JPWO2019177132A1 - Orally disintegrating tablet - Google Patents
Orally disintegrating tablet Download PDFInfo
- Publication number
- JPWO2019177132A1 JPWO2019177132A1 JP2020506662A JP2020506662A JPWO2019177132A1 JP WO2019177132 A1 JPWO2019177132 A1 JP WO2019177132A1 JP 2020506662 A JP2020506662 A JP 2020506662A JP 2020506662 A JP2020506662 A JP 2020506662A JP WO2019177132 A1 JPWO2019177132 A1 JP WO2019177132A1
- Authority
- JP
- Japan
- Prior art keywords
- orally disintegrating
- disintegrating tablet
- tablet
- iron oxide
- compound
- 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.)
- Granted
Links
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 69
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000007884 disintegrant Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 33
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 22
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 claims description 22
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 20
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
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- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 8
- -1 1,3-benzodioxole-5-yl Chemical group 0.000 abstract description 6
- FFCZQVKVWGGQFB-UHFFFAOYSA-N 9h-pyrido[3,4-b]indole-1,4-dione Chemical compound N1C2=CC=CC=C2C2=C1C(=O)N=CC2=O FFCZQVKVWGGQFB-UHFFFAOYSA-N 0.000 abstract description 4
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- 238000000034 method Methods 0.000 description 5
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- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 4
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
（６Ｒ，ｌ２ａＲ）−６−（１，３−ベンゾジオキソール−５−イル）−２−メチル−２，３，６，７，１２，ｌ２ａ−ヘキサヒドロピラジノ［１’，２’：１，６］ピリド［３，４−ｂ］インドール−１，４−ジオンを含んで光安定性を向上できる口腔内崩壊錠を提供する。
口腔内崩壊錠は、（６Ｒ，ｌ２ａＲ）−６−（１，３−ベンゾジオキソール−５−イル）−２−メチル−２，３，６，７，１２，ｌ２ａ−ヘキサヒドロピラジノ［１’，２’：１，６］ピリド［３，４−ｂ］インドール−１，４−ジオンと、崩壊剤と、酸化鉄とを含む。
【選択図】なし(6R, l2aR) -6- (1,3-benzodioxole-5-yl) -2-methyl-2,3,6,7,12, l2a-hexahydropyrazino [1', 2': To provide an orally disintegrating tablet containing 1,6] pyrido [3,4-b] indole-1,4-dione and capable of improving photostability.
Orally disintegrating tablets are (6R, l2aR) -6- (1,3-benzodioxol-5-yl) -2-methyl-2,3,6,7,12, l2a-hexahydropyrazino [ It contains 1', 2': 1,6] pyrido [3,4-b] indole-1,4-dione, a disintegrant, and iron oxide.
[Selection diagram] None
Description
本発明は、（６Ｒ，ｌ２ａＲ）−６−（１，３−ベンゾジオキソール−５−イル）−２−メチル−２，３，６，７，１２，ｌ２ａ−ヘキサヒドロピラジノ［１’，２’：１，６］ピリド［３，４−ｂ］インドール−１，４−ジオンと呼ばれる化合物（以下、化合物（Ｉ）と称する）を含む口腔内崩壊錠に関する。 The present invention relates to (6R, l2aR) -6- (1,3-benzodioxol-5-yl) -2-methyl-2,3,6,7,12, l2a-hexahydropyrazino [1'. , 2': 1,6] The present invention relates to an orally disintegrating tablet containing a compound called pyrido [3,4-b] indole-1,4-dione (hereinafter referred to as compound (I)).
化合物（Ｉ）は、優れたホスホジエステラーゼ５阻害活性を有し、日本国内においては、勃起不全（非特許文献１）、肺動脈性肺高血圧症（非特許文献２）、および前立腺肥大による排尿障害（非特許文献３）の治療に用いられている。また、化合物（Ｉ）は普通錠として処方されている。
小児や高齢の患者は、疾患、加齢、唾液分泌量の低下などが原因で普通錠を嚥下する機能が低下していることが多いため、服用が困難である。このため、化合物（Ｉ）を含む錠剤として、口腔内崩壊錠（ＯＤ錠）が望まれている。口腔内崩壊錠は水なしで服用されても口腔内で速やかに崩壊するため、小児や高齢者も口腔内崩壊錠を服用しやすい。また、口腔内崩壊錠は服用時に水を必要としないため、頻尿の患者や排尿が困難な患者のＱｕａｌｉｔｙ Ｏｆ Ｌｉｆｅ（ＱＯＬ）を向上させることができる。 It is difficult for pediatric and elderly patients to take ordinary tablets because their ability to swallow ordinary tablets is often impaired due to illness, aging, decreased saliva production, and the like. Therefore, an orally disintegrating tablet (OD tablet) is desired as a tablet containing compound (I). Even if the orally disintegrating tablet is taken without water, it quickly disintegrates in the oral cavity, so that children and the elderly can easily take the orally disintegrating tablet. In addition, since the orally disintegrating tablet does not require water when taken, it is possible to improve the quality of life (QOL) of patients with frequent urination or patients who have difficulty urinating.
現在使用されている化合物（Ｉ）を含む普通錠は、フィルムコート層で被覆されている。しかしながら、フィルムコート層が製剤全体に被覆されている場合、口腔内での速崩性を得るためには、コーティングに用いる成分や方法が制限されるため、速崩性を得るのは困難である。 The ordinary tablets containing compound (I) currently in use are coated with a film-coated layer. However, when the film coat layer is coated on the entire preparation, it is difficult to obtain the quick-disintegrating property in the oral cavity because the components and methods used for the coating are limited. ..
そこで、化合物（Ｉ）を含む口腔内崩壊錠を提供すべく種々処方検討を行ったところ、現在使用されている普通錠、および化合物（Ｉ）自体は光に対して安定であるにもかかわらず、口腔内崩壊錠の場合には、処方によって製剤が変色することが明らかとなった。 Therefore, various prescription studies were conducted to provide an orally disintegrating tablet containing compound (I), and despite the fact that the ordinary tablets currently used and compound (I) itself are stable to light. In the case of orally disintegrating tablets, it was clarified that the formulation discolored depending on the prescription.
本発明は、化合物（Ｉ）を含み、フィルムコートによらず光安定性を向上できる口腔内崩壊錠を提供することを目的とする。 An object of the present invention is to provide an orally disintegrating tablet containing compound (I) and capable of improving photostability regardless of film coating.
本発明者は、上記の課題を解決するために鋭意検討を行った結果、化合物（Ｉ）と酸化鉄とを配合することにより、口腔内崩壊錠の光安定性を向上できることを見出し、本発明の完成に至った。 As a result of diligent studies to solve the above problems, the present inventor has found that the photostability of an orally disintegrating tablet can be improved by blending compound (I) and iron oxide. Has been completed.
本発明の口腔内崩壊錠は、化合物（Ｉ）と、崩壊剤と、酸化鉄とを含む。 The orally disintegrating tablet of the present invention contains compound (I), a disintegrant, and iron oxide.
また本発明は、上記構成の口腔内崩壊錠において、前記酸化鉄は黄色三二酸化鉄または三二酸化鉄であることが好ましい。 Further, in the present invention, in the orally disintegrating tablet having the above constitution, the iron oxide is preferably yellow iron sesquioxide or iron sesquioxide.
また本発明は、上記構成の口腔内崩壊錠において、前記酸化鉄は黄色三二酸化鉄であることがより好ましい。 Further, in the present invention, in the orally disintegrating tablet having the above constitution, it is more preferable that the iron oxide is yellow ferric dioxide.
また本発明は、上記構成の口腔内崩壊錠において、前記酸化鉄の含有量が製剤総重量の０．０１〜３重量％であることが好ましい。 Further, in the present invention, the content of iron oxide in the orally disintegrating tablet having the above structure is preferably 0.01 to 3% by weight based on the total weight of the preparation.
また本発明は、上記構成の口腔内崩壊錠において、前記崩壊剤がクロスポビドンであることが好ましい。 Further, in the present invention, it is preferable that the disintegrant is crospovidone in the orally disintegrating tablet having the above constitution.
また本発明は、上記構成の口腔内崩壊錠において、前記クロスポビドンの含有量が、製剤総重量の３〜１０重量％であることが好ましい。 Further, in the present invention, the content of the crospovidone in the orally disintegrating tablet having the above structure is preferably 3 to 10% by weight based on the total weight of the preparation.
また本発明は、上記構成の口腔内崩壊錠において、さらにＤ−マンニトールを含むことが好ましい。 Further, in the present invention, it is preferable that the orally disintegrating tablet having the above structure further contains D-mannitol.
また本発明は、上記構成の口腔内崩壊錠において、前記Ｄ−マンニトールの含有量が、製剤総重量の５０〜９５重量％であることが好ましい。 Further, in the present invention, the content of the D-mannitol in the orally disintegrating tablet having the above structure is preferably 50 to 95% by weight based on the total weight of the preparation.
本発明によれば、化合物（Ｉ）を含む口腔内崩壊錠の光安定性を向上させることができる。 According to the present invention, the photostability of an orally disintegrating tablet containing compound (I) can be improved.
以下、本発明の実施の形態について、詳しく説明する。以下の実施形態は、本発明を説明するための例示であり、本発明は実施形態にのみ限定されるものではない。本発明は、その要旨を逸脱しない限り、さまざまな形態で実施することができる。 Hereinafter, embodiments of the present invention will be described in detail. The following embodiments are examples for explaining the present invention, and the present invention is not limited to the embodiments. The present invention can be implemented in various forms as long as it does not deviate from the gist thereof.
本明細書において「口腔内崩壊錠」とは、水を摂取することなく口腔内で迅速に崩壊して服用が可能な錠剤を意味する。口腔内崩壊錠の崩壊時間は９０秒以内であり、４５秒以内が好ましく、３０秒以内がより好ましい。なお、崩壊時間は第１７改正日本薬局方に記載の崩壊試験法に従って測定される値である。 As used herein, the term "orally disintegrating tablet" means a tablet that can be rapidly disintegrated and taken in the oral cavity without ingesting water. The disintegration time of the orally disintegrating tablet is 90 seconds or less, preferably 45 seconds or less, and more preferably 30 seconds or less. The disintegration time is a value measured according to the disintegration test method described in the 17th revised Japanese Pharmacopoeia.
本発明の一実施形態の口腔内崩壊錠は、医薬有効成分である化合物（Ｉ）と、崩壊剤と、酸化鉄とを含む。口腔内崩壊錠の平面形状は特に制限されず、例えば、円形、楕円形、涙型、カプレット型、ドーナツ型等でもよい。また、公知の方法により口腔内崩壊錠に徐放性や腸溶性を付与し、化合物（Ｉ）の溶出性を制御してもよい。さらに口腔内崩壊錠の風味の改善等のため、口腔内崩壊錠は矯味剤および香料を含んでもよい。 The orally disintegrating tablet of one embodiment of the present invention contains compound (I), which is a pharmaceutical active ingredient, a disintegrant, and iron oxide. The planar shape of the orally disintegrating tablet is not particularly limited, and may be, for example, circular, oval, tear-shaped, caplet-shaped, donut-shaped, or the like. Further, the orally disintegrating tablet may be imparted with sustained release or enteric properties by a known method to control the elution of compound (I). Further, in order to improve the flavor of the orally disintegrating tablet, the orally disintegrating tablet may contain a flavoring agent and a flavoring agent.
＜１．化合物（Ｉ）＞
化合物（Ｉ）は、（６Ｒ，ｌ２ａＲ）−６−（１，３−ベンゾジオキソール−５−イル）−２−メチル−２，３，６，７，１２，ｌ２ａ−ヘキサヒドロピラジノ［１’，２’：１，６］ピリド［３，４−ｂ］インドール−１，４−ジオンと命名される化合物である。口腔内崩壊錠における化合物（Ｉ）の含有量としては、使用時に化合物（Ｉ）の有効量を患者に投与できるような含有量であれば特に制限はなく、目的に応じて適宜選択することができるが、口腔内崩壊錠１００重量％に対して、０．５〜２０重量％が好ましく、０．７５〜１５重量％がより好ましく、１〜１２重量％がさらに好ましい。<1. Compound (I)>
Compound (I) is (6R, l2aR) -6- (1,3-benzodioxol-5-yl) -2-methyl-2,3,6,7,12, l2a-hexahydropyrazino [ It is a compound named 1', 2': 1,6] pyrido [3,4-b] indole-1,4-dione. The content of compound (I) in the orally disintegrating tablet is not particularly limited as long as the effective amount of compound (I) can be administered to the patient at the time of use, and it may be appropriately selected according to the purpose. However, it is preferably 0.5 to 20% by weight, more preferably 0.75 to 15% by weight, still more preferably 1 to 12% by weight, based on 100% by weight of the orally disintegrating tablet.
＜２．崩壊剤＞
崩壊剤としては、例えば、カルメロース、カルメロースカルシウム、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、デンプングリコール酸ナトリウム、クロスポビドン、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース、トウモロコシデンプン等を挙げることができる。なお、崩壊剤としてはクロスポビドンが好ましく、クロスポビドンの含有量が口腔内崩壊錠の総重量（製剤総重量）の３〜１０重量％であるとより好ましい。含有量が３％より多いと、崩壊時間がより速くなって崩壊性が向上する。一方、含有量が１０重量％よりも少ないと錠剤の形状変化を防止できるので、錠剤の外観安定性を維持することができる。<2. Disintegrant>
Examples of the disintegrant include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, partially pregelatinized starch, low-substituted hydroxypropyl cellulose, corn starch and the like. .. The disintegrant is preferably crospovidone, and the content of crospovidone is more preferably 3 to 10% by weight based on the total weight of the orally disintegrating tablet (total weight of the preparation). When the content is more than 3%, the disintegration time becomes faster and the disintegration property is improved. On the other hand, if the content is less than 10% by weight, the shape of the tablet can be prevented from changing, so that the appearance stability of the tablet can be maintained.
＜３．酸化鉄＞
酸化鉄としては特に制限はなく、目的に応じて適宜選択することができる。酸化鉄の例としては、例えば、三二酸化鉄（Ｆｅ２Ｏ３）、黄色三二酸化鉄（Ｆｅ２Ｏ３・Ｈ２０）、および黒酸化鉄（Ｆｅ３Ｏ４）等を挙げることができ、黄色三二酸化鉄、または三二酸化鉄が好ましく、黄色三二酸化鉄がより好ましい。<3. Iron oxide>
The iron oxide is not particularly limited and may be appropriately selected depending on the intended purpose. Examples of iron oxide include iron sesquioxide (Fe 2 O 3 ), yellow iron sesquioxide (Fe 2 O 3 · H 20 ), black iron oxide (Fe 3 O 4 ) and the like. , Yellow iron sesquioxide, or iron sesquioxide is preferred, more preferably yellow iron sesquioxide.
三二酸化鉄は赤色から赤褐色、または暗赤紫色の粉末であり、黄色三二酸化鉄は黄色から帯褐黄色の粉末であり、黒酸化鉄は黒色の粉末であり、これらは水にほとんど溶けない。 Iron sesquioxide is a red to reddish brown or dark reddish purple powder, yellow iron sesquioxide is a yellow to brownish yellow powder, and black iron oxide is a black powder, which are practically insoluble in water.
黄色三二酸化鉄に特に制限はなく、目的に応じて適宜選択することができ、例えば、癸巳化成株式会社の商品名：黄色三二酸化鉄等を挙げることができる。三二酸化鉄に特に制限はなく、目的に応じて適宜選択することができ、例えば、癸巳化成株式会社の商品名：三二酸化鉄等を挙げることができる。黒酸化鉄に特に制限はなく、目的に応じて適宜選択することができ、例えば、癸巳化成株式会社の商品名：黒酸化鉄等を挙げることができる。 The yellow ferrous sesquioxide is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the trade name of Ayumi Kasei Co., Ltd .: yellow sesquioxide and the like can be mentioned. The iron sesquioxide is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the trade name of 癸巳 Kasei Co., Ltd .: iron sesquioxide and the like can be mentioned. The black iron oxide is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the trade name of Ami Kasei Co., Ltd .: black iron oxide and the like can be mentioned.
なお、口腔内崩壊錠において、各種の酸化鉄をそれぞれ単独で使用してもよいし、２種以上を混合して使用してもよい。 In the orally disintegrating tablet, various types of iron oxide may be used alone, or two or more types may be mixed and used.
口腔内崩壊錠における酸化鉄の含有量は、口腔内崩壊錠１００重量％に対して、０．０１〜３重量％が好ましく、０．０５〜１重量％がより好ましく、０．０５〜０．５重量％がさらに好ましい。含有量が０．０１％よりも少ないと、口腔内崩壊錠の変色や類縁物質の生成を抑制できず、十分な光安定性を維持できない恐れがある。含有量が３重量％よりも多いと錠剤製造の打錠時において、スティッキングやキャッピングなどの打錠障害を起こす恐れがある。 The content of iron oxide in the orally disintegrating tablet is preferably 0.01 to 3% by weight, more preferably 0.05 to 1% by weight, and 0.05 to 0% by weight, based on 100% by weight of the orally disintegrating tablet. 5% by weight is more preferable. If the content is less than 0.01%, discoloration of the orally disintegrating tablet and formation of related substances cannot be suppressed, and sufficient photostability may not be maintained. If the content is more than 3% by weight, there is a risk of causing tableting problems such as sticking and capping during tableting in tablet production.
口腔内崩壊錠は化合物（Ｉ）、崩壊剤、および酸化鉄に加えて、本発明の効果を阻害しない限り、製剤学的に許容される医薬品添加剤を含んでもよい。医薬品添加剤として、例えば賦形剤、結合剤、流動化剤、滑沢剤、矯味剤、および香料等が挙げられる。口腔内崩壊錠には医薬品添加剤を適宜・適量配合することができ、単独で用いても、２種以上を組み合わせて用いてもよい。 The orally disintegrating tablet may contain, in addition to compound (I), a disintegrant, and iron oxide, a pharmaceutically acceptable pharmaceutical additive as long as it does not interfere with the effects of the present invention. Pharmaceutical additives include, for example, excipients, binders, fluidizers, lubricants, flavoring agents, fragrances and the like. An appropriate amount of a pharmaceutical additive can be added to the orally disintegrating tablet, and the tablet may be used alone or in combination of two or more.
賦形剤としては、Ｄ−マンニトール、Ｄ−ソルビトール、エリスリトール、キシリトール、イソマルト、白糖、ブドウ糖、麦芽糖、トウモロコシデンプン、バレイショデンプン、小麦デンプン、デキストリン、カルボキシメチルスターチナトリウム、リン酸カルシウム、乳糖、炭酸カルシウム、結晶セルロース等を挙げることができる。賦形剤としてはＤ−マンニトールが好ましく、Ｄ−マンニトールの含有量が口腔内崩壊錠の総重量（製剤総重量）の５０〜９５重量％であるとより好ましい。 Excipients include D-mannitol, D-sorbitol, erythritol, xylitol, isomalt, sucrose, glucose, malt sugar, corn starch, potato starch, wheat starch, dextrin, sodium carboxymethyl starch, calcium phosphate, lactose, calcium carbonate, crystals. Examples include cellulose. As the excipient, D-mannitol is preferable, and the content of D-mannitol is more preferably 50 to 95% by weight based on the total weight of the orally disintegrating tablet (total weight of the preparation).
結合剤としては、例えば、ゼラチン、プルラン、ヒプロメロース、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルピロリドン、マクロゴール、アラビアゴム、デキストリン、ポリビニルアルコール、アルファー化デンプン等を挙げることができる。 Examples of the binder include gelatin, pullulan, hypromellose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, macrogol, gum arabic, dextrin, polyvinyl alcohol, pregelatinized starch and the like.
流動化剤としては、例えば、軽質無水ケイ酸、含水二酸化ケイ素、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム等を挙げることができる。 Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like.
滑沢剤としては、例えば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、タルク、ワックス類、ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウム、ショ糖脂肪酸エステル、またはマクロゴール等を挙げることができる。 Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, waxes, sodium lauryl sulfate, magnesium lauryl sulfate, sucrose fatty acid ester, macrogol and the like. ..
矯味剤としては、例えば、果糖、キシリトール、ブドウ糖、ＤＬ−リンゴ酸、炭酸水素ナトリウム等を挙げることができる。 Examples of the flavoring agent include fructose, xylitol, glucose, DL-malic acid, sodium hydrogen carbonate and the like.
香料としては、例えば、Ｌ−メントール、ペパーミント等を挙げることができる。 Examples of the fragrance include L-menthol, peppermint and the like.
＜４．口腔内崩壊錠の製造方法＞
公知の方法により上記構成の口腔内崩壊錠を製造することができるが、例えば以下の方法によっても製造することができる。<4. Manufacturing method of orally disintegrating tablets>
An orally disintegrating tablet having the above constitution can be produced by a known method, but it can also be produced by, for example, the following method.
粉末状の化合物（Ｉ）と、崩壊剤と、酸化鉄と、賦形剤等とを撹拌造粒機、流動層造粒機、混合機、粉砕機等を用いて混合または造粒する。これにより、粉末状または顆粒状の混合物が形成される。
なお、混合または造粒において、酸化鉄と、賦形剤とを混合または造粒した後、崩壊剤と化合物（Ｉ）を添加してもよいし、あるいは、化合物（Ｉ）と酸化鉄を混合または造粒した後、崩壊剤と賦形剤とを添加してもよい。
次に、打錠機を用いて混合物を圧縮成形する。これにより、口腔内崩壊錠が形成される。なお、混合物を圧縮成形する際に混合物に滑沢剤および流動化剤等を加えてもよい。これにより、圧縮成形時に口腔内崩壊錠の割れ等の損傷を防止することができる。The powdery compound (I), the disintegrant, the iron oxide, the excipient and the like are mixed or granulated by using a stirring granulator, a fluidized bed granulator, a mixer, a pulverizer or the like. This forms a powdery or granular mixture.
In mixing or granulation, iron oxide and excipients may be mixed or granulated, and then a disintegrant and compound (I) may be added, or compound (I) and iron oxide may be mixed. Alternatively, after granulation, a disintegrant and an excipient may be added.
The mixture is then compression molded using a locker. As a result, an orally disintegrating tablet is formed. When the mixture is compression molded, a lubricant, a fluidizing agent and the like may be added to the mixture. This makes it possible to prevent damage such as cracking of the orally disintegrating tablet during compression molding.
＜５．口腔内崩壊錠の包装形態＞
このようにして得られる口腔内崩壊錠は、収納部材に収納する。収納部材としては、瓶、袋、ＰＴＰシート（Ｐｒｅｓｓ Ｔｈｒｏｕｇｈ Ｐａｃｋ ｓｈｅｅｔ）等を挙げることができるが、これにより本発明が限定されるのものではない。<5. Orally disintegrating tablet packaging form>
The orally disintegrating tablet thus obtained is stored in a storage member. Examples of the storage member include a bottle, a bag, a PTP sheet (Press Through Pack sheet), and the like, but the present invention is not limited thereto.
収納部材は透明、半透明、不透明であってもよい。収納部材内の口腔内崩壊錠の視認性の観点から、収納部材は透明であることが望ましい。口腔内崩壊錠は、上記の通り酸化鉄を含むため、収納部材が透明であっても、口腔内崩壊錠の光安定性を向上させることができる。 The storage member may be transparent, translucent or opaque. From the viewpoint of visibility of the orally disintegrating lock in the storage member, it is desirable that the storage member is transparent. Since the orally disintegrating tablet contains iron oxide as described above, the photostability of the orally disintegrating tablet can be improved even if the storage member is transparent.
以下に本発明を実施例に基づいてさらに具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail based on Examples, but the present invention is not limited to these Examples.
５．７７ｇの化合物（Ｉ）と、２４６．０ｇのＤ−マンニトール（グラニュトール（登録商標）、フロイント産業株式会社製）と、３０ｇの結晶セルロース（セオラス（登録商標）ＰＨ−１０１、旭化成ケミカルズ株式会社製）と、１５ｇのクロスポビドン（コリドンＣＬ−Ｆ、ＢＡＳＦジャパン株式会社製）と、０．２ｇの黄色三二酸化鉄（癸巳化成株式会社製）とを高速攪拌式混合造粒機を用いて５分間混合し、混合物を得た。得られた混合物と３ｇのステアリン酸マグネシウム（太平化学産業株式会社製）とをボーレコンテナミキサーを用いて２０分間混合し、錠剤の素材を得た。得られた素材に、ロータリー打錠機で２０６ＭＰａの打錠圧を加え、１錠あたり１３０ｍｇとなるように打錠して、錠径７ｍｍの錠剤を複数得た。得られた錠剤を実施例１の口腔内崩壊錠として使用した。 5.77 g of compound (I), 246.0 g of D-mannitol (Granutol®, manufactured by Freund Sangyo Co., Ltd.) and 30 g of crystalline cellulose (Theoras® PH-101, Asahi Kasei Chemicals Co., Ltd.) (Manufactured by the company), 15 g of crospovidone (Corridon CL-F, manufactured by BASF Japan Co., Ltd.), and 0.2 g of yellow ferrous sesquioxide (manufactured by Ami Kasei Co., Ltd.) using a high-speed stirring type mixer granulator. Mixing for 5 minutes gave the mixture. The obtained mixture and 3 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) were mixed for 20 minutes using a Bole container mixer to obtain a tablet material. A tableting pressure of 206 MPa was applied to the obtained material with a rotary tableting machine, and the tablets were tableted so as to be 130 mg per tablet to obtain a plurality of tablets having a tablet diameter of 7 mm. The obtained tablet was used as an orally disintegrating tablet of Example 1.
実施例２の口腔内崩壊錠では、黄色三二酸化鉄の重量を０．７ｇ、Ｄ−マンニトールの重量を２４５．５ｇとした。その他は実施例１と同様に調製した。 In the orally disintegrating tablet of Example 2, the weight of yellow iron sesquioxide was 0.7 g, and the weight of D-mannitol was 245.5 g. Others were prepared in the same manner as in Example 1.
実施例３の口腔内崩壊錠では、黄色三二酸化鉄に替えて０．７ｇの三二酸化鉄（癸巳化成株式会社製）を用いた。その他は実施例２と同様に調製した。 In the orally disintegrating tablet of Example 3, 0.7 g of iron sesquioxide (manufactured by Ami Kasei Co., Ltd.) was used instead of yellow iron sesquioxide. Others were prepared in the same manner as in Example 2.
［比較例１］
実施例１の口腔内崩壊錠に対して黄色三二酸化鉄を省き、比較例１とした。また、Ｄ−マンニトールの重量を２４６．２ｇとした。その他は実施例１と同様に調製した。[Comparative Example 1]
Yellow iron sesquioxide was omitted from the orally disintegrating lock of Example 1 and used as Comparative Example 1. The weight of D-mannitol was 246.2 g. Others were prepared in the same manner as in Example 1.
［比較例２］
実施例３の口腔内崩壊錠に対して、三二酸化鉄に替えて０．７ｇの酸化チタン（タイペーク（登録商標）Ａ−１００、石原産業株式会社製）を用いて、比較例２とした。その他は実施例３と同様に調製した。[Comparative Example 2]
For the orally disintegrating tablet of Example 3, 0.7 g of titanium oxide (Typake (registered trademark) A-100, manufactured by Ishihara Sangyo Co., Ltd.) was used instead of iron sesquioxide to make Comparative Example 2. Others were prepared in the same manner as in Example 3.
なお、以下の説明において、実施例１〜３および比較例１、２の錠剤を総称して「試験錠剤」という場合がある。 In the following description, the tablets of Examples 1 to 3 and Comparative Examples 1 and 2 may be collectively referred to as "test tablets".
実施例１〜３の口腔内崩壊錠および比較例１、２について、光による影響を調べる試験を実施した。まず、光安定性試験器（ＬＳＴ−２０１０型、東京理化器械株式会社製）内に静置した実施例１〜３の口腔内崩壊錠、および比較例１、２に対して白色光（昼光）および近紫外光を照射した。白色光の光源としてＤ６５ランプを用い、近紫外光の光源として近紫外蛍光ランプを用いた。この時、白色光の総照度を１２０万ルクス・時間とし、近紫外照射エネルギーを２００Ｗ・ｈ／ｍ２以上とした。光照射後に、実施例１〜３および比較例１、２について、変色の度合い、および試験錠剤における後述の類縁物質の量を評価した。A test for examining the influence of light was carried out on the orally disintegrating tablets of Examples 1 to 3 and Comparative Examples 1 and 2. First, the orally disintegrating tablets of Examples 1 to 3 placed statically in a light stability tester (LST-2010 type, manufactured by Tokyo Rika Kikai Co., Ltd.), and white light (daylight) with respect to Comparative Examples 1 and 2. ) And near-ultraviolet light. A D65 lamp was used as a light source for white light, and a near-ultraviolet fluorescent lamp was used as a light source for near-ultraviolet light. At this time, the total illuminance of the white light was set to 1.2 million lux / hour, and the near-ultraviolet irradiation energy was set to 200 W · h / m 2 or more. After light irradiation, the degree of discoloration and the amount of related substances described below in the test tablets were evaluated for Examples 1 to 3 and Comparative Examples 1 and 2.
実施例１〜３および比較例１、２の変色の度合いを色差△Ｅに基づいて評価した。色差計（ＳＥ６０００型、日本電色工業社製）を用いて、国際照明委員会（ＣＩＥ）のＬ＊ａ＊ｂ＊色空間表示系におけるＬ＊値、ａ＊値、及びｂ＊値を測定した。なお、Ｌ＊ａ＊ｂ＊色空間表示系は日本工業規格（ＪＩＳ Ｚ ８７８１−４）にも規定されている。The degree of discoloration of Examples 1 to 3 and Comparative Examples 1 and 2 was evaluated based on the color difference ΔE. Using a color difference meter (SE6000 type, manufactured by Nippon Denshoku Kogyo Co., Ltd.), measure the L * a * b * L * value, a * value, and b * value in the L * a * b * color space display system of the International Commission on Illumination (CIE). did. The L * a * b * color space display system is also specified in the Japanese Industrial Standards (JIS Z 8781-4).
光照射前および光照射後における実施例１〜３および比較例１、２のＬ＊値、ａ＊値、ｂ＊値に基づいて、下記の式（１）によって光照射前後の実施例１〜３および比較例１、２の色差ΔＥをそれぞれ算出した。式（１）において、Ｌ１、Ｌ０はそれぞれ光照射後および光照射前における試験錠剤のＬ＊値を示し、ａ１、ａ０はそれぞれ光照射後および光照射前における試験錠剤のａ＊値を示し、ｂ１、ｂ０はそれぞれ光照射後および光照射前における試験錠剤のｂ＊値を示す。実施例１〜３および比較例１、２において各々５個の試験錠剤について色差ΔＥを算出した。色差ΔＥが大きいほど試験錠剤の変色の度合いが大きいと判断した。 Based on the L * value, a * value, and b * value of Examples 1 to 3 and Comparative Examples 1 and 2 before and after light irradiation, Examples 1 to before and after light irradiation according to the following formula (1). The color difference ΔE of 3 and Comparative Examples 1 and 2 were calculated, respectively. In formula (1), L1 and L0 indicate the L * values of the test tablets after and before light irradiation, respectively, and a1 and a0 indicate the a * values of the test tablets after and before light irradiation, respectively. b1 and b0 indicate the b * values of the test tablets after and before light irradiation, respectively. The color difference ΔE was calculated for each of the five test tablets in Examples 1 to 3 and Comparative Examples 1 and 2. It was judged that the larger the color difference ΔE, the greater the degree of discoloration of the test tablet.
ΔＥ＝｛（Ｌ１−Ｌ０）２＋（ａ１−ａ０）２＋（ｂ１−ｂ０）２｝１／２・・・（１）ΔE = {(L1-L0) 2 + (a1-a0) 2 + (b1-b0) 2 } 1/2 ... (1)
（類縁物質の量の測定）
実施例１〜３および比較例１、２の各々２０個の試験錠剤を５０％アセトニトリル・水混液で溶解し、ろ過した液を試料溶液とした。この時、試料溶液における化合物（Ｉ）の濃度を０．２５ｍｇ／ｍＬにした。試料溶液を高速液体クロマトグラフ法により分析し、試験錠剤における化合物（Ｉ）のピーク面積と、試験錠剤における化合物（Ｉ）のピークに対する相対保持時間０．３４のピーク面積とを測定した。試験錠剤における化合物（Ｉ）のピークに対する相対保持時間が０．３４である物質を試験錠剤におけるの類縁物質と規定する。そして、試験錠剤における化合物（Ｉ）のピーク面積に対する類縁物質のピーク面積の割合を百分率で算出し、「類縁物質の量」（単位：％）とした。(Measurement of the amount of related substances)
Twenty test tablets of Examples 1 to 3 and Comparative Examples 1 and 2 were each dissolved in a 50% acetonitrile / water mixture, and the filtered solution was used as a sample solution. At this time, the concentration of compound (I) in the sample solution was adjusted to 0.25 mg / mL. The sample solution was analyzed by a high-speed liquid chromatograph method, and the peak area of compound (I) in the test tablet and the peak area with a retention time of 0.34 relative to the peak of compound (I) in the test tablet were measured. A substance having a relative retention time of 0.34 relative to the peak of compound (I) in the test tablet is defined as a related substance in the test tablet. Then, the ratio of the peak area of the related substance to the peak area of the compound (I) in the test tablet was calculated as a percentage and used as the "amount of the related substance" (unit:%).
表１は、実施例１〜３の口腔内崩壊錠および比較例１、２の色差ΔＥおよび類縁物質の量を示す。なお、表中の色差ΔＥは５個の試験錠剤の平均値を示す。黄色三二酸化鉄を含む実施例１、２、および三二酸化鉄を含む実施例３の口腔内崩壊錠では比較例１、２よりも色差ΔＥおよび類縁物質の量が小さかった。これにより、化合物（Ｉ）に黄色三二酸化鉄または三二酸化鉄を配合することによって初めて、口腔内崩壊錠の変色と類縁物質の生成を抑制でき、口腔内崩壊錠の光安定性を向上できることが判明した。 Table 1 shows the amounts of the orally disintegrating tablets of Examples 1 to 3 and the color difference ΔE and related substances of Comparative Examples 1 and 2. The color difference ΔE in the table indicates the average value of the five test tablets. The orally disintegrating tablets of Examples 1 and 2 containing yellow iron sesquioxide and Example 3 containing iron sesquioxide had a smaller amount of color difference ΔE and related substances than Comparative Examples 1 and 2. As a result, the discoloration of the orally disintegrating tablet and the formation of related substances can be suppressed and the photostability of the orally disintegrating tablet can be improved only by adding yellow ferrous sesquioxide or iron sesquioxide to the compound (I). found.
なお、実施例１〜３および比較例１、２の崩壊時間を第１７改正日本薬局方に記載の崩壊試験法に従って測定したところ、いずれも３０秒以内であった。 When the disintegration times of Examples 1 to 3 and Comparative Examples 1 and 2 were measured according to the disintegration test method described in the 17th revised Japanese Pharmacopoeia, they were all within 30 seconds.
口腔内崩壊錠が酸化鉄を含むことによって口腔内崩壊錠の光安定性が向上する詳細なメカニズムは現状では不明であるが、酸化鉄が黄色光の波長（５７０〜５９０ｎｍ）よりも短い波長の光を吸収することによって口腔内崩壊錠の光安定性を向上させると推定される。 The detailed mechanism by which the orally disintegrating tablet contains iron oxide to improve the photostability of the orally disintegrating tablet is currently unknown, but iron oxide has a wavelength shorter than the wavelength of yellow light (570 to 590 nm). It is presumed that the absorption of light improves the photostability of the orally disintegrating tablet.
本発明の一実施形態の口腔内崩壊錠は、光遮断剤を含むフィルムコーティングにより光安定性を確保しているのではないため、錠剤の種類に限らず、化合物（Ｉ）を含有する種々の形態の固形製剤に適用することができる。 Since the orally disintegrating tablet of one embodiment of the present invention does not ensure photostability by film coating containing a light blocking agent, it is not limited to the type of tablet, and various types containing compound (I) are contained. It can be applied to solid preparations in the form.
本発明は、化合物（Ｉ）を含む口腔内崩壊錠に利用することができる。
The present invention can be used for an orally disintegrating tablet containing compound (I).
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