JP2021036003A - Calcium folinate-containing tablet - Google Patents
Calcium folinate-containing tablet Download PDFInfo
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- JP2021036003A JP2021036003A JP2020202331A JP2020202331A JP2021036003A JP 2021036003 A JP2021036003 A JP 2021036003A JP 2020202331 A JP2020202331 A JP 2020202331A JP 2020202331 A JP2020202331 A JP 2020202331A JP 2021036003 A JP2021036003 A JP 2021036003A
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- disintegrant
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- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 title abstract 4
- 235000008207 calcium folinate Nutrition 0.000 title abstract 4
- 239000011687 calcium folinate Substances 0.000 title abstract 4
- 239000007884 disintegrant Substances 0.000 claims abstract description 32
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 22
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 11
- 239000000314 lubricant Substances 0.000 claims abstract description 10
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical group O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims abstract description 9
- 239000001913 cellulose Substances 0.000 claims abstract description 8
- 229920002678 cellulose Polymers 0.000 claims abstract description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 20
- 239000011575 calcium Substances 0.000 claims description 20
- 229910052791 calcium Inorganic materials 0.000 claims description 20
- 229920000881 Modified starch Polymers 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 13
- 238000004090 dissolution Methods 0.000 abstract description 5
- 238000003860 storage Methods 0.000 abstract description 3
- 229920002472 Starch Polymers 0.000 abstract 1
- 239000008107 starch Substances 0.000 abstract 1
- 235000019698 starch Nutrition 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 15
- 239000000126 substance Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 9
- -1 2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydropteridine-6-yl Chemical group 0.000 description 7
- 229920003109 sodium starch glycolate Polymers 0.000 description 7
- 229940079832 sodium starch glycolate Drugs 0.000 description 7
- 239000008109 sodium starch glycolate Substances 0.000 description 7
- 239000004698 Polyethylene Substances 0.000 description 6
- 235000010980 cellulose Nutrition 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 229920000573 polyethylene Polymers 0.000 description 6
- 238000007922 dissolution test Methods 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 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 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明はホリナートカルシウムを含んでなる錠剤で、水中における錠剤からのホリナートの溶出速度が速く、かつ、湿度に対して安定な錠剤に関するものである。 The present invention relates to a tablet containing holinate calcium, which has a high elution rate of holinate from the tablet in water and is stable to humidity.
ホリナートカルシウム（日本医薬品一般名称）は、Ｎ−{４−[（２−アミノ−５−ホルミル−４−オキソ−１，４，５，６，７，８−ヘキサヒドロプテリジン−６−イル）メチルアミノ］ベンゾイル｝−Ｌ−グルタミン酸モノカルシウム塩であり、胃ガン、結腸・直腸ガンに対するフルオロウラシルの抗腫瘍効果の増強剤として用いられている。 Holinate calcium (generic name for Japanese pharmaceuticals) is N- {4-[(2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydropteridine-6-yl) methyl). Amino] benzoyl} -L-glutamic acid monocalcium salt, which is used as an enhancer of the antitumor effect of fluorouracil on gastric cancer and colon / rectal cancer.
一方、ホリナートカルシウムを含有する製剤は湿度に対して不安定であることから、水中における錠剤からの原薬の溶出が速やかで、湿度に対して安定な錠剤の設計が困難であるという問題を有している。湿度に対して不安定な錠剤は、高防湿のフィルム素材でＰＴＰ包装した後に、そのＰＴＰシートをアルミニウム製の袋に封入して湿度の影響を受けない形態とするのが一般的であるが、薬局で包装が開封されて錠剤が患者に手渡されることを考慮すれば、無包装の状態でも原薬の保存安定性にすぐれていることが望ましい。
従来技術として、ホリナートカルシウム等のバイオアベイラビリティを向上させた組成物の発明について開示はあるが（特許文献１）、ホリナートカルシウムを含有する錠剤について、湿度環境下での安定性を改善する技術に関する発明や報告は見当たらない。
On the other hand, since the preparation containing holinate calcium is unstable to humidity, there is a problem that it is difficult to design a tablet that is stable to humidity because the drug substance dissolves quickly from the tablet in water. doing. Humidity-unstable tablets are generally PTP-wrapped in a highly moisture-proof film material and then sealed in an aluminum bag so that they are not affected by humidity. Considering that the packaging is opened at the pharmacy and the tablets are handed to the patient, it is desirable that the drug substance has excellent storage stability even in the unpackaged state.
As a prior art, there is a disclosure about an invention of a composition having improved bioavailability such as holinate calcium (Patent Document 1), but an invention relating to a technique for improving the stability of a tablet containing holinate calcium in a humidity environment. And no reports.
本発明の課題は、ホリナートカルシウムを含有する錠剤で、水中における錠剤からのホリナートカルシウムの溶出速度が速く、かつ、無包装の状態で高湿度環境下に保存されても安定な錠剤を提供することである。 An object of the present invention is to provide a tablet containing holinate calcium, which has a high elution rate of holinate calcium from the tablet in water and is stable even when stored in a high humidity environment in an unwrapped state. Is.
本発明者は鋭意検討した結果、意外にも、崩壊剤としてデンプングリコール酸ナトリウム等の塩基性崩壊剤でないものを使用すると、水中における錠剤からのホリナートカルシウムの溶出速度が速やかで、かつ、湿度環境下で保存しても安定な錠剤が得られることを見出し、さらに検討を加え、本発明を完成するに至った。
すなわち、本発明は
（１）錠剤の全重量に対し、ホリナートカルシウムを１５〜２５重量パーセント含み、塩基性崩壊剤を含まず、塩基性崩壊剤でない崩壊剤を５〜２０重量パーセント含み、さらに賦形剤及び滑沢剤を含有する錠剤、
（２）塩基性崩壊剤でない崩壊剤が部分アルファー化デンプンである前記（１）に記載の錠剤、
（３）賦形剤が乳糖水和物及び結晶セルロースであり、滑沢剤がステアリン酸マグネシウムである前記（１）又は（２）に記載の錠剤、
（４）錠剤の全重量に対し、賦形剤の含有量が５３〜７９．５重量パーセントであり、ステアリン酸マグネシウムの含有量が０．５〜２重量パーセントである前記（３）に記載の錠剤、を提供するものである。
なお、本発明における、崩壊剤、賦形剤、滑沢剤とは「医薬品添加物辞典（日本医薬品添加剤協会編集、薬事日報社、２００７年発行）」の「用途別索引」で当該名に分類されたものを指し、本発明における塩基性崩壊剤とは前記崩壊剤の中で強塩基の塩であるものを指す。
As a result of diligent studies by the present inventor, surprisingly, when a non-basic disintegrant such as sodium starch glycolate is used as the disintegrant, the elution rate of holinate calcium from tablets in water is rapid and the humidity environment. We have found that stable tablets can be obtained even when stored underneath, and further studies have led to the completion of the present invention.
That is, the present invention (1) contains 15 to 25% by weight of holinate calcium, does not contain a basic disintegrant, and contains 5 to 20% by weight of a disintegrant that is not a basic disintegrant, based on the total weight of the tablet. Tablets containing excipients and lubricants,
(2) The tablet according to (1) above, wherein the disintegrant that is not a basic disintegrant is partially pregelatinized starch.
(3) The tablet according to (1) or (2) above, wherein the excipient is lactose hydrate and crystalline cellulose, and the lubricant is magnesium stearate.
(4) The above-mentioned (3), wherein the content of the excipient is 53 to 79.5% by weight and the content of magnesium stearate is 0.5 to 2% by weight with respect to the total weight of the tablet. It provides tablets.
In the present invention, disintegrants, excipients, and lubricants are referred to as "Pharmaceutical Additives Dictionary (edited by Japan Pharmaceutical Additives Association, Yakuji Nippo Co., Ltd., published in 2007)" in the "Index by Use". The classified ones, and the basic disintegrant in the present invention refers to those which are salts of strong bases among the disintegrants.
本発明の錠剤は、水中における錠剤からのホリナートの溶出速度が速やかである。例えば、本発明の錠剤を、第１５改正日本薬局方溶出試験法に基づいて、精製水９００ｍＬ、パドル回転数５０ｒｐｍの試験条件にて溶出試験した際、溶出試験開始から１５分後のホリナートの溶出率は８５％以上である。 The tablet of the present invention has a rapid elution rate of holinate from the tablet in water. For example, when the tablet of the present invention was subjected to an dissolution test under the test conditions of 900 mL of purified water and a paddle rotation speed of 50 rpm based on the 15th revised Japanese Pharmacopoeia dissolution test method, the elution of holinate 15 minutes after the start of the dissolution test was performed. The rate is 85% or more.
また、本発明の錠剤は湿度に対して安定である。例えば、本発明の錠剤を無包装の状態で温度５０℃相対湿度７５％の環境下で１週間保存した際、ホリナートカルシウムの類縁物質総量の増加量は０．２％未満である。 Also, the tablets of the present invention are stable to humidity. For example, when the tablet of the present invention is stored in an unwrapped state in an environment of a temperature of 50 ° C. and a relative humidity of 75% for one week, the increase in the total amount of related substances of holinate calcium is less than 0.2%.
本発明の錠剤は、１５〜２５重量パーセントのホリナートカルシウムを含み、塩基性崩壊剤を含まず、５〜２０重量パーセントの塩基性崩壊剤でない崩壊剤を含み、賦形剤、滑沢剤を含有する。 The tablets of the present invention contain 15 to 25 weight percent holinate calcium, no basic disintegrant, 5 to 20 weight percent non-basic disintegrant disintegrant, excipients, lubricants. To do.
含有を避けるべき塩基性崩壊剤とは、例えば、デンプングリコール酸ナトリウム、カルメロースナトリウム、クロスカルメロースナトリウムである。
使用が可能な塩基性崩壊剤でない崩壊剤としては、例えば、部分アルファー化デンプン、クロスポビドン、コーンスターチ、カルメロース、ヒドロキシプロピルセルロース等を挙げることができ、なかでも部分アルファー化デンプンが好ましい。
The basic disintegrant that should be avoided is, for example, sodium starch glycolate, sodium carmellose, and sodium croscarmellose.
Examples of the disintegrant that is not a basic disintegrant that can be used include partially pregelatinized starch, crospovidone, cornstarch, carmellose, hydroxypropyl cellulose, and the like, and the partially pregelatinized starch is particularly preferable.
本発明で用いられる賦形剤としては、例えば乳糖水和物、結晶セルロース、Ｄ−マンニトール、トウモロコシデンプン等であり、好ましくは乳糖水和物及び結晶セルロースからなる群から少なくとも１種が選ばれる。乳糖水和物の好ましい含有量は５３〜７９．５重量パーセントである。 The excipient used in the present invention is, for example, lactose hydrate, crystalline cellulose, D-mannitol, corn starch and the like, and preferably at least one is selected from the group consisting of lactose hydrate and crystalline cellulose. The preferred content of lactose hydrate is 53-79.5 weight percent.
本発明で用いられる滑沢剤としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク等であり、好ましくはステアリン酸マグネシウムである。ステアリン酸マグネシウムの好ましい含有量は０．５〜２重量パーセントである。 Examples of the lubricant used in the present invention include magnesium stearate, calcium stearate, talc and the like, and magnesium stearate is preferable. The preferred content of magnesium stearate is 0.5-2 weight percent.
本発明の錠剤には、必要に応じて、軽質無水ケイ酸、ケイ酸カルシウム等の流動化剤や、黄色三二酸化鉄、アルミニウムレーキ色素等の着色剤を含有せしめることができる。 The tablet of the present invention may contain a fluidizing agent such as light anhydrous silicic acid and calcium silicate and a coloring agent such as yellow iron sesquioxide and aluminum lake pigment, if necessary.
本発明の錠剤は、ホリナートカルシウムに、賦形剤、塩基性崩壊剤でない崩壊剤、滑沢剤を混合し、これをロータリー打錠機で圧縮成形する直接打錠法で製することができる。
本発明の錠剤は、素錠の表面にフィルムをコーティングしてフィルム錠とすることができる。コーティングするフィルム液には、例えばヒドロキシプロピルセルロースやポリビニルアルコール系ポリマーの水溶性ポリマーを水に溶解した液に、例えばタルクや酸化チタンを懸濁した液が用いられる。コーティングにはフィルムコーティング装置が用いられる。
The tablet of the present invention can be produced by a direct tableting method in which an excipient, a disintegrant that is not a basic disintegrant, and a lubricant are mixed with holinate calcium, and the mixture is compression-molded by a rotary tableting machine.
The tablet of the present invention can be made into a film tablet by coating the surface of the uncoated tablet with a film. As the film liquid to be coated, for example, a liquid in which a water-soluble polymer such as hydroxypropyl cellulose or a polyvinyl alcohol-based polymer is dissolved in water, for example, a liquid in which talc or titanium oxide is suspended is used. A film coating device is used for coating.
以下に実施例等により本発明を詳細に説明する。
[実施例１]
ホリナートカルシウムを２７ｍｇ（ホリナートとして２５ｍｇ）含有し、塩基性崩壊剤でない崩壊剤として部分アルファー化デンプンを含有する錠剤を直接打錠法で製した例を説明する。錠剤の組成を表１に示す。
［比較例１］
Hereinafter, the present invention will be described in detail with reference to Examples and the like.
[Example 1]
An example will be described in which a tablet containing 27 mg of holinate calcium (25 mg as holinate) and containing partially pregelatinized starch as a disintegrant that is not a basic disintegrant is produced by a direct tableting method. The composition of the tablets is shown in Table 1.
[Comparative Example 1]
ホリナートカルシウムを２７ｍｇ（ホリナートとして２５ｍｇ）含有し、塩基性崩壊剤であるデンプングリコール酸ナトリウムを１８ｍｇ含有する錠剤を直接打錠法で製した例を説明する。錠剤の組成を表２に示す。
［比較例２］
An example will be described in which a tablet containing 27 mg of holinate calcium (25 mg as holinate) and 18 mg of sodium starch glycolate, which is a basic disintegrant, is produced by a direct tableting method. The composition of the tablets is shown in Table 2.
[Comparative Example 2]
ホリナートカルシウムを２７ｍｇ（ホリナートとして２５ｍｇ）含有し、塩基性崩壊剤であるデンプングリコール酸ナトリウムを９ｍｇ含有する錠剤を直接打錠法で製した例を説明する。錠剤の組成を表３に示す。
［試験例１］
An example will be described in which a tablet containing 27 mg of holinate calcium (25 mg as holinate) and 9 mg of sodium starch glycolate, which is a basic disintegrant, is produced by a direct tableting method. The composition of the tablets is shown in Table 3.
実施例１及び比較例１、２の錠剤について、第１５改正日本薬局方溶出試験法に基づき、錠剤からのホリナートの溶出速度を測定した。試験液には精製水９００ｍＬを用い、パドル回転数は５０ｒｐｍとした。試験液中に溶出したホリナートの量を紫外可視分光光度計にて測定した。
溶出率の測定結果を表４に示した。実施例及び比較例１、２のいずれの錠剤も溶出試験開始から１５分後の溶出率は８５％以上で、優れた溶出性を示した。
［試験例２］
For the tablets of Example 1 and Comparative Examples 1 and 2, the dissolution rate of holinate from the tablets was measured based on the 15th revised Japanese Pharmacopoeia dissolution test method. 900 mL of purified water was used as the test solution, and the paddle rotation speed was 50 rpm. The amount of holinate eluted in the test solution was measured with an ultraviolet-visible spectrophotometer.
The measurement results of the dissolution rate are shown in Table 4. In both Examples and Comparative Examples 1 and 2, the dissolution rate 15 minutes after the start of the dissolution test was 85% or more, showing excellent dissolution property.
[Test Example 2]
実施例１及び比較例１、２の錠剤を無包装の状態で温度５０℃相対湿度７５％の環境下で１週間保存し、原薬の類縁物資総量の増加量を測定した。
原薬の類縁物資量はＨＰＬＣ法により測定し、個々の類縁物質量を面積百分率法によって求め、この和を類縁物質総量とした。保存前後の検体の類縁物質総量の差を類縁物質総量の増加量とした。
類縁物質総量を測定した結果を表４に示した。比較例１、２の塩基性崩壊剤であるデンプングリコール酸ナトリウムを含有する錠剤は温度６０℃相対湿度７５％の環境下で１週間保存すると類縁物質総量が０．４〜０．６％増加するが、本発明の実施例１の錠剤は類縁物質総量の増加量は０．２％未満であり、湿度に対して安定であることを確認することができた。
The amount of related substances of the drug substance was measured by the HPLC method, the amount of each related substance was determined by the area percentage method, and the sum was taken as the total amount of related substances. The difference in the total amount of related substances before and after storage was defined as the increase in the total amount of related substances.
The results of measuring the total amount of related substances are shown in Table 4. The tablets containing sodium starch glycolate, which is a basic disintegrant of Comparative Examples 1 and 2, are stored for one week in an environment of a temperature of 60 ° C. and a relative humidity of 75%, and the total amount of related substances increases by 0.4 to 0.6%. However, it was confirmed that the tablet of Example 1 of the present invention had an increase in the total amount of related substances of less than 0.2% and was stable with respect to humidity.
本発明によれば、ホリナートカルシウムを含有する錠剤で、水中における錠剤からのホリナートの溶出速度が速く、かつ、無包装の状態で高湿度環境下に保存されても類縁物質総量が有意に増加しない安定な錠剤を提供することができる。
According to the present invention, a tablet containing holinate calcium has a high elution rate of holinate from the tablet in water, and the total amount of related substances does not increase significantly even when stored in a high humidity environment in an unwrapped state. A stable tablet can be provided.
Claims (4)
The tablet according to claim 3, wherein the content of the excipient is 53 to 79.5% by weight and the content of magnesium stearate is 0.5 to 2% by weight based on the total weight of the tablet.
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| JP2004534833A (en) * | 2001-06-26 | 2004-11-18 | ファーマトロン リミテッド | Oral pharmaceutical composition with improved active ingredient release ability |
| JP2011515478A (en) * | 2008-03-25 | 2011-05-19 | シェーリング コーポレイション | Methods for treating or preventing colorectal cancer |
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