JP6231959B2 - Pharmaceutical preparation containing calcium antagonist / angiotensin II receptor antagonist - Google Patents
Pharmaceutical preparation containing calcium antagonist / angiotensin II receptor antagonist Download PDFInfo
- Publication number
- JP6231959B2 JP6231959B2 JP2014182380A JP2014182380A JP6231959B2 JP 6231959 B2 JP6231959 B2 JP 6231959B2 JP 2014182380 A JP2014182380 A JP 2014182380A JP 2014182380 A JP2014182380 A JP 2014182380A JP 6231959 B2 JP6231959 B2 JP 6231959B2
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- JP
- Japan
- Prior art keywords
- pharmaceutical preparation
- angiotensin
- antagonist
- mass
- disintegrant
- 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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- 229940127291 Calcium channel antagonist Drugs 0.000 title claims description 57
- 239000002333 angiotensin II receptor antagonist Substances 0.000 title claims description 54
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 54
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 title claims description 50
- 239000000480 calcium channel blocker Substances 0.000 title claims description 48
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Description
本発明は、カルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を有効成分として含む医薬製剤に関する。 The present invention relates to a pharmaceutical preparation comprising a calcium antagonist and an angiotensin II receptor antagonist as active ingredients.
高血圧とは、血圧が正常範囲よりも持続的に高くなっている状態をいう。高血圧は生活習慣病の１つであり、高血圧状態が持続されると、動脈硬化症や、虚血性心疾患、脳卒中などを発症することがある。
現在、高血圧患者の治療には、高血圧治療薬（降圧剤）を用いた血圧コントロールが広く一般に行われている。高血圧治療薬としては、カルシウム拮抗薬（ＣＣＢ）、アンジオテンシン交換酵素阻害薬、アンジオテンシンＩＩ受容体拮抗薬（ＡＲＢ）等が一般に使用されている。
High blood pressure refers to a state in which blood pressure is continuously higher than the normal range. High blood pressure is one of lifestyle-related diseases, and arteriosclerosis, ischemic heart disease, stroke, etc. may develop if the hypertensive state persists.
Currently, blood pressure control using antihypertensive drugs (hypertensive agents) is widely used for the treatment of hypertensive patients. As antihypertensive drugs, calcium antagonists (CCB), angiotensin exchange enzyme inhibitors, angiotensin II receptor antagonists (ARB) and the like are generally used.
カルシウム拮抗薬（ＣＣＢ）は、イオンチャネルを介した細胞内へのＣａ2+の取り込みを抑制し、平滑筋の収縮を減弱化させることにより、降圧作用を奏することが知られている。カルシウム拮抗薬は、現在、日本で最も汎用されている降圧薬であり、重篤な副作用が少ないこと、利尿薬に次いで安価であることから第一選択薬として勧められている。
アンジオテンシンＩＩ受容体拮抗薬（ＡＲＢ）は、アンジオテンシンＩＩ受容体に対して特異的に拮抗することにより、レニン・アンジオテンシン系で産生されて強い昇圧作用を持つアンジオテンシンＩＩの生理作用を抑制し、降圧作用を奏することが知られている。
Calcium antagonists (CCB) are known to exert a hypotensive effect by suppressing the uptake of Ca 2+ into cells via ion channels and attenuating the contraction of smooth muscle. Calcium antagonists are currently the most widely used antihypertensive drugs in Japan, and are recommended as first-line drugs because they have few serious side effects and are inexpensive after diuretics.
Angiotensin II receptor antagonist (ARB) suppresses the physiological action of angiotensin II, which is produced in the renin-angiotensin system and has a strong pressor action, by specifically antagonizing the angiotensin II receptor. It is known to play.
このように、カルシウム拮抗薬とアンジオテンシンＩＩ受容体拮抗薬とは、異なる機序により降圧作用をもたらす。したがって、単剤投与で症状の改善があまりみられない高血圧患者に対しては、治療効果を高める目的で、カルシウム拮抗薬とアンジオテンシンＩＩ受容体拮抗薬とを併用することも試みられている（特許文献１）。 Thus, calcium antagonists and angiotensin II receptor antagonists have antihypertensive effects by different mechanisms. Therefore, for hypertensive patients whose symptoms do not improve much with single-agent administration, it has been attempted to use a calcium antagonist and an angiotensin II receptor antagonist together for the purpose of enhancing the therapeutic effect (patent) Reference 1).
しかしながら、両薬剤はいずれも保存安定性に欠け、カルシウム拮抗薬は光に対して経時的に分解が進むという問題点を有する。一方、アンジオテンシンＩＩ受容体拮抗薬は、高い温度条件下で保存すると、溶出速度が極端に低下するといった問題点を有する。そのため、カルシウム拮抗薬製剤は遮光条件下で保存することが求められ、アンジオテンシンＩＩ受容体拮抗薬製剤は温度に留意して保存することが求められる。 However, both drugs lack the storage stability, and calcium antagonists have the problem that degradation proceeds with time with respect to light. On the other hand, angiotensin II receptor antagonists have a problem that the elution rate is extremely reduced when stored under high temperature conditions. Therefore, the calcium antagonist preparation is required to be stored under light-shielding conditions, and the angiotensin II receptor antagonist preparation is required to be stored with attention to temperature.
単に両薬剤を併用するのであれば、両薬剤をそれぞれ異なる方法で別個に保存すればよいため、上記の欠点はそれほど大きな問題とはならない。
しかしながら、配合剤の場合には、両薬剤を別個に保存することができないため、併用薬のようにして問題を解決することはできない。したがって、常に温度と光の両方に留意しながら保存しなければならない。
If both drugs are simply used in combination, the above disadvantages are not a significant problem because both drugs need to be stored separately in different ways.
However, in the case of a combination drug, since both drugs cannot be stored separately, the problem cannot be solved like a concomitant drug. Therefore, it must always be stored with attention to both temperature and light.
また、カルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬の原薬は、いずれも水への溶解度が低く、原薬を投与しても効果が表れるまで時間がかかるという問題がある。例えば、カルシウム拮抗薬の１つであるシルニジピンは、室温での水への溶解度が数ｎｇ／ｍＬであり、アンジオテンシンＩＩ受容体拮抗薬の１つであるバルサルタンは、水への溶解度が０．１７ｍｇ／ｍＬ程度である。そのため、現在市販されているカルシウム拮抗薬製剤及びアンジオテンシンＩＩ受容体拮抗薬製剤は、溶出速度が大きくなるようそれぞれ工夫がなされている。
しかしながら、市販のカルシウム拮抗薬製剤と、アンジオテンシンＩＩ受容体拮抗薬製剤は、それぞれ別個の方法で溶出速度を向上させているため、１つの医薬製剤（配合剤）で両者の溶出プロファイルを実現することは難しい。
In addition, both the calcium antagonist and the angiotensin II receptor antagonist drug substance have low water solubility, and there is a problem that it takes time until the drug substance is administered even if the drug substance is administered. For example, cilnidipine, which is one of calcium antagonists, has a solubility in water of several ng / mL at room temperature, and valsartan, which is one of angiotensin II receptor antagonists, has a solubility in water of 0.17 mg. / ML. Therefore, the calcium antagonist preparation and the angiotensin II receptor antagonist preparation currently on the market have been devised to increase the elution rate.
However, since the commercial calcium antagonist preparation and the angiotensin II receptor antagonist preparation improve the dissolution rate by different methods, respectively, both dissolution profiles should be realized with one pharmaceutical preparation (compound). Is difficult.
本発明は、上記問題点に鑑みてなされたものであり、アンジオテンシンＩＩ受容体拮抗薬の保存安定性を高め、これにより保存条件の緩和された医薬製剤を提供することを目的とする。さらには、市販のカルシウム拮抗薬製剤及びアンジオテンシンＩＩ受容体拮抗薬製剤それぞれの溶出プロファイルに近い溶出プロファイルを実現できる医薬製剤（配合剤）を提供することを目的とする。 The present invention has been made in view of the above-described problems, and an object of the present invention is to provide a pharmaceutical preparation with improved storage stability of an angiotensin II receptor antagonist, thereby relaxing storage conditions. Furthermore, it aims at providing the pharmaceutical formulation (formulation) which can implement | achieve the elution profile close | similar to each elution profile of a commercially available calcium antagonist formulation and an angiotensin II receptor antagonist formulation.
上記課題を解決するため、本発明は以下の構成を採用した。 In order to solve the above problems, the present invention employs the following configuration.
（１） 有効成分としてのカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬と、 ５質量％以上の崩壊剤と、
を含み、且つ、少なくともカルシウム拮抗薬が固体分散体の形態にあることを特徴とする医薬製剤。
（２） カルシウム拮抗薬が顆粒の形態にあり、該カルシウム拮抗薬を含む顆粒の一部又は全部を覆うようにしてアンジオテンシンＩＩ受容体拮抗薬が存在する、上記（１）に記載の医薬製剤。
（３） 崩壊剤が、前記顆粒中に含まれる、上記（２）に記載の医薬製剤。
（４） 崩壊剤が、前記アンジオテンシンＩＩ受容体拮抗薬とともに前記顆粒の一部又は全部を覆うようにして存在する、上記（２）又は（３）に記載の医薬製剤。
（５） 崩壊剤が、クロスカルメロースナトリウム、クロスカルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルスターチナトリウム、クロスポビドン及びα化澱粉からなる群から選択される少なくとも１種である、上記（１）〜（４）のいずれかに記載の医薬製剤。
（６） 前記カルシウム拮抗薬が、シルニジピン、アムロジピン、ニルバジピン、ニフェジピン、アゼルニジピン、ニソルジピン、ニカルジピン、ニモジピン、ニトレンジピン及びマニジピンからなる群から選択される少なくとも１種である、上記（１）〜（５）のいずれかに記載の医薬製剤。
（７） 前記カルシウム拮抗薬が、シルニジピンである、上記（６）に記載の医薬製剤。
（８） 前記アンジオテンシンＩＩ受容体拮抗薬が、バルサルタン、カンデサルタン、イルベサルタン、ロサルタン、テルミサルタン、オルメサルタン、イルベサルタン、及びエプロサルタンからなる群から選択される少なくとも１種である、上記（１）〜（７）のいずれかに記載の医薬製剤。
（９） 前記アンジオテンシンＩＩ受容体拮抗薬が、バルサルタンである、上記（８）に記載の医薬製剤。
（１０） カルシウム拮抗薬とアンジオテンシンＩＩ受容体拮抗薬との質量比が、１：１〜１：３２である、上記（１）〜（９）のいずれかに記載の医薬製剤。
（１１） 黄色三二酸化鉄、三二酸化鉄及び黒酸化鉄からなる群から選択される少なくとも１種の着色剤を含むコーティング被膜を含む、上記（１）〜（１０）のいずれかに記載の医薬製剤。
（１２） 前記着色剤の割合がコーティング被膜１００質量部に対して、０．１〜５質量部の範囲内である、上記（１１）に記載の医薬製剤。
（１３） 前記コーティング被膜が更に酸化チタンを含む、上記（１１）又は（１２）に記載の医薬製剤。
（１４） 錠剤、カプセル剤、細粒剤又は顆粒の形態にある、上記（１）〜（１３）のいずれかに記載の医薬製剤。
（１５） 錠剤の形態にある上記（１４）に記載の医薬製剤。
（１６） 降圧剤である、上記（１）〜（１５）のいずれかに記載の医薬製剤。
(1) Calcium antagonist and angiotensin II receptor antagonist as active ingredients, 5 mass% or more disintegrant,
And at least the calcium antagonist is in the form of a solid dispersion.
(2) The pharmaceutical preparation according to (1) above, wherein the calcium antagonist is in the form of granules, and the angiotensin II receptor antagonist is present so as to cover part or all of the granules containing the calcium antagonist.
(3) The pharmaceutical preparation according to (2), wherein a disintegrant is contained in the granule.
(4) The pharmaceutical preparation according to (2) or (3), wherein a disintegrating agent is present so as to cover a part or all of the granules together with the angiotensin II receptor antagonist.
(5) The above, wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, crospovidone and pregelatinized starch ( The pharmaceutical formulation in any one of 1)-(4).
(6) The above (1) to (5), wherein the calcium antagonist is at least one selected from the group consisting of cilnidipine, amlodipine, nilvadipine, nifedipine, azelnidipine, nisoldipine, nicardipine, nimodipine, nitrendipine and manidipine. The pharmaceutical formulation in any one.
(7) The pharmaceutical preparation according to (6), wherein the calcium antagonist is cilnidipine.
(8) The above-mentioned (1) to (7), wherein the angiotensin II receptor antagonist is at least one selected from the group consisting of valsartan, candesartan, irbesartan, losartan, telmisartan, olmesartan, irbesartan, and eprosartan. The pharmaceutical formulation in any one of.
(9) The pharmaceutical preparation according to (8), wherein the angiotensin II receptor antagonist is valsartan.
(10) The pharmaceutical preparation according to any one of (1) to (9), wherein the mass ratio of the calcium antagonist to the angiotensin II receptor antagonist is 1: 1 to 1:32.
(11) The medicament according to any one of (1) to (10) above, comprising a coating film containing at least one colorant selected from the group consisting of yellow iron sesquioxide, iron sesquioxide and black iron oxide. Formulation.
(12) The pharmaceutical preparation according to (11), wherein the ratio of the colorant is within a range of 0.1 to 5 parts by mass with respect to 100 parts by mass of the coating film.
(13) The pharmaceutical preparation according to the above (11) or (12), wherein the coating film further contains titanium oxide.
(14) The pharmaceutical preparation according to any one of (1) to (13), which is in the form of a tablet, capsule, fine granule, or granule.
(15) The pharmaceutical preparation according to the above (14), which is in the form of a tablet.
(16) The pharmaceutical preparation according to any one of (1) to (15), which is an antihypertensive agent.
本発明の医薬製剤は、アンジオテンシンＩＩ受容体拮抗薬の保存安定性を向上させることができる。また、該医薬製剤は、市販のカルシウム拮抗薬製剤及びアンジオテンシンＩＩ受容体拮抗薬それぞれの溶出プロファイルに近い溶出プロファイルを実現することができる。 The pharmaceutical preparation of the present invention can improve the storage stability of an angiotensin II receptor antagonist. Moreover, this pharmaceutical formulation can implement | achieve the elution profile close | similar to each elution profile of a commercially available calcium antagonist formulation and an angiotensin II receptor antagonist.
以下、本発明を実施するための形態を説明する。 Hereinafter, modes for carrying out the present invention will be described.
本発明の医薬製剤は、有効成分としてのカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬と５質量％以上の崩壊剤とを含み、且つ、少なくともカルシウム拮抗薬が固体分散体の形態にあることを特徴とする。
また、本発明の医薬製剤は、カルシウム拮抗薬を含む顆粒とアンジオテンシンＩＩ受容体拮抗薬とを含むことが好ましく、カルシウム拮抗薬を含む顆粒の一部又は全部を覆うようにしてアンジオテンシンＩＩ受容体拮抗薬が存在することがより好ましい。このような医薬製剤としては、例えば、カルシウム拮抗薬含有顆粒の周囲をアンジオテンシンＩＩ受容体拮抗薬が覆ってなる顆粒、細粒や、１又は複数のカルシウム拮抗薬含有顆粒とアンジオテンシンＩＩ受容体拮抗薬との混合物を打錠して得られる錠剤などが挙げられる。
また、本発明の医薬製剤は、カルシウム拮抗薬を含む顆粒の一部又は全部を覆うようにしてアンジオテンシンＩＩ受容体拮抗薬が存在し、且つ少なくともカルシウム拮抗薬が固体分散体の形態であることが好ましい。カルシウム拮抗薬とともにアンジオテンシンＩＩ受容体拮抗薬が固体分散体の形態にあってもよい。
The pharmaceutical preparation of the present invention comprises a calcium antagonist and angiotensin II receptor antagonist as active ingredients and 5% by mass or more of a disintegrant, and at least the calcium antagonist is in the form of a solid dispersion. And
In addition, the pharmaceutical preparation of the present invention preferably contains a granule containing a calcium antagonist and an angiotensin II receptor antagonist, and an angiotensin II receptor antagonist so as to cover part or all of the granule containing a calcium antagonist. More preferably the drug is present. Examples of such pharmaceutical preparations include, for example, granules, fine granules, and one or more calcium antagonist-containing granules and an angiotensin II receptor antagonist, which are surrounded by an angiotensin II receptor antagonist. Tablets obtained by tableting a mixture with
In the pharmaceutical preparation of the present invention, the angiotensin II receptor antagonist is present so as to cover a part or all of the granule containing the calcium antagonist, and at least the calcium antagonist is in the form of a solid dispersion. preferable. An angiotensin II receptor antagonist together with the calcium antagonist may be in the form of a solid dispersion.
本明細書及び特許請求の範囲において、「固体分散体」とは、不活性担体の中に薬物が単分子状に分散した固体を意味する。固体分散体内では、薬物が非晶質の状態で担体中に存在する。不活性担体としては、高分子化合物であれば特に制限なく用いることができ、例えば、結合剤、懸濁化剤、界面活性剤などの高分子化合物が挙げられる。懸濁化剤としては、アラビアゴム、キサンタンガム、アルギン酸ナトリウムなどが挙げられる。界面活性剤としては、ポリオキシエチレン硬化ヒマシ油、ラウリル硫酸ナトリウム、ポリオキシエチレン―ポリオキシプロピレングリコールなどが挙げられる。
固体分散体は、例えば、薬物及び担体成分を有機溶媒に溶解させた溶液を用いて造粒した後、乾燥させることによって得ることができる。
In the present specification and claims, the “solid dispersion” means a solid in which a drug is dispersed in a monomolecular form in an inert carrier. Within the solid dispersion, the drug is present in the carrier in an amorphous state. As the inert carrier, any polymer compound can be used without particular limitation, and examples thereof include polymer compounds such as a binder, a suspending agent, and a surfactant. Suspending agents include gum arabic, xanthan gum, sodium alginate and the like. Examples of the surfactant include polyoxyethylene hydrogenated castor oil, sodium lauryl sulfate, polyoxyethylene-polyoxypropylene glycol and the like.
The solid dispersion can be obtained, for example, by granulating using a solution in which a drug and a carrier component are dissolved in an organic solvent and then drying.
＜カルシウム拮抗薬＞
カルシウム拮抗薬は、イオンチャネルを介した細胞内へのＣａ2+の取り込みを抑制し、平滑筋の収縮を減弱化させることにより、血圧の降下作用を示す薬物である。
本発明で用いられるカルシウム拮抗薬としては、１，４−ジヒドロピリジン誘導体が好ましく、シルニジピン、アムロジピン、ニルバジピン、ニフェジピン、アゼルニジピン、ニソルジピン、ニカルジピン、ニモジピン、ニトレンジピン及びマニジピンからなる群から選択される少なくとも１種であることがより好ましい。これらのなかでも、シルニジピン（化学名：（±）−２−ｍｅｔｈｏｘｙｅｔｈｙｌ ３−ｐｈｅｎｙｌ−２（Ｅ）−ｐｒｏｐｅｎｙｌ １，４−ｄｉｈｙｄｒｏ−２，６−ｄｉｍｅｔｈｙｌ−４−（３−ｎｉｔｒｏｐｈｅｎｙｌ）−３，５−ｐｙｒｉｄｉｎｅｄｉｃａｒｂｏｘｙｌａｔｅ）が特に好ましい。
シルニジピンは、Ｌ型カルシウムチャネル及びＮ型カルシウムチャネルを共に阻害するＬ／Ｎ型カルシウム拮抗薬として公知の化合物であり、公知の製造方法により製造することが可能である。また、市販でその製剤を入手することも可能である。さらには、シルニジピンは該製剤から抽出等により取得することもできる。
カルシウム拮抗薬は必要に応じ、薬理的に許容される塩、水和物、溶媒和物としてもよい。薬理学的に許容される塩としては、例えば、無機酸との塩（塩酸塩、臭化水素酸塩、リン酸塩、硫酸塩など）、有機酸との塩（酢酸塩、コハク酸塩、マレイン酸塩、フマール酸塩、リンゴ酸塩、酒石酸塩など）などが挙げられる。さらに、本発明において使用されるカルシウム拮抗薬は必要に応じ、適当なその光学活性体を用いてもよい。
カルシウム拮抗薬は、医薬製剤１００質量％に対して、０．１〜１０質量％含まれることが好ましく、０．５〜５質量％含まれることがより好ましい。
<Calcium antagonist>
Calcium antagonists are drugs that have a blood pressure lowering action by suppressing the uptake of Ca 2+ into cells via ion channels and attenuating smooth muscle contraction.
The calcium antagonist used in the present invention is preferably a 1,4-dihydropyridine derivative, and is at least one selected from the group consisting of cilnidipine, amlodipine, nilvadipine, nifedipine, azelnidipine, nisoldipine, nicardipine, nimodipine, nitrendipine and manidipine. More preferably. Among these, cilnidipine (chemical name: (±) -2-methoxyethyl 3-phenyl-2 (E) -propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5 -Pyridine dicarboxylate) is particularly preferred.
Silnidipine is a known compound as an L / N-type calcium antagonist that inhibits both L-type and N-type calcium channels, and can be produced by a known production method. It is also possible to obtain the formulation on the market. Furthermore, cilnidipine can be obtained from the preparation by extraction or the like.
The calcium antagonist may be a pharmacologically acceptable salt, hydrate, or solvate as necessary. Examples of pharmacologically acceptable salts include salts with inorganic acids (hydrochlorides, hydrobromides, phosphates, sulfates, etc.), salts with organic acids (acetates, succinates, Maleate, fumarate, malate, tartrate, etc.). Furthermore, as the calcium antagonist used in the present invention, an appropriate optically active form thereof may be used as necessary.
It is preferable that 0.1-10 mass% is contained with respect to 100 mass% of pharmaceutical preparations, and it is more preferable that a calcium antagonist is contained 0.5-5 mass%.
＜アンジオテンシンＩＩ受容体拮抗薬＞
アンジオテンシンＩＩ受容体拮抗薬とは、昇圧物質であるアンジオテンシンＩＩと拮抗し、アンジオテンシンＩＩがアンジオテンシンＩＩ受容体に結合するのを妨げることにより血圧の降下作用を示す薬物である。アンジオテンシンＩＩ受容体拮抗薬としては、例えば、バルサルタン、カンデサルタン、ロサルタン、テルミサルタン、オルメサルタン、イルベサルタン、エプロサルタンなどが挙げられる。なかでも、バルサルタン（化学名：（−）−Ｎ−｛４−［２−（１Ｈ−ｔｅｔｒａｚｏｌ−５−ｙｌ）ｐｈｅｎｙｌ］ｂｅｎｚｙｌ｝−Ｎ−ｖａｌｅｒｙｌ−Ｌ−ｖａｌｉｎｅ）が特に好ましい。
アンジオテンシンＩＩ受容体拮抗薬は必要に応じ、薬理的に許容される塩、水和物、溶媒和物としてもよい。薬理学的に許容される塩としては、例えば、無機酸との塩（塩酸塩、臭化水素酸塩、リン酸塩、硫酸塩など）、有機酸との塩（酢酸塩、コハク酸塩、マレイン酸塩、フマール酸塩、リンゴ酸塩、酒石酸塩など）などが挙げられる。さらに、本発明において使用されるアンジオテンシンＩＩ受容体拮抗薬は必要に応じ、適当なその光学活性体を用いてもよい。
アンジオテンシンＩＩ受容体拮抗薬は１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
アンジオテンシンＩＩ受容体拮抗薬は、医薬製剤１００質量％に対して、５〜５０質量％含まれることが好ましく、１０〜４０質量％含まれることがより好ましい。
<Angiotensin II receptor antagonist>
An angiotensin II receptor antagonist is a drug that exhibits an action of lowering blood pressure by antagonizing angiotensin II, which is a pressor substance, and preventing angiotensin II from binding to the angiotensin II receptor. Examples of the angiotensin II receptor antagonist include valsartan, candesartan, losartan, telmisartan, olmesartan, irbesartan, eprosartan, and the like. Among them, valsartan (chemical name: (−)-N- {4- [2- (1H-tetrazol-5-yl) phenyl] benzyl} -N-valeryl-L-valine) is particularly preferable.
The angiotensin II receptor antagonist may be a pharmacologically acceptable salt, hydrate, or solvate as necessary. Examples of pharmacologically acceptable salts include salts with inorganic acids (hydrochlorides, hydrobromides, phosphates, sulfates, etc.), salts with organic acids (acetates, succinates, Maleate, fumarate, malate, tartrate, etc.). Furthermore, as the angiotensin II receptor antagonist used in the present invention, an appropriate optically active substance thereof may be used as necessary.
An angiotensin II receptor antagonist may be used individually by 1 type, and may be used in combination of 2 or more type.
The angiotensin II receptor antagonist is preferably contained in an amount of 5 to 50% by mass, more preferably 10 to 40% by mass with respect to 100% by mass of the pharmaceutical preparation.
また、カルシウム拮抗薬とアンジオテンシンＩＩ受容体拮抗薬との質量比は、１：１〜１：３２の範囲内であることが好ましく、１：４〜１：１６の範囲内であることがより好ましい。 The mass ratio of the calcium antagonist to the angiotensin II receptor antagonist is preferably in the range of 1: 1 to 1:32, more preferably in the range of 1: 4 to 1:16. .
＜崩壊剤＞
崩壊剤とは、服用又は水に入れたとき、水にぬれ、製剤を崩壊させる添加物を意味する。
本発明の医薬製剤に含まれる崩壊剤としては、クロスカルメロースナトリウム、クロスカルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルスターチナトリウム、クロスポビドン及びα化澱粉が好ましく、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルスターチナトリウム及びクロスポビドンがより好ましく、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロースがさらにより好ましく、クロスカルメロースナトリウムが特に好ましい。崩壊剤は１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
<Disintegrant>
The disintegrant means an additive that gets wet when taken or put in water, and disintegrates the preparation.
As the disintegrant contained in the pharmaceutical preparation of the present invention, croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, crospovidone and pregelatinized starch are preferable, croscarmellose sodium, low Substituted hydroxypropylcellulose, sodium carboxymethyl starch and crospovidone are more preferred, croscarmellose sodium, low substituted hydroxypropylcellulose are even more preferred, and croscarmellose sodium is particularly preferred. A disintegrating agent may be used individually by 1 type, and may be used in combination of 2 or more type.
崩壊剤は、医薬製剤１００質量％に対して合計で５質量％以上含まれ、５〜３５質量％が好ましく、６〜３０質量％の範囲内であることがより好ましい。 The total amount of the disintegrant is 5% by mass or more with respect to 100% by mass of the pharmaceutical preparation, preferably 5 to 35% by mass, and more preferably 6 to 30% by mass.
崩壊剤は、顆粒中にカルシウム拮抗薬とともに含まれることが好ましい。また、崩壊剤は、アンジオテンシンＩＩ受容体拮抗薬とともに前記顆粒の一部又は全部を覆うようにして存在することが好ましい。カルシウム拮抗薬を含む顆粒中に含まれる崩壊剤（第１の崩壊剤）と、顆粒周囲にアンジオテンシンＩＩ受容体拮抗薬とともに存在する崩壊剤（第２の崩壊剤）は、同一の崩壊剤であってもよく、互いに異なる種類の崩壊剤であってもよい。第１の崩壊剤及び第２の崩壊剤のどちらか一方のみが医薬製剤中に含まれていてもよいが、第１の崩壊剤と第２の崩壊剤の両方が医薬製剤中に含まれていることが好ましい。
第１の崩壊剤は、医薬製剤１００質量％に対して、１〜１５質量％含まれることが好ましく、１〜１０質量％がより好ましい。
第２の崩壊剤は、医薬製剤１００質量％に対して、１〜３０質量％含まれることが好ましく、２〜２５質量％がより好ましい。
The disintegrant is preferably included in the granule together with the calcium antagonist. Moreover, it is preferable that a disintegrating agent exists so that a part or all of the said granule may be covered with an angiotensin II receptor antagonist. The disintegrant contained in the granule containing the calcium antagonist (first disintegrant) and the disintegrant present along with the angiotensin II receptor antagonist (second disintegrant) were the same disintegrant. Alternatively, different types of disintegrants may be used. Only one of the first disintegrant and the second disintegrant may be included in the pharmaceutical preparation, but both the first disintegrant and the second disintegrant are included in the pharmaceutical preparation. Preferably it is.
It is preferable that 1-15 mass% is contained with respect to 100 mass% of pharmaceutical preparations, and 1-10 mass% is more preferable.
It is preferable that 1-30 mass% is contained with respect to 100 mass% of pharmaceutical preparations, and 2-25 mass% is more preferable for a 2nd disintegrating agent.
＜結合剤＞
本発明の医薬製剤は、結合剤を含んでいてもよい。結合剤としては、種々のものを用いることができ、特に限定されることはなく、例えば、水溶性高分子が挙げられる。なかでも、ヒドロキシプロピルセルロース、ヒプロメロースフタル酸エステル、メチルセルロース、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルボキシメチルエチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシエチルセルロース、ヒドロキシエチルメエチルセルロース、酢酸フタル酸セルロースが好ましく、ヒドロキシプロピルセルロース、ヒプロメロースフタル酸エステルがより好ましい。
結合剤は、医薬製剤１００質量％に対して、１〜９０質量％含まれることが好ましく、３〜４０質量％がより好ましく、５〜２０質量％がさらにより好ましい。
結合剤を用いる場合には、該結合剤は、カルシウム拮抗薬を含む顆粒内に含まれることが好ましい。
<Binder>
The pharmaceutical preparation of the present invention may contain a binder. Various binders can be used and are not particularly limited, and examples thereof include water-soluble polymers. Among these, hydroxypropylcellulose, hypromellose phthalate, methylcellulose, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, cellulose acetate phthalate, hydroxypropylcellulose, Hypromellose phthalate is more preferred.
It is preferable that 1-90 mass% is contained with respect to 100 mass% of pharmaceutical formulations, 3-40 mass% is more preferable, and 5-20 mass% is still more preferable.
When a binder is used, the binder is preferably contained in a granule containing a calcium antagonist.
＜滑沢剤＞
本発明の医薬製剤は、滑沢剤を含んでいてもよい。滑沢剤としては、種々のものを用いることができ、特に限定されることはなく、例えば、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、炭酸マグネシウムが挙げられる。滑沢剤は、医薬製剤１００質量％に対して、０．５〜２質量％含まれることが好ましい。
滑沢剤を用いる場合には、該滑沢剤は、アンジオテンシンＩＩ受容体拮抗薬とともに前記顆粒の一部又は全部を覆うようにして存在することが好ましい。
<Lubricant>
The pharmaceutical preparation of the present invention may contain a lubricant. Various lubricants can be used, and are not particularly limited. Examples thereof include magnesium stearate, stearic acid, calcium stearate, and magnesium carbonate. The lubricant is preferably contained in an amount of 0.5 to 2% by mass with respect to 100% by mass of the pharmaceutical preparation.
When a lubricant is used, the lubricant is preferably present so as to cover part or all of the granule together with the angiotensin II receptor antagonist.
＜賦形剤＞
本発明の医薬製剤は、賦形剤を含んでいてもよい。賦形剤としては、種々のものを用いることができ、特に限定されることはなく、例えば、乳糖水和物、白糖、ブドウ糖、還元麦芽糖、マンニトール、ソルビトール等の糖類、トウモロコシデンプン、バレイショデンプン、部分アルファー化デンプン、デキストリン、プルラン等のデンプン類およびその誘導体、結晶セルロース、微結晶セルロース等のセルロース類、マクロゴール、メタケイ酸アルミン酸マグネシウムの１種又は２種以上の混合物が挙げられる。なかでも、乳糖水和物、マンニトール、部分アルファー化デンプン、結晶セルロースが好ましく、乳糖水和物、結晶セルロースがより好ましい。
賦形剤は、１種類を単独で用いてもよく、２種以上を組み合わせて用いてもよい。また、賦形剤を用いる場合には、カルシウム拮抗薬を含む顆粒内に含む賦形剤（第１の賦形剤）と、アンジオテンシンＩＩ受容体拮抗薬とともに前記顆粒の一部又は全部を覆うようにして存在する賦形剤（第２の賦形剤）とが同一であってもよく、異なっていてもよい。第１の賦形剤及び第２の賦形剤のどちらか一方のみが医薬製剤中に含まれていてもよい。
第１の賦形剤は、医薬製剤１００質量％に対して、１〜４０質量％含まれることが好ましく、１〜３０質量％がより好ましい。
第２の賦形剤は、医薬製剤１００質量％に対して、１〜４０質量％含まれることが好ましく、５〜３０質量％がより好ましい。
<Excipient>
The pharmaceutical preparation of the present invention may contain an excipient. Various excipients can be used, and are not particularly limited. For example, sugars such as lactose hydrate, sucrose, glucose, reduced maltose, mannitol, sorbitol, corn starch, potato starch, Examples thereof include starches such as partially pregelatinized starch, dextrin and pullulan and derivatives thereof, celluloses such as crystalline cellulose and microcrystalline cellulose, macrogol, and one or a mixture of two or more of magnesium aluminate metasilicate. Of these, lactose hydrate, mannitol, partially pregelatinized starch, and crystalline cellulose are preferable, and lactose hydrate and crystalline cellulose are more preferable.
One type of excipient may be used alone, or two or more types may be used in combination. In addition, when an excipient is used, the excipient (first excipient) contained in the granule containing the calcium antagonist and the angiotensin II receptor antagonist are covered with a part or all of the granule. The excipient (second excipient) present in this manner may be the same or different. Only one of the first excipient and the second excipient may be contained in the pharmaceutical preparation.
It is preferable that 1-40 mass% is contained with respect to 100 mass% of pharmaceutical preparations, and 1-30 mass% is more preferable for a 1st excipient | filler.
The second excipient is preferably contained in an amount of 1 to 40% by mass, more preferably 5 to 30% by mass with respect to 100% by mass of the pharmaceutical preparation.
＜流動化剤＞
本発明の医薬製剤は、流動化剤を含んでいてもよい。流動化剤としては、種々のものを用いることができ、特に限定されることはなく、例えば、含水二酸化ケイ素、軽質無水ケイ酸、タルクが挙げられる。なかでも、含水二酸化ケイ素がより好ましい。
流動化剤は、医薬製剤１００質量％に対して、１〜１０質量％含まれることが好ましく、１〜５質量％がより好ましい。
流動化剤を用いる場合には、該流動化剤は、アンジオテンシンＩＩ受容体拮抗薬とともに前記顆粒の一部又は全部を覆うようにして存在することが好ましい。
<Fluidizer>
The pharmaceutical preparation of the present invention may contain a fluidizing agent. Various fluidizing agents can be used, and are not particularly limited. Examples thereof include hydrous silicon dioxide, light silicic anhydride, and talc. Of these, hydrous silicon dioxide is more preferable.
It is preferable that 1-10 mass% is contained with respect to 100 mass% of pharmaceutical preparations, and 1-5 mass% is more preferable.
When a fluidizing agent is used, the fluidizing agent is preferably present so as to cover part or all of the granule together with the angiotensin II receptor antagonist.
＜コーティング被膜＞
また、本発明の医薬製剤は、その表面にコーティング被膜を有していることが好ましい。コーティング被膜の質量割合は目的に応じて調節すればよいが、医薬製剤１００質量％に対して１〜１０質量％であることが好ましく、３〜８質量％であることがより好ましい。
<Coating film>
Moreover, it is preferable that the pharmaceutical formulation of this invention has a coating film on the surface. The mass ratio of the coating film may be adjusted according to the purpose, but is preferably 1 to 10 mass%, more preferably 3 to 8 mass% with respect to 100 mass% of the pharmaceutical preparation.
コーティング被膜は、例えば、コーティング剤を水に溶かしたコーティング液を、パンコーディング装置、ドラムタイプコーティング装置、流動コーティング装置などを用いて塗布することにより、医薬製剤表面に形成させることができる。
コーティング剤としては、ヒプロメロース、マグロゴール６０００などが挙げられる。
The coating film can be formed on the surface of a pharmaceutical preparation, for example, by applying a coating solution obtained by dissolving a coating agent in water using a pan coding device, a drum type coating device, a fluid coating device, or the like.
Examples of the coating agent include hypromellose and tuna gogol 6000.
＜着色剤＞
コーティング被膜は、黄色三二酸化鉄、三二酸化鉄、黒酸化鉄などの酸化鉄系の着色剤を含んでいることが好ましい。上記着色剤は１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
前記着色剤は、コーティング被膜１００質量部に対し、０．１〜５質量部の割合で含まれることが好ましく、０．２５〜１質量部の割合で含まれることがより好ましい。
上記着色剤を含むコーティング被膜を有することにより、医薬製剤中に含まれるカルシウム拮抗薬の光安定性を向上させることができる。すなわち、高温保存時に溶出速度が低下するアンジオテンシンＩＩ受容体拮抗薬の問題点だけでなく、光分解されやすいカルシウム拮抗薬の問題点をも改善することができる。
また、コーティング被膜は、上記酸化鉄系の着色剤に加え、更に酸化チタンなどの他の着色剤を含んでいてもよい。酸化チタンを含む場合には、酸化チタンは、コーティング被膜１００質量部に対し、５〜２５質量部含まれることが好ましく、１０〜２０質量部含まれることがより好ましい。
<Colorant>
The coating film preferably contains an iron oxide-based colorant such as yellow iron sesquioxide, iron sesquioxide, and black iron oxide. The said coloring agent may be used individually by 1 type, and may be used in combination of 2 or more type.
The colorant is preferably contained in a proportion of 0.1 to 5 parts by mass, more preferably 0.25 to 1 part by mass, with respect to 100 parts by mass of the coating film.
By having a coating film containing the colorant, the light stability of the calcium antagonist contained in the pharmaceutical preparation can be improved. That is, not only the problem of an angiotensin II receptor antagonist whose elution rate decreases during high-temperature storage, but also the problem of a calcium antagonist that is easily photodegraded can be improved.
The coating film may further contain other colorant such as titanium oxide in addition to the iron oxide colorant. When titanium oxide is included, the titanium oxide is preferably included in an amount of 5 to 25 parts by mass, more preferably 10 to 20 parts by mass with respect to 100 parts by mass of the coating film.
本発明の医薬製剤は、固体製剤であることが好ましく、錠剤、カプセル剤、細粒剤又は顆粒の形態にあることがより好ましく、錠剤の形態にあることが特に好ましい。また、錠剤の形状は特に制限されず、例えば、丸形、楕円形（正円を除くあらゆる長円形：オーバル形、卵形、楕円胴形、小判形など）、ひし形、三角形等、が挙げられる。割線を設ける場合には、割線の形状は平溝型、Ｕ字溝型、Ｖ字溝型のいずれでもよく、錠剤が楕円形状である場合には、短軸に沿って形成することが好ましい。 The pharmaceutical preparation of the present invention is preferably a solid preparation, more preferably in the form of a tablet, capsule, fine granule or granule, and particularly preferably in the form of a tablet. The shape of the tablet is not particularly limited, and examples thereof include a round shape, an oval shape (any oval shape except for a perfect circle: an oval shape, an oval shape, an oval shape, an oval shape, etc.), a rhombus, a triangle, and the like. . When the dividing line is provided, the shape of the dividing line may be any of a flat groove type, a U-shaped groove type, and a V-shaped groove type. When the tablet is elliptical, it is preferably formed along the minor axis.
本発明の医薬製剤は、パドル法に基づく溶出試験で、カルシウム拮抗薬が、試験開始から１５分後にその４８〜７８質量％が水に溶解することが好ましい。同様に、パドル法に基づく溶出試験で、カルシウム拮抗薬が、試験開始から９０分後にその７５質量％以上が水に溶解することが好ましい。
また、パドル法に基づく溶出試験で、アンジオテンシンＩＩ受容体拮抗薬は、試験開始から１５分後にその７５質量％以上が水に溶解することが好ましい。同様に、パドル法に基づく溶出試験で、アンジオテンシンＩＩ受容体拮抗薬が、試験開始から３０分後にその８５質量％以上が水に溶解することが好ましい。
溶出率が上記範囲内であると、市販のカルシウム拮抗薬製剤、アンジオテンシンＩＩ受容体拮抗薬製剤それぞれの溶出プロファイルに近い溶出プロファイルを達成することができる。したがって、２種の製剤を併用投与した場合と同様の効果を奏する医薬製剤（配合剤）を得ることができる。
In the dissolution test based on the paddle method, it is preferable that 48 to 78% by mass of the calcium antagonist is dissolved in water 15 minutes after the start of the test. Similarly, in a dissolution test based on the paddle method, it is preferable that 75% by mass or more of the calcium antagonist is dissolved in water 90 minutes after the start of the test.
Further, in the dissolution test based on the paddle method, it is preferable that 75% by mass or more of the angiotensin II receptor antagonist is dissolved in water 15 minutes after the start of the test. Similarly, in the dissolution test based on the paddle method, it is preferable that 85% by mass or more of the angiotensin II receptor antagonist is dissolved in water 30 minutes after the start of the test.
When the dissolution rate is within the above range, dissolution profiles close to the dissolution profiles of the commercially available calcium antagonist preparation and angiotensin II receptor antagonist preparation can be achieved. Therefore, it is possible to obtain a pharmaceutical preparation (combination agent) that exhibits the same effect as when two kinds of preparations are administered in combination.
＜製造方法＞
本発明の医薬製剤は、当該分野で従来公知の方法で製造することが出来る。例えば、乾式造粒法、湿式造粒法、直接打錠法などの方法で製造することができる。より具体的には、例えば、カルシウム拮抗薬を顆粒化し、得られたカルシウム拮抗薬含有顆粒に、アンジオテンシンＩＩ受容体拮抗薬を混合し、乾式造粒法により造粒後、打錠することによって製造することができる。
<Manufacturing method>
The pharmaceutical formulation of this invention can be manufactured by a conventionally well-known method in the said field | area. For example, it can be produced by a dry granulation method, a wet granulation method, a direct tableting method or the like. More specifically, for example, it is manufactured by granulating a calcium antagonist, mixing an angiotensin II receptor antagonist into the obtained granule containing granule, granulating by dry granulation method, and then tableting can do.
＜用途＞
本発明の医薬製剤は、降圧作用を有するため、高血圧患者治療用の降圧剤として有用である。
<Application>
Since the pharmaceutical preparation of the present invention has an antihypertensive action, it is useful as an antihypertensive agent for treating hypertensive patients.
＜投与対象＞
本発明の医薬製剤の投与対象としては、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒトなどの哺乳動物が挙げられる。特に、ヒトが投与対象として好ましい。
<Subject of administration>
Examples of the administration target of the pharmaceutical preparation of the present invention include mammals such as mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, and humans. In particular, humans are preferable as administration subjects.
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれらの例によって限定されるものではない。実施例中、特に断りがない限り、「％」は質量％を意味する。 EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these examples. In Examples, unless otherwise specified, “%” means mass%.
［実施例１］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表１記載のシルニジピン顆粒を得た。
[Example 1]
The silnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).
［実施例２］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表１記載のシルニジピン顆粒を得た。得られたシルニジピン顆粒に表４に示す成分を混合、乾式造粒、整粒、打錠することにより、シルニジピン／バルサルタン配合剤の素錠を得た（崩壊剤添加量：５２．５ｍｇ／錠、素錠１錠あたり２１％）。得られた素錠をパン型コーティング機を用いて、表３の処方をコーティングしてフィルムコート錠を得た。錠剤中に含まれるシルニジピンの割合：１．９％、バルサルタンの割合：１５．２％、第１の崩壊剤の割合：４．８％、第２の崩壊剤の割合：１５．２％（崩壊剤合計：２０．０％）
[Example 2]
The silnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). By mixing the ingredients shown in Table 4 into the obtained cilnidipine granules, dry granulation, sizing, and tableting, an uncoated tablet of the cilnidipine / valsartan compound was obtained (disintegrant addition amount: 52.5 mg / tablet, 21% per uncoated tablet). The obtained uncoated tablets were coated with the formulation shown in Table 3 using a pan-type coating machine to obtain film-coated tablets. The proportion of cilnidipine contained in the tablet: 1.9%, the proportion of valsartan: 15.2%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 15.2% (disintegration) Agent total: 20.0%)
［実施例３］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表１記載のシルニジピン顆粒を得た。得られたシルニジピン顆粒に表５に示す成分を混合、乾式造粒、整粒、打錠することにより、シルニジピン／バルサルタン配合剤の素錠を得た（崩壊剤添加量：１２．５ｍｇ／錠、素錠１錠あたり２９％）。得られた素錠をパン型コーティング機を用いて、表３の処方をコーティングしてフィルムコート錠を得た。錠剤中に含まれるシルニジピンの割合：１．９％、バルサルタンの割合：１５．２％、第１の崩壊剤の割合：４．８％、第２の崩壊剤の割合：２２．９％（崩壊剤合計：２７．６％）
[Example 3]
The silnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). By mixing the ingredients shown in Table 5 into the obtained cilnidipine granules, dry granulation, sizing, and tableting, an uncoated tablet of the cilnidipine / valsartan compound was obtained (disintegrant addition amount: 12.5 mg / tablet, 29% per uncoated tablet). The obtained uncoated tablets were coated with the formulation shown in Table 3 using a pan-type coating machine to obtain film-coated tablets. The proportion of cilnidipine contained in the tablet: 1.9%, the proportion of valsartan: 15.2%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 22.9% (disintegration) (Total agent: 27.6%)
［比較例１］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表１記載のシルニジピン顆粒を得た。得られたシルニジピン顆粒に表６に示す成分を混合、乾式造粒、整粒、打錠することにより、シルニジピン／バルサルタン配合剤の素錠を得た（崩壊剤添加量：１２．５ｍｇ／錠、素錠１錠あたり５％）。得られた素錠をパン型コーティング機を用いて、表３の処方をコーティングしてフィルムコート錠を得た。錠剤中に含まれるシルニジピンの割合：１．９％、バルサルタンの割合：１５．２％、第１の崩壊剤の割合：４．８％、第２の崩壊剤の割合：０．０％（崩壊剤合計：４．８％）
[Comparative Example 1]
The silnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The ingredients shown in Table 6 were mixed into the obtained cilnidipine granules, dry granulation, sizing, and tableting to obtain uncoated tablets of the cilnidipine / valsartan compound (disintegrant addition amount: 12.5 mg / tablet, 5% per uncoated tablet). The obtained uncoated tablets were coated with the formulation shown in Table 3 using a pan-type coating machine to obtain film-coated tablets. The proportion of cilnidipine contained in the tablet: 1.9%, the proportion of valsartan: 15.2%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 0.0% (disintegration) Agent total: 4.8%)
［試験例１］
バルサルタンの溶出試験については、第十六改正日本薬局方の項に記載されている溶出試験法（パドル法）に従い、毎分５０回転、試験液として水９００ｍＬを用い、試験を行った。試験開始から１５分、３０分後の試験液を採取し、液体クロマトグラフィーにより試験を行い、バルサルタンの溶出率を算出した。
[Test Example 1]
About the dissolution test of valsartan, according to the dissolution test method (paddle method) described in the 16th revised Japanese Pharmacopoeia section, the test was performed using 50 mL per minute and 900 mL of water as a test solution. Test solutions 15 and 30 minutes after the start of the test were collected and tested by liquid chromatography to calculate the dissolution rate of valsartan.
［試験例２］
シルニジピンの溶出試験については、第十六改正日本薬局方の項に記載されている溶出試験法（パドル法）に従い、毎分５０回転、試験液として０．１ｗ／ｖ％ポリソルベート８０を添加した溶出試験第２液９００ｍＬを用い、試験を行った。試験開始から１５分、９０分後の試験液を採取し、液体クロマトグラフィーにより試験を行い、シルニジピンの溶出率を算出した。
[Test Example 2]
For the dissolution test of cilnidipine, in accordance with the dissolution test method (paddle method) described in the 16th revised Japanese Pharmacopoeia section, dissolution at 50 rpm, 0.1 w / v% polysorbate 80 was added as a test solution. The test was conducted using 900 mL of the second test liquid. Test solutions 15 and 90 minutes after the start of the test were collected and tested by liquid chromatography to calculate the elution rate of cilnidipine.
［試験例３］
気密状態にて温度６０℃の条件にて１ヶ月保管し、試験例１に従い溶出率を算出した。
[Test Example 3]
The sample was stored for one month in an airtight state at a temperature of 60 ° C., and the dissolution rate was calculated according to Test Example 1.
＜結果＞
実施例１〜３、比較例１を試験例１及び２に従い溶出率（％）を算出した。
なお、シルニジピンの市販製剤であるアテレック（登録商標）錠及びバルサルタンの市販製剤であるディオバン（登録商標）錠の溶出速度を考慮して目標値を設定し、シルニジピン、バルサルタンの溶出率が全て目標値を満たすものを○、一つでも満たさないものを×と評価した。
その結果、実施例１〜３については、シルニジピン及びバルサルタン共に目標値の溶出率を示したことから目的の溶出速度を有する製剤であることを確認した。しかし、比較例１については、目標値の溶出率を示さず目的の溶出速度を有する製剤ではないことを確認した。
<Result>
In Examples 1 to 3 and Comparative Example 1, the dissolution rate (%) was calculated according to Test Examples 1 and 2.
The target values were set in consideration of the dissolution rate of Atelec (registered trademark) tablets, which are commercial preparations of cilnidipine, and Diovan (registered trademark) tablets, which are commercial preparations of valsartan. Those satisfying the criteria were evaluated as ◯, and those not satisfying at least one were evaluated as ×.
As a result, about Examples 1-3, since the elution rate of the target value was shown for both cilnidipine and valsartan, it confirmed that it was a formulation which has the target elution rate. However, it was confirmed that Comparative Example 1 was not a preparation having a target dissolution rate without showing a target dissolution rate.
実施例１、実施例２及びディオバン錠４０ｍｇ（市販品）を用いて試験例３に従い、安定性を確認した。その結果、実施例１及び実施例２の処方の製剤については、保存後も高い溶出率を保持していた。 The stability was confirmed according to Test Example 3 using Example 1, Example 2 and Diovan Tablets 40 mg (commercially available). As a result, the preparations of the formulations of Example 1 and Example 2 maintained a high dissolution rate even after storage.
［実施例４］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表９記載のシルニジピン顆粒を得た。
[Example 4]
The silnidipine granules shown in Table 9 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).
［比較例２］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表９記載のシルニジピン顆粒を得た。
得られたシルニジピン顆粒に、表１０に示す成分を混合、乾式造粒、整粒、打錠することにより、シルニジピン／バルサルタン配合剤の素錠を得た。
得られた素錠をパン型コーティング機を用いて、表１２の処方をコーティングしてフィルムコート錠を得た。該錠剤中に含まれるシルニジピンの割合：１．９％、バルサルタンの割合：１５．２％、第１の崩壊剤の割合：４．８％、第２の崩壊剤の割合：７．６％（崩壊剤合計：１２．４％）。コーティング被膜１００質量部に対する酸化鉄系着色剤の割合：０．０質量部、酸化チタンの割合：１５．０質量部。
[Comparative Example 2]
The silnidipine granules shown in Table 9 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).
The obtained cilnidipine granules were mixed with the components shown in Table 10 , dry granulation, sizing, and tableting to obtain plain tablets of the cilnidipine / valsartan compound.
The obtained uncoated tablets were coated with the formulation shown in Table 12 using a pan-type coating machine to obtain film-coated tablets. The proportion of cilnidipine contained in the tablet: 1.9%, the proportion of valsartan: 15.2%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 7.6% ( Disintegrant total: 12.4%). Ratio of iron oxide colorant to 100 parts by mass of coating film: 0.0 part by mass, ratio of titanium oxide: 15.0 parts by mass.
［実施例５］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表１３記載のシルニジピン顆粒を得た。
[Example 5]
The silnidipine granules shown in Table 13 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).
［実施例６］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表１３記載のシルニジピン顆粒を得た。得られたシルニジピン顆粒に、表１４に示す成分を混合、乾式造粒、整粒、打錠することにより、シルニジピン／バルサルタン配合剤の素錠を得た。得られた素錠をパン型コーティング機を用いて、表１６の処方をコーティングしてフィルムコート錠を得た。該錠剤中に含まれるシルニジピンの割合：１．９％、バルサルタンの割合：１５．５％、第１の崩壊剤の割合：４．８％、第２の崩壊剤の割合：１５．４％（崩壊剤合計：２０．２％）。コーティング被膜１００質量部に対する酸化鉄系着色剤の割合：０．２５質量部、酸化チタンの割合：１５．０質量部。
[Example 6]
The silnidipine granules shown in Table 13 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The ingredients shown in Table 14 were mixed into the obtained cilnidipine granules, dry granulation, sizing and tableting to obtain plain tablets of the cilnidipine / valsartan compound. The obtained uncoated tablets were coated with the formulation shown in Table 16 using a pan-type coating machine to obtain film-coated tablets. The proportion of cilnidipine contained in the tablet: 1.9%, the proportion of valsartan: 15.5%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 15.4% ( Disintegrant total: 20.2%). Ratio of iron oxide colorant to 100 parts by mass of coating film: 0.25 part by mass, ratio of titanium oxide: 15.0 parts by mass.
［実施例７］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表１３記載のシルニジピン顆粒を得た。得られたシルニジピン顆粒に表１４に示す成分を混合、乾式造粒、整粒、打錠することにより、シルニジピン／バルサルタン配合剤の素錠を得た。得られた素錠をパン型コーティング機を用いて、表１７の処方をコーティングしてフィルムコート錠を得た。該錠剤中に含まれるシルニジピンの割合：１．９％、バルサルタンの割合：１５．５％、第１の崩壊剤の割合：４．８％、第２の崩壊剤の割合：１５．４％（崩壊剤合計：２０．２％）。コーティング被膜１００質量部に対する酸化鉄系着色剤の割合：０．２５質量部、酸化チタンの割合：１５．０質量部。
[Example 7]
The silnidipine granules shown in Table 13 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The ingredients shown in Table 14 were mixed with the obtained cilnidipine granules, dry granulation, sizing and tableting to obtain plain tablets of the cilnidipine / valsartan compounding agent. The obtained uncoated tablets were coated with the formulation shown in Table 17 using a pan-type coating machine to obtain film-coated tablets. The proportion of cilnidipine contained in the tablet: 1.9%, the proportion of valsartan: 15.5%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 15.4% ( Disintegrant total: 20.2%). Ratio of iron oxide colorant to 100 parts by mass of coating film: 0.25 part by mass, ratio of titanium oxide: 15.0 parts by mass.
［比較例３］
有機溶媒（ジクロロメタン及びメタノール）を用いた攪拌造粒により、表１３記載のシルニジピン顆粒を得た。得られたシルニジピン顆粒に表１４に示す成分を混合、乾式造粒、整粒、打錠することにより、シルニジピン／バルサルタン配合剤の素錠を得た。得られた素錠をパン型コーティング機を用いて、表１８の処方をコーティングしてフィルムコート錠を得た。該錠剤中に含まれるシルニジピンの割合：１．９％、バルサルタンの割合：１５．５％、第１の崩壊剤の割合：４．８％、第２の崩壊剤の割合：１５．４％（崩壊剤合計：２０．２％）。コーティング被膜１００質量部に対する酸化鉄系着色剤の割合：０．０質量部、酸化チタンの割合：１５．０質量部。
[Comparative Example 3]
The silnidipine granules shown in Table 13 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The ingredients shown in Table 14 were mixed with the obtained cilnidipine granules, dry granulation, sizing and tableting to obtain plain tablets of the cilnidipine / valsartan compounding agent. The obtained uncoated tablets were coated with the formulation shown in Table 18 using a pan-type coating machine to obtain film-coated tablets. The proportion of cilnidipine contained in the tablet: 1.9%, the proportion of valsartan: 15.5%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 15.4% ( Disintegrant total: 20.2%). Ratio of iron oxide colorant to 100 parts by mass of coating film: 0.0 part by mass, ratio of titanium oxide: 15.0 parts by mass.
［試験例４］
１２０万Ｌｕｘ照射における光安定性試験を実施し、シルニジピン類縁物質総量値を算出した。
＜結果＞
実施例４〜７、比較例２及び３について、試験例４に従いシルニジピン類縁物質総量値を算出した。その結果、酸化チタンのみを添加した比較例２及び比較例３に比べて、実施例４〜７はいずれもシルニジピン類縁物質総量は低値を示し、光に安定であることを確認した。
[Test Example 4]
The photostability test at 1.2 million Lux irradiation was carried out, and the total amount of cilnidipine related substances was calculated.
<Result>
For Examples 4 to 7 and Comparative Examples 2 and 3, the total amount of cilnidipine-related substances was calculated according to Test Example 4. As a result, as compared with Comparative Example 2 and Comparative Example 3 in which only titanium oxide was added, Examples 4 to 7 all showed a low value for the total amount of cilnidipine-related substances, and it was confirmed that they were stable to light.
本発明の医薬製剤は、アンジオテンシンＩＩ受容体拮抗薬の保存安定性を向上させることができる。また、該医薬製剤は、市販のカルシウム拮抗薬製剤及びアンジオテンシンＩＩ受容体拮抗薬それぞれの溶出プロファイルに近い溶出プロファイルを実現することができる。したがって、産業上極めて有用である。 The pharmaceutical preparation of the present invention can improve the storage stability of an angiotensin II receptor antagonist. Moreover, this pharmaceutical formulation can implement | achieve the elution profile close | similar to each elution profile of a commercially available calcium antagonist formulation and an angiotensin II receptor antagonist. Therefore, it is very useful industrially.
Claims (9)
５〜３５質量％の崩壊剤と、３〜４０質量％の結合剤と、賦形剤と、
黄色三二酸化鉄、三二酸化鉄及び黒酸化鉄からなる群から選択される少なくとも１種の着色剤及び酸化チタンを含むコーティング被膜と
を含み、且つ、少なくともカルシウム拮抗薬が固体分散体の形態にある医薬製剤であって、
前記カルシウム拮抗薬がシルニジピンであり、
前記アンジオテンシンＩＩ受容体拮抗薬がバルサルタンであり、
前記崩壊剤が、クロスカルメロースナトリウム及び低置換度ヒドロキシプロピルセルロースからなる群から選択される少なくとも１種であり、
前記結合剤が、ヒドロキシプロピルセルロース及びヒプロメロースフタル酸エステルからなる群から選択される少なくとも１種であり、且つ
前記賦形剤が、メタケイ酸アルミン酸マグネシウム、結晶セルロース、乳糖水和物及びマクロゴールからなる群から選択される少なくとも１種である、前記医薬製剤。 0.5-5% by weight calcium antagonist and 10-40% by weight angiotensin II receptor antagonist as active ingredients,
5-35 % by weight disintegrant, 3-40% by weight binder, excipients,
A coating film containing at least one colorant selected from the group consisting of yellow iron sesquioxide, iron sesquioxide and black iron oxide and titanium oxide , and at least a calcium antagonist is a solid dispersion A pharmaceutical preparation in the form of
The calcium antagonist is cilnidipine,
The angiotensin II receptor antagonist is valsartan;
The disintegrant is at least one selected from the group consisting of croscarmellose sodium and low-substituted hydroxypropylcellulose;
The binder is at least one selected from the group consisting of hydroxypropylcellulose and hypromellose phthalate; and
The pharmaceutical preparation, wherein the excipient is at least one selected from the group consisting of magnesium aluminate metasilicate, crystalline cellulose, lactose hydrate, and macrogol .
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