明の課題を生じる。このため、本実施形態の内服医薬製剤によれば、（Ａ）成分と（Ｂ）成分との共存下において、（Ｃ）成分が存在することで、如何なる剤形においても、内服医薬製剤の変色を抑制できる。 The problem of the present invention arises in dosage forms in which the (A) and (B) components coexist (single-layer tablets, multi-layer tablets in which the (A) and (B) components are contained in the same layer, capsules, microcapsules, granules, fine granules, powders, etc.). Therefore, according to the oral pharmaceutical formulation of this embodiment, discoloration of the oral pharmaceutical formulation can be suppressed in any dosage form by the presence of the (C) component in the coexistence of the (A) and (B) components.
（第二の実施形態）
本実施形態の固形医薬製剤は、（Ａ）成分を含有し、実質的に（Ｂ）成分を含有しない粒子の群（α１）と、（Ｂ）成分を含有し、実質的に（Ａ）成分を含有しない粒子の群（β１）とを有する。粒子の群（α１）及び粒子の群（β１）の少なくとも一方は、造粒粒子である。本実施形態の固形医薬製剤は、内服固形製剤であることが好ましい。
なお、「実質的に含有しない」とは、全く含有しないか、又は各成分の影響を生じない程度に含有することをいう。
Second Embodiment
The solid pharmaceutical formulation of this embodiment has a particle group (α1) containing the (A) component and substantially not containing the (B) component, and a particle group (β1) containing the (B) component and substantially not containing the (A) component. At least one of the particle group (α1) and the particle group (β1) is a granulated particle. The solid pharmaceutical formulation of this embodiment is preferably an oral solid formulation.
The term "substantially free of" means that each component is not contained at all or is contained to such an extent that it does not have an effect on the other components.
＜粒子の群（α１）＞
粒子の群（α１）は、（Ａ）成分を含有し、（Ｂ）成分を実質的に含有しない造粒粒子群である。後述する粒子の群（β１）が造粒粒子の群である場合、粒子の群（α１）は造粒粒子の群でもよいし（Ａ）成分の粒子が独立して存在する粒子の群でもよい。後述する粒子の群（β１）が造粒粒子でない場合、粒子の群（α１）は、造粒粒子の群である。
（Ａ）成分の種類、含有量及び含有割合は、第一の実施形態と同様である。
粒子の群（α１）の総質量に対する（Ｂ）成分の含有量は、例えば、５質量％以下が好ましく、３質量％以下がより好ましく、０質量％がさらに好ましい。
<Particle group (α1)>
The particle group (α1) is a granulated particle group that contains the (A) component and does not substantially contain the (B) component. When the particle group (β1) described later is a granulated particle group, the particle group (α1) may be a granulated particle group or a particle group in which the particles of the (A) component exist independently. When the particle group (β1) described later is not a granulated particle group, the particle group (α1) is a granulated particle group.
The type, content and content ratio of the component (A) are the same as those in the first embodiment.
The content of the component (B) relative to the total mass of the particle group (α1) is, for example, preferably 5 mass % or less, more preferably 3 mass % or less, and even more preferably 0 mass %.
粒子の群（α１）は、（Ｃ）成分を含有する造粒粒子の群としてもよい。粒子の群（α１）が（Ｃ）成分を含有することで、固形医薬製剤における変色のさらなる抑制が図れる。
（Ｃ）成分の種類は、第一の実施形態と同様である。
本実施形態における固形医薬製剤中の（Ｃ）成分の含有量は、服用１回当たりの量として、５～１２００ｍｇが好ましく、６～５４０ｍｇがより好ましい。固形医薬製剤中の（Ｃ）成分の含有割合は、１０～９５質量％が好ましく、２０～９１質量％がより好ましい。前記含有量や含有割合が好ましい理由は、第一の実施形態と同様である。
The particle group (α1) may be a group of granulated particles containing the component (C). By containing the particle group (α1) in the component (C), discoloration in the solid pharmaceutical preparation can be further suppressed.
The type of component (C) is the same as in the first embodiment.
The content of component (C) in the solid pharmaceutical formulation in this embodiment is preferably 5 to 1200 mg, more preferably 6 to 540 mg, per dose. The content ratio of component (C) in the solid pharmaceutical formulation is preferably 10 to 95% by mass, more preferably 20 to 91% by mass. The reasons why the above content and content ratio are preferable are the same as those in the first embodiment.
粒子の群（α１）において、（Ｃ）成分／（Ａ）成分で表される質量比（Ｃ／Ａ比）の下限値は、０．５以上が好ましく、２以上がより好ましい。Ｃ／Ａ比が上記下限値以上であれば、固形医薬製剤の変色のさらなる抑制が図れる。Ｃ／Ａ比の上限値は、５０以下が好ましく、４０以下がより好ましい。Ｃ／Ａ比が上記上限値以下であれば、固形医薬製剤を錠剤とした場合に、摩損が生じにくい硬度を維持しつつ、（Ａ）成分の溶出性をより高められる。 In the particle group (α1), the lower limit of the mass ratio (C/A ratio) represented by the (C) component/(A) component is preferably 0.5 or more, more preferably 2 or more. If the C/A ratio is equal to or more than the above lower limit, discoloration of the solid pharmaceutical formulation can be further suppressed. The upper limit of the C/A ratio is preferably 50 or less, more preferably 40 or less. If the C/A ratio is equal to or less than the above upper limit, when the solid pharmaceutical formulation is made into a tablet, the dissolution of the (A) component can be further improved while maintaining a hardness that is resistant to abrasion.
粒子の群（α１）は、（Ａ）成分及び（Ｃ）成分以外の任意成分を含有してもよい。
任意成分としては、第一の実施形態と同様の成分が挙げられる。
The particle group (α1) may contain an optional component other than the component (A) and the component (C).
Optional components include the same components as in the first embodiment.
粒子の群（α１）が造粒粒子の群である場合、粒子の群（α１）の製造方法は、（Ａ）成分と、必要に応じて（Ｃ）成分又は任意成分とを粉体混合物とし、これを造粒する製造方法が挙げられる。造粒方法は、第一の実施形態と同様の造粒方法が挙げられる。 When the particle group (α1) is a group of granulated particles, the particle group (α1) can be produced by preparing a powder mixture of the (A) component and, if necessary, the (C) component or an optional component, and granulating the mixture. The granulation method can be the same as that of the first embodiment.
粒子の群（α１）が造粒粒子の群である場合、粒子の群（α１）の平均粒子径は、１０～７００μｍが好ましく、５０～５００μｍがより好ましい。平均粒子径が上記下限値以上であれば、体積に対する表面積の割合が小さく、粒子の群（α１）を構成する造粒粒子が、粒子の群（β１）を構成する粒子と接触しても、粒子の群（α１）内の（Ａ）成分に対する（Ｂ）成分の影響が少ない。このため、固形医薬製剤の変色を良好に抑制できる。平均粒子径が上記上限値以下であれば、固形医薬製剤を錠剤とした場合に、（Ａ）成分の溶出性を高められる。
粒子の群（α１）が造粒粒子の群ではなく、（Ａ）成分の粒子が独立して存在する粒子の群である場合、その平均粒子径は、５～５００μｍが好ましく、２０～３５０μｍが好ましい。前記平均粒子径が好ましい理由は、粒子の群（α１）が造粒粒子の群である場合と同様である。
なお、上記平均粒子径は、ロータップ法又はレーザー回折散乱法で測定できる。ロータップ法で測定される平均粒子径は質量基準において頻度の累積が５０質量％となる粒子径に相当する。
When the particle group (α1) is a group of granulated particles, the average particle size of the particle group (α1) is preferably 10 to 700 μm, more preferably 50 to 500 μm. If the average particle size is equal to or greater than the lower limit, the ratio of surface area to volume is small, and even if the granulated particles constituting the particle group (α1) come into contact with the particles constituting the particle group (β1), the effect of the (B) component on the (A) component in the particle group (α1) is small. Therefore, discoloration of the solid pharmaceutical preparation can be well suppressed. If the average particle size is equal to or less than the upper limit, the dissolution of the (A) component can be improved when the solid pharmaceutical preparation is made into a tablet.
When the particle group (α1) is not a group of granulated particles but a group of particles in which the particles of component (A) exist independently, the average particle size is preferably 5 to 500 μm, more preferably 20 to 350 μm. The reason why the above average particle size is preferable is the same as when the particle group (α1) is a group of granulated particles.
The average particle size can be measured by a low-tap method or a laser diffraction scattering method. The average particle size measured by the low-tap method corresponds to the particle size at which the cumulative frequency is 50% by mass on a mass basis.
＜粒子の群（β１）＞
粒子の群（β１）は、（Ｂ）成分を含有し、（Ａ）成分を実質的に含有しない粒子群である。粒子の群（α１）が造粒粒子の群である場合、粒子の群（β１）は、造粒粒子の群でもよいし、（Ｂ）成分の粒子が独立して存在する粒子群でもよい。粒子の群（α１）が造粒粒子でない場合、粒子の群（β１）は、造粒粒子の群である。
（Ｂ）成分の種類、含有量及び含有割合は、第一の実施形態と同様である。但し、固形医薬製剤が（Ｃ）成分を実質的に含有しない場合には、（Ｂ）成分の含有割合は、固形医薬製剤の総質量に対して、４～９８質量％が好ましく、７～９０質量％がより好ましい。
粒子の群（β１）の総質量に対する（Ａ）成分の含有割合は、例えば、５質量％以下が好ましく、３質量％以下がより好ましく、０質量％がさらに好ましい。
<Particle group (β1)>
The particle group (β1) is a particle group that contains the component (B) and does not substantially contain the component (A). When the particle group (α1) is a group of granulated particles, the particle group (β1) may be a group of granulated particles or a group of particles in which the particles of the component (B) exist independently. When the particle group (α1) is not a granulated particle, the particle group (β1) is a group of granulated particles.
The type, content and content ratio of the component (B) are the same as those in the first embodiment. However, when the solid pharmaceutical preparation does not substantially contain the component (C), the content ratio of the component (B) is preferably 4 to 98% by mass, more preferably 7 to 90% by mass, based on the total mass of the solid pharmaceutical preparation.
The content of the component (A) relative to the total mass of the particle group (β1) is, for example, preferably 5 mass % or less, more preferably 3 mass % or less, and even more preferably 0 mass %.
粒子の群（β１）は、（Ｃ）成分を含有する造粒粒子の群としてもよい。粒子の群（β１）が（Ｃ）成分を含有することで、固形医薬製剤の変色をより良好に抑制できる。
（Ｃ）成分の種類は、第一の実施形態と同様である。
本実施形態における固形医薬製剤中の（Ｃ）成分の含有量は、服用１回当たりの量として、５～１２００ｍｇが好ましく、６～５４０ｍｇがより好ましい。固形医薬製剤中の（Ｃ）成分の含有割合は、０．５～５０質量％が好ましく、１～４０質量％がより好ましい。前記含有量や含有割合が好ましい理由は、第一の実施形態と同様である。
The particle group (β1) may be a group of granulated particles containing the component (C). When the particle group (β1) contains the component (C), discoloration of the solid pharmaceutical preparation can be more effectively suppressed.
The type of component (C) is the same as in the first embodiment.
The content of component (C) in the solid pharmaceutical formulation in this embodiment is preferably 5 to 1200 mg, more preferably 6 to 540 mg, per dose. The content ratio of component (C) in the solid pharmaceutical formulation is preferably 0.5 to 50 mass %, more preferably 1 to 40 mass %. The reasons why the above content and content ratio are preferable are the same as those in the first embodiment.
粒子の群（β１）において、（Ｃ）成分／（Ｂ）成分で表される質量比（Ｃ／Ｂ比）の下限値は、０．０１以上が好ましく、０．０３以上がより好ましい。Ｃ／Ｂ比が上記下限値以上であれば、固形医薬製剤の変色のさらなる抑制が図れる。Ｃ／Ｂ比の上限値は、１２以下が好ましく、４以下がより好ましい。Ｃ／Ｂ比が上記上限値以下であれば、固形医薬製剤を錠剤とした場合に、摩損が生じにくい強度を維持しつつ、（Ａ）成分の溶出性をより高められる。 In the particle group (β1), the lower limit of the mass ratio (C/B ratio) represented by the (C) component/(B) component is preferably 0.01 or more, more preferably 0.03 or more. If the C/B ratio is equal to or more than the above lower limit, discoloration of the solid pharmaceutical formulation can be further suppressed. The upper limit of the C/B ratio is preferably 12 or less, more preferably 4 or less. If the C/B ratio is equal to or less than the above upper limit, when the solid pharmaceutical formulation is made into a tablet, the dissolution of the (A) component can be further improved while maintaining a strength that is resistant to abrasion.
また、固形医薬組成物中、Ｃ／Ｂ比の下限値は、０．０１以上が好ましく、０．０３以上がより好ましい。Ｃ／Ｂ比が上記下限値以上であれば、固形医薬製剤の変色のさらなる抑制が図れる。Ｃ／Ｂ比の上限値は、１２以下が好ましく、４以下がより好ましい。Ｃ／Ｂ比が上記上限値以下であれば、固形医薬製剤を錠剤とした場合に、（Ａ）成分の溶出性をより高め、硬度を高められる。 In addition, in the solid pharmaceutical composition, the lower limit of the C/B ratio is preferably 0.01 or more, and more preferably 0.03 or more. If the C/B ratio is equal to or more than the above lower limit, discoloration of the solid pharmaceutical formulation can be further suppressed. The upper limit of the C/B ratio is preferably 12 or less, and more preferably 4 or less. If the C/B ratio is equal to or less than the above upper limit, the dissolution of component (A) can be further improved and the hardness can be increased when the solid pharmaceutical formulation is made into a tablet.
粒子の群（β１）は、（Ｂ）成分及び（Ｃ）成分以外の任意成分を含有してもよい。
任意成分としては、第一の実施形態と同様の成分が挙げられる。
The particle group (β1) may contain an optional component other than the components (B) and (C).
Optional components include the same components as in the first embodiment.
粒子の群（β１）が造粒粒子の群の場合、粒子の群（β１）の製造方法は、（Ｂ）成分と、必要に応じて（Ｃ）成分又は任意成分とを粉体混合物とし、これを造粒する製造方法が挙げられる。造粒方法は、第一の実施形態と同様の造粒方法が挙げられる。 When the particle group (β1) is a group of granulated particles, the particle group (β1) can be produced by preparing a powder mixture of the (B) component and, if necessary, the (C) component or an optional component, and granulating the mixture. The granulation method can be the same as that of the first embodiment.
粒子の群（β１）の平均粒子径は、１０～７００μｍが好ましく、５０～５００μｍがより好ましい。平均粒子径が上記下限値以上であれば、体積に対する表面積の割合が小さく、造粒粒子（β１）が造粒粒子（α１）と接触しても、造粒粒子（α１）内の（Ａ）成分に対する（Ｂ）成分の影響が少ない。このため、固形医薬製剤の変色を良好に抑制できる。平均粒子径が上記上限値以下であれば、固形医薬製剤を錠剤とした場合に、服用後の錠剤の崩壊を早められる。
粒子の群（β１）が造粒粒子の群ではなく、（Ｂ）成分の粒子が独立して存在する粒子の群である場合、その平均粒子径は、５～５００μｍが好ましく、２０～３５０μｍが好ましい。前記平均粒子径が好ましい理由は、粒子の群（β１）が造粒粒子の群である場合と同様である。
なお、粒子の群（β１）の平均粒子径の測定方法は、粒子の群（α１）の平均粒子径の測定方法と同様である。
The average particle size of the particle group (β1) is preferably 10 to 700 μm, more preferably 50 to 500 μm. If the average particle size is equal to or greater than the lower limit, the ratio of surface area to volume is small, and even if the granulated particles (β1) come into contact with the granulated particles (α1), the influence of the component (B) on the component (A) in the granulated particles (α1) is small. Therefore, discoloration of the solid pharmaceutical preparation can be effectively suppressed. If the average particle size is equal to or less than the upper limit, when the solid pharmaceutical preparation is made into a tablet, the disintegration of the tablet after taking it can be accelerated.
When the particle group (β1) is not a group of granulated particles but a group of particles in which the particles of component (B) exist independently, the average particle size is preferably 5 to 500 μm, more preferably 20 to 350 μm. The reason why the above average particle size is preferable is the same as when the particle group (β1) is a group of granulated particles.
The method for measuring the average particle size of the particle group (β1) is the same as the method for measuring the average particle size of the particle group (α1).
＜任意粒子群＞
本実施形態の固形医薬製剤は、粒子の群（α１）及び粒子の群（β１）の他に他の粒子の群（任意粒子群）を有してもよい。任意粒子群としては、例えば、（Ｃ）成分を含有し、実質的に（Ａ）成分及び（Ｂ）成分を含有しない粒子群が挙げられる。即ち、（Ｃ）成分は、粒子の群（α１）及び粒子の群（β１）とは異なる粒子群として、固形医薬製剤中に存在してもよい。
<Arbitrary particle group>
The solid pharmaceutical formulation of this embodiment may have other particle groups (arbitrary particle groups) in addition to the particle group (α1) and particle group (β1).The arbitrary particle group may be, for example, a particle group that contains the (C) component and does not substantially contain the (A) component and the (B) component.That is, the (C) component may be present in the solid pharmaceutical formulation as a particle group different from the particle group (α1) and the particle group (β1).
＜製造方法＞
本実施形態の固形医薬製剤の製造方法は、粒子の群（α１）と粒子の群（β１）とを粉体混合し、これを顆粒剤とする。あるいは、得られた顆粒剤をカプセル剤としてもよい。また、例えば、得られた顆粒剤を打錠して、粒子の群（α１）と粒子の群（β１）とを同一層に含む錠剤としてもよい。
<Production Method>
In the method for producing a solid pharmaceutical formulation of the present embodiment, the particle group (α1) and the particle group (β1) are mixed in powder form to form a granule. Alternatively, the obtained granule may be made into a capsule. In addition, for example, the obtained granule may be compressed into a tablet containing the particle group (α1) and the particle group (β1) in the same layer.
本実施形態の固形医薬製剤によれば、（Ａ）成分と（Ｂ）成分とは、それぞれ異なる粒子に含まれるため、両者が直接接触する機会が少ない。このため、固形医薬製剤における変色を抑制できる。 According to the solid pharmaceutical formulation of this embodiment, component (A) and component (B) are contained in different particles, so there is little opportunity for the two to come into direct contact with each other. This makes it possible to suppress discoloration of the solid pharmaceutical formulation.
（Ａ）成分と（Ｂ）成分とが共存する剤形（単層錠、（Ａ）成分と（Ｂ）成分とが同一層に含有されている積層錠、カプセル剤、マイクロカプセル剤、顆粒剤、細粒剤、散剤等）においては、本発明の課題を生じる。このため、本実施形態の固形医薬製剤によれば、（Ａ）成分と（Ｂ）成分とを各々に含有する粒子を独立させることで、如何なる剤形においても、固形医薬製剤の変色を抑制できる。加えて、（Ｂ）成分がマグネシウム原子を含有するため、（Ａ）成分を早期に溶出させ、即効性を高められる。 The problem of the present invention arises in dosage forms in which the (A) and (B) components coexist (single-layer tablets, layered tablets in which the (A) and (B) components are contained in the same layer, capsules, microcapsules, granules, fine granules, powders, etc.). Therefore, according to the solid pharmaceutical formulation of this embodiment, by separating the particles each containing the (A) and (B) components, discoloration of the solid pharmaceutical formulation can be suppressed in any dosage form. In addition, since the (B) component contains magnesium atoms, the (A) component is dissolved early, enhancing its immediate effect.
以下、実施例を示して本発明を詳細に説明するが、本発明は以下の記載によって限定されるものではない。 The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following description.
（使用原料）
＜（Ａ）成分＞
・Ａ－１：メロキシカム（商品名：メロキシカム、ＳＵＮ Ｐｈａｒｍａ社製）。
(Raw materials used)
<Component (A)>
A-1: Meloxicam (trade name: Meloxicam, manufactured by SUN Pharma).
＜（Ｂ）成分＞
・Ｂ－１：酸化マグネシウム（商品名：日局酸化マグネシウム重質、規格：日局、協和化学工業株式会社製）。
・Ｂ－２：炭酸マグネシウム（商品名：重質、規格：日局、協和化学工業株式会社製）。
・Ｂ－３：メタケイ酸アルミン酸マグネシウム（商品名：ノイシリン、規格：局外規、富士化学工業株式会社製）。
<Component (B)>
B-1: Magnesium oxide (product name: Japanese Pharmacopoeia Magnesium Oxide Heavy, specification: Japanese Pharmacopoeia, manufactured by Kyowa Chemical Industry Co., Ltd.).
B-2: Magnesium carbonate (product name: heavy, specification: Japanese Pharmacopoeia, manufactured by Kyowa Chemical Industry Co., Ltd.).
B-3: Magnesium aluminometasilicate (product name: Neusilin, standard: extra-official regulation, manufactured by Fuji Chemical Industry Co., Ltd.).
＜（Ｂ’）成分：（Ｂ）成分の比較品＞
・Ｂ’－１：乾燥水酸化アルミニウムゲル（商品名：Ｓ－１００、規格：日局、協和化学工業株式会社製）。
<Component (B'): Comparative product of component (B)>
B'-1: Dried aluminum hydroxide gel (product name: S-100, specification: Japanese Pharmacopoeia, manufactured by Kyowa Chemical Industry Co., Ltd.).
＜（Ｃ）成分＞
・Ｃ－１：乳糖（水和物、Ｐｈａｒｍａｔｏｓｅ２００Ｍ、規格：日局、ＤＭＶ社製）。
・Ｃ－２：乳糖造粒物（商品名：乳糖Ｇ、規格：薬添規、フロイント産業株式会社製）。
・Ｃ－３：トウモロコシデプン（商品名：局方松谷コーンスターチ、松谷化学工業株式会社製）。
・Ｃ－４：低置換度ヒドロキシプロピルセルロース（商品名：ＬＨ－３１、規格：日局、信越化学工業株式会社製）。
・Ｃ－５：結晶セルロース（商品名：セオラス、グレード：ＰＨ－３０２、規格：日局、旭化成株式会社製）。
・Ｃ－６：マンニトール（商品名：ペアリトール２００ＳＤ、規格：日局、ロケット社製）。
・Ｃ－７：クロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ－ＳＦ、規格：日局、ＢＡＳＦ社製）。
<Component (C)>
C-1: Lactose (hydrate, Pharmatose 200M, standard: Japanese Pharmacopoeia, manufactured by DMV).
C-2: Lactose granules (product name: Lactose G, specification: Pharmaceutical Additives Regulations, manufactured by Freund Corporation).
C-3: Corn starch (product name: Pharmacopoeia Matsutani Corn Starch, manufactured by Matsutani Chemical Industry Co., Ltd.).
C-4: Low-substituted hydroxypropyl cellulose (trade name: LH-31, specification: Japanese Pharmacopoeia, manufactured by Shin-Etsu Chemical Co., Ltd.).
C-5: Crystalline cellulose (trade name: Ceolas, grade: PH-302, standard: Japanese Pharmacopoeia, manufactured by Asahi Kasei Corporation).
C-6: Mannitol (product name: Pearitol 200SD, standard: Japanese Pharmacopoeia, manufactured by Rocket Co., Ltd.).
C-7: Crospovidone (trade name: Kollidon CL-SF, standard: Japanese Pharmacopoeia, manufactured by BASF).
＜（Ｃ’）成分：（Ｃ）成分の比較品＞
・Ｃ’－１：ソルビトール（規格：日局、メルク株式会社製）。
・Ｃ’－２：リン酸二水素カリウム二水和物（規格：局外規、太平化学産業株式会社製）。
<Component (C'): Comparative product of component (C)>
C'-1: Sorbitol (standard: Japanese Pharmacopoeia, manufactured by Merck Ltd.).
C'-2: Potassium dihydrogen phosphate dihydrate (specification: extra-official regulation, manufactured by Taihei Chemical Industry Co., Ltd.).
＜任意成分＞
・ステアリン酸マグネシウム（規格：日局、太平化学産業株式会社製）。
・ポリビニルアルコール（商品名：ゴーノセール、規格：薬添規、三菱ケミカル株式会社製）。
<Optional ingredients>
- Magnesium stearate (standard: Japanese Pharmacopoeia, manufactured by Taihei Chemical Industry Co., Ltd.).
- Polyvinyl alcohol (product name: Gonosel, specification: Pharmaceutical Additives Regulations, manufactured by Mitsubishi Chemical Corporation).
（評価方法）
＜変色度＞
各例の固形医薬組成物を６０℃、７５％ＲＨの条件下にて２週間保存した。
色差計（ＣＭ／７００Ｄ、コニカミノルタ社製）を用いて、固形医薬組成物について、保存前後のＬ＊値（明度）を測定し、保存前後の明度の差の絶対値（変色度［ΔＬ］）を下記（ｓ）式により算出した。
保存前後でのΔＬが３以内の場合は、「課題が発生しない」とみなした。
(Evaluation method)
<Discoloration degree>
The solid pharmaceutical composition of each example was stored under conditions of 60° C. and 75% RH for 2 weeks.
Using a color difference meter (CM/700D, manufactured by Konica Minolta), the L* value (lightness) of the solid pharmaceutical composition was measured before and after storage, and the absolute value of the difference in lightness before and after storage (degree of discoloration [ΔL]) was calculated according to the following formula (s).
When ΔL before and after storage was within 3, it was considered that "no problem occurred."
ΔＬ＝｜（Ｌ１－Ｌ０）｜ ・・・（ｓ）
（ｓ）式中、Ｌ０は、保存前のＬ＊であり、Ｌ１は、２週間保存後のＬ＊である。
ΔL=|(L 1 −L 0 )| . . . (s)
In formula (s), L 0 is L* before storage, and L 1 is L* after storage for 2 weeks.
＜溶出率＞
上記変色度の測定における２週間保存後の固形医薬組成物について、日局精製水で溶出試験を行った。３７℃±１℃の試験液（日局精製水）９００ｍＬにて、回転バスケット法１００ｒｐｍにてサンプル１錠を攪拌した。撹拌開始後、５分経過時点で液部を採取して試験液とした。試験液を孔径０．４５μｍのメンブレンフィルターにてろ過し、液体クロマトグラフィーを用いてメロキシカム量を定量した。メロキシカム量の定量は、ＵＳＰ収載のメロキシカム錠の定量法に基づき、分光光度計（ＵＶ－２７００、株式会社島津製作所製）を用いて、ＵＶで測定した。
下記（ｔ）式により、メロキシカムの溶出率（％）を求めた。
<Dissolution rate>
The solid pharmaceutical composition after 2 weeks of storage in the measurement of discoloration was subjected to a dissolution test using Japanese Pharmacopoeia purified water. One sample tablet was stirred in 900 mL of test liquid (Japanese Pharmacopoeia purified water) at 37°C ± 1°C using a rotating basket method at 100 rpm. After the start of stirring, the liquid portion was collected at 5 minutes and used as the test liquid. The test liquid was filtered through a membrane filter with a pore size of 0.45 μm, and the amount of meloxicam was quantified using liquid chromatography. The amount of meloxicam was measured by UV using a spectrophotometer (UV-2700, manufactured by Shimadzu Corporation) based on the quantitative method for meloxicam tablets listed in the USP.
The dissolution rate (%) of meloxicam was calculated according to the following formula (t).
溶出率（％）＝［５分経過時点でのメロキシカムの溶出量（ｍｇ）］÷［１錠中のメロキシカムの含有量］×１００ ・・・（ｔ） Dissolution rate (%) = [amount of meloxicam dissolved (mg) after 5 minutes] ÷ [content of meloxicam in one tablet] x 100 ... (t)
（実施例１－１～１－１１、１－１３、１－１５、比較例１－１～１－６、参考例１－１～１－６）
表１～４に示す配合比に基づき、（Ａ）成分、（Ｂ）成分（又は（Ｂ’）成分）及び（Ｃ）成分（（Ｃ’）成分）をプラスチック製の袋内で粉体混合して、１００ｇの粉末の固形医薬組成物（表中、「混合粉」と記載）を得た。
得られた固形医薬組成物について、変色度を評価し、その結果を表中に示す。
なお、（Ｂ’）成分又は（Ｃ’）成分を用いた場合には、それぞれを（Ｂ）成分又は（Ｃ）成分を読み替えて、表中の「Ｃ／Ｂ比」を表す（以降において同様）。
(Examples 1-1 to 1-11, 1-13, 1-15, Comparative Examples 1-1 to 1-6, Reference Examples 1-1 to 1-6)
Based on the blending ratios shown in Tables 1 to 4, component (A), component (B) (or component (B')), and component (C) (component (C')) were powder-mixed in a plastic bag to obtain 100 g of a powdered solid pharmaceutical composition (referred to as "mixed powder" in the tables).
The degree of discoloration of the obtained solid pharmaceutical composition was evaluated, and the results are shown in the table.
When component (B') or component (C') is used, it is replaced with component (B) or component (C), respectively, to represent the "C/B ratio" in the table (the same applies hereinafter).
（実施例１－１２、１－１４）
表２に示す配合比に基づき、（Ａ）～（Ｃ）成分及び任意成分をプラスチック製の袋内で粉体混合して、３０００ｇの粉体混合物を得た。
実施例１－１２、１－１４は、上記で得られた粉体混合物をＬＩＢＲＡ２（菊水製作所社製）で打錠して、各例の錠剤（標準Ｒ錠、３００ｍｇ／錠）を得た。打錠に用いた杵はφ８．５ｍｍであり、硬度は２ｋｇｆ～１５ｋｇｆとした。
得られた錠剤について、変色度を評価し、その結果を表中に示す。
(Examples 1-12 and 1-14)
Based on the blending ratios shown in Table 2, components (A) to (C) and any optional components were powder-mixed in a plastic bag to obtain 3,000 g of a powder mixture.
In Examples 1-12 and 1-14, the powder mixture obtained above was tableted using LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets of each example (standard R tablet, 300 mg/tablet). The punch used for tableting had a diameter of 8.5 mm and a hardness of 2 kgf to 15 kgf.
The degree of discoloration of the obtained tablets was evaluated, and the results are shown in the table.
表１～４に示す通り、本発明を適用した実施例１－１～１－１５は、いずれも変色度が４．１以下であった。
（Ｃ）成分を欠く比較例や、（Ｃ）成分に代えて（Ｃ’）成分を用いた比較例１－１～１－６は、変色度が５．９以上であった。
（Ａ）成分又は（Ｂ）成分のいずれかを欠く参考例は、いずれも変色度が２．５以下であった。
As shown in Tables 1 to 4, in all of Examples 1-1 to 1-15 in which the present invention was applied, the degree of discoloration was 4.1 or less.
In the comparative examples 1-1 to 1-6 in which the component (C) was absent or the component (C') was used instead of the component (C), the discoloration index was 5.9 or more.
In the reference examples lacking either component (A) or component (B), the degree of discoloration was 2.5 or less.
（実施例２－１～２－３）
表５に示す配合比に基づき、粒子の群（α１）の原料の粉体（但し、ヒドロキシプロピルセルロース及びポリビニルアルコールを除く）をプラスチック製の袋内で粉体混合して、３０００ｇの粉体混合物を得た。得られた粉体混合物を流動層造粒機（フロイント産業株式会社製、「ＦＬＯ－５」）に投入し、４質量％の結合液（ヒドロキシプロピルセルロース又はポリビニルアルコールの水溶液）を噴霧しながら、流動層造粒を行った。造粒条件を給気温度６０～１００℃、給気風量１．０～４．０ｍ３／分とした。粒子の群（α１）中のヒドロキシプロピルセルロース又はポリビニルアルコールの含有量が固形物換算で表中に示す値となるように結合液を噴霧して流動層造粒を完了させ、各例の粒子の群（α１）を造粒粒子の群として得た。引き続き同じ流動層造粒機を用いて給気温度７０℃、給気風量１．５ｍ３／分にて２０分間、粒子の群（α１）を乾燥した。得られた粒子の群（α１）に対して、表に示す配合比に従い、粒子の群（β１）を加え、プラスチック製の袋内で粉体混合して、各例の粉末の固形医薬組成物を得た。なお、粒子の群（β１）は、造粒粒子ではなく、各々の成分が粒子として独立した混合粉体である。表５においては、比較対象として、比較例１－１を記載した。
得られた固形医薬製剤について、変色率を評価し、その結果を表中に示す。
(Examples 2-1 to 2-3)
Based on the blending ratio shown in Table 5, the raw powders of the particle group (α1) (excluding hydroxypropyl cellulose and polyvinyl alcohol) were powder-mixed in a plastic bag to obtain 3000 g of a powder mixture. The obtained powder mixture was charged into a fluidized bed granulator (manufactured by Freund Corporation, "FLO-5"), and fluidized bed granulation was performed while spraying 4 mass% of a binding liquid (aqueous solution of hydroxypropyl cellulose or polyvinyl alcohol). The granulation conditions were an inlet air temperature of 60 to 100°C and an inlet air volume of 1.0 to 4.0 m 3 /min. The binding liquid was sprayed so that the content of hydroxypropyl cellulose or polyvinyl alcohol in the particle group (α1) was the value shown in the table in terms of solid matter, and the particle group (α1) of each example was obtained as a group of granulated particles. The particle group (α1) was then dried for 20 minutes using the same fluidized bed granulator at an inlet air temperature of 70° C. and an inlet air volume of 1.5 m 3 /min. The particle group (β1) was added to the obtained particle group (α1) in the blending ratio shown in the table, and the powders were mixed in a plastic bag to obtain a powdered solid pharmaceutical composition of each example. Note that the particle group (β1) is not a granulated particle, but a mixed powder in which each component is independent as a particle. Comparative Example 1-1 is listed in Table 5 as a comparison.
The discoloration rate of the obtained solid pharmaceutical preparation was evaluated, and the results are shown in the table.
表５に示すように、本発明を適用した実施例２－１～２－３は、いずれも変色度が１．４以下であった。（Ａ）成分と（Ｂ）成分とを単に混合した比較例１－１は、変色度が７．８であった。 As shown in Table 5, in Examples 2-1 to 2-3 in which the present invention was applied, the discoloration degree was 1.4 or less. In Comparative Example 1-1 in which components (A) and (B) were simply mixed, the discoloration degree was 7.8.
（実施例３－１～３－５、参考例３－１）
表６に示す配合比に基づき、（Ａ）成分、（Ｂ）成分（又は（Ｂ’）成分）、（Ｃ）成分及びステアリン酸マグネシウム（滑剤）をプラスチック製の袋内で粉体混合して、３０００ｇの粉体混合物を得た。
得られた粉体混合物をＬＩＢＲＡ２（菊水製作所社製）で打錠して、各例の錠剤（標準Ｒ錠、３００ｍｇ／錠）を得た。打錠に用いた杵はφ８．５ｍｍであり、硬度を２ｋｇｆ～１５ｋｇｆとした。
得られた錠剤について、変色度及び溶出率を評価し、その結果を表中に示す。
(Examples 3-1 to 3-5, Reference Example 3-1)
Based on the blending ratio shown in Table 6, component (A), component (B) (or component (B')), component (C) and magnesium stearate (lubricant) were powder-mixed in a plastic bag to obtain 3,000 g of a powder mixture.
The obtained powder mixture was tableted using LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets of each example (standard R tablet, 300 mg/tablet). The punch used for tableting had a diameter of 8.5 mm and a hardness of 2 kgf to 15 kgf.
The resulting tablets were evaluated for discoloration and dissolution rate, and the results are shown in the table.
表６に示すように、本発明を適用した実施例３－１～３－５は、変色度が０．４～２．５で、溶出率が４０～６１％であった。（Ｂ）成分に代えて（Ｂ’）成分を用いた参考例３－１は、変色度が１．９で、溶出率が２１％であった。
なお、実施例３－１～３－５は、１錠３００ｍｇの標準Ｒ錠であるが、１錠質量は任意で設定可能であり、例えば、実施例３－２は（Ａ）成分を５ｍｇ含有する１錠１９６ｍｇの錠剤としてもよく、実施例３－３は（Ａ）成分を１０ｍｇ含有する１錠２６２ｍｇの錠剤としてもよく、これらの錠剤の変色度や溶出率は、対応する実施例と同様の効果が得られる。
As shown in Table 6, in Examples 3-1 to 3-5 in which the present invention was applied, the discoloration degree was 0.4 to 2.5, and the dissolution rate was 40 to 61%. In Reference Example 3-1 in which component (B') was used instead of component (B), the discoloration degree was 1.9, and the dissolution rate was 21%.
In addition, although Examples 3-1 to 3-5 are standard R tablets weighing 300 mg per tablet, the mass of each tablet can be set arbitrarily. For example, Example 3-2 may be a tablet containing 5 mg of component (A) and weighing 196 mg per tablet, and Example 3-3 may be a tablet containing 10 mg of component (A) and weighing 262 mg per tablet. The discoloration degree and dissolution rate of these tablets will have the same effects as those of the corresponding Examples.
Claims (4)
前記（Ｂ）成分を含有し、前記（Ａ）成分を実質的に含有しない粒子の群（β１）と、
を有し、
前記粒子の群（α１）及び前記粒子の群（β１）の少なくとも一方は、造粒粒子の群であり、
前記粒子の群（α１）及び前記粒子の群（β１）の少なくとも一方に、乳糖、結晶セルロース、トウモロコシデンプン、低置換度ヒドロキシプロピルセルロース、Ｄ－マンニトール及びクロスポビドンからなる群から選ばれる少なくとも１種（Ｃ）をさらに含有する、固形医薬製剤。 A group (α1) of particles containing at least one kind (A) selected from meloxicam and a pharma- ceutically acceptable salt thereof and substantially not containing an antacid (B) containing a magnesium atom;
A group (β1) of particles containing the component (B) and substantially not containing the component (A);
having
At least one of the particle group (α1) and the particle group (β1) is a group of granulated particles,
At least one of the particle group (α1) and the particle group (β1) further contains at least one kind (C) selected from the group consisting of lactose, crystalline cellulose, corn starch , low- substituted hydroxypropyl cellulose, D- mannitol and crospovidone.
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| JP2006328000A (en) | 2005-05-27 | 2006-12-07 | Ss Pharmaceut Co Ltd | Preparation for oral administration |
| JP2012021025A (en) | 2003-07-09 | 2012-02-02 | Boehringer Ingelheim Internatl Gmbh | Composition comprising meloxicam |
| JP2015229663A (en) | 2014-06-06 | 2015-12-21 | ライオン株式会社 | Tablet and production method thereof |
| JP2016190793A (en) | 2015-03-30 | 2016-11-10 | ライオン株式会社 | Tablet and method for producing the same |
| JP2017226611A (en) | 2016-06-22 | 2017-12-28 | ライオン株式会社 | Oral solid preparation |
| JP2019142840A (en) | 2018-02-23 | 2019-08-29 | ライオン株式会社 | Solid pharmaceutical formulation |
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| JP2012021025A (en) | 2003-07-09 | 2012-02-02 | Boehringer Ingelheim Internatl Gmbh | Composition comprising meloxicam |
| JP2006328000A (en) | 2005-05-27 | 2006-12-07 | Ss Pharmaceut Co Ltd | Preparation for oral administration |
| JP2015229663A (en) | 2014-06-06 | 2015-12-21 | ライオン株式会社 | Tablet and production method thereof |
| JP2016190793A (en) | 2015-03-30 | 2016-11-10 | ライオン株式会社 | Tablet and method for producing the same |
| JP2017226611A (en) | 2016-06-22 | 2017-12-28 | ライオン株式会社 | Oral solid preparation |
| JP2019142840A (en) | 2018-02-23 | 2019-08-29 | ライオン株式会社 | Solid pharmaceutical formulation |
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