JP2015003915A - Method for producing calcium channel blocker/angiotensin ii receptor antagonist-containing pharmaceutical formulation - Google Patents
Method for producing calcium channel blocker/angiotensin ii receptor antagonist-containing pharmaceutical formulation Download PDFInfo
- Publication number
- JP2015003915A JP2015003915A JP2014182381A JP2014182381A JP2015003915A JP 2015003915 A JP2015003915 A JP 2015003915A JP 2014182381 A JP2014182381 A JP 2014182381A JP 2014182381 A JP2014182381 A JP 2014182381A JP 2015003915 A JP2015003915 A JP 2015003915A
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- Japan
- Prior art keywords
- angiotensin
- receptor antagonist
- antagonist
- water
- calcium antagonist
- 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 abstract description 91
- 239000000480 calcium channel blocker Substances 0.000 title claims abstract description 84
- 239000002333 angiotensin II receptor antagonist Substances 0.000 title claims abstract description 78
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 title claims abstract description 74
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 47
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
- 108090000312 Calcium Channels Proteins 0.000 title 1
- 102000003922 Calcium Channels Human genes 0.000 title 1
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Abstract
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の製造方法に関する。 The present invention relates to a method for producing 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 produced in the renin-angiotensin system and having a strong pressor action by specifically antagonizing the angiotensin II receptor, and has a hypotensive action. 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、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、２０℃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、２０℃での水への溶解度が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。
However, 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, one of the calcium antagonists, has a water solubility of several ng / mL at 20 ° C., and valsartan, one of the angiotensin II receptor antagonists, is water-soluble at 20 ° C. The solubility is about 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、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）の製造方法を提供することを目的とする。 The present invention has been made in view of the above problems, and a method for producing a pharmaceutical preparation (compound) capable of realizing an elution profile close to the elution profile of each of a commercially available calcium antagonist preparation and an angiotensin II receptor antagonist preparation The purpose is to provide.
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） 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の製造方法であって、水を用いることなくカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を一緒に又は別々に造粒する造粒工程を含むことを特徴とする医薬製剤の製造方法。
（２） 前記造粒工程において、有機溶媒を用いる、上記（１）に記載の製造方法。
（３） 前記造粒工程において、水を用いずにカルシウム拮抗薬をアンジオテンシンＩＩ受容体拮抗薬と共に造粒し、カルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を含む顆粒を得る、上記（１）又は（２）に記載の製造方法。
（４） 水を用いずにカルシウム拮抗薬を造粒してカルシウム拮抗薬含有顆粒を得た後、アンジオテンシンＩＩ受容体拮抗薬を該顆粒と水を用いずに混合して造粒することにより、水を用いずにカルシウム拮抗薬をアンジオテンシンＩＩ受容体拮抗薬と共に造粒し、カルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を含む顆粒を得る、上記（３）に記載の製造方法。
（５） 前記造粒工程において、水を用いずにカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を別々に造粒し、カルシウム拮抗薬含有顆粒とアンジオテンシンＩＩ受容体拮抗薬含有顆粒とを得る、上記（１）又は（２）に記載の製造方法。
（６） 造粒工程後に得られた顆粒を圧縮成形する工程を更に含む、上記（３）〜（５）のいずれかに記載の製造方法。
（７） カルシウム拮抗薬が、１，４−ジヒドロピリジン誘導体を含む、上記（１）〜（６）のいずれかに記載の製造方法。
（８） １，４−ジヒドロピリジン誘導体が、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（７）に記載の製造方法。
（９） 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）〜（８）のいずれかに記載の製造方法。
（１０） 前記有機溶媒が、ジクロロメタン、ジクロロエタン、クロロホルム、メタノール、エタノール、プロパノール、イソプロパノール、アセトン及びジエチルエーテルからなる群から選択される少なくとも１種である、上記（２）〜（９）のいずれかに記載の製造方法。
（１１） 医薬製剤中に含まれるカルシウム拮抗薬とアンジオテンシンＩＩ受容体拮抗薬とが、質量比で１：１〜１：３２である、上記（１）〜（１０）のいずれかに記載の製造方法。
（１２） 造粒工程において、崩壊剤を用いる、上記（１）〜（１１）のいずれかに記載の製造方法。
（１３） 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７分後にその２５〜５５質量％が水に溶解し、アンジオテンシンＩＩ受容体拮抗薬が試験開始１５分後にその７５質量％以上が水に溶解する溶出プロファイルを有する、上記（１）〜（１２）のいずれかに記載の製造方法。
（１４） 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９０分後にその７５質量％以上が水に溶解し、アンジオテンシンＩＩ受容体拮抗薬が試験開始３０分後にその８５質量％以上が水に溶解する溶出プロファイルを有する、上記（１）〜（１３）のいずれかに記載の製造方法。
（１５） 医薬製剤が降圧剤である、上記（１）〜（１４）のいずれかに記載の製造方法。
(1) A method for producing a pharmaceutical preparation comprising a calcium antagonist and an angiotensin II receptor antagonist as active ingredients, wherein the calcium antagonist and the angiotensin II receptor antagonist are granulated together or separately without using water. The manufacturing method of the pharmaceutical formulation characterized by including the granulation process to do.
(2) The manufacturing method as described in said (1) using an organic solvent in the said granulation process.
(3) In the granulation step, the calcium antagonist is granulated together with the angiotensin II receptor antagonist without using water to obtain granules containing the calcium antagonist and the angiotensin II receptor antagonist (1) or The manufacturing method as described in (2).
(4) After granulating a calcium antagonist without using water to obtain a calcium antagonist-containing granule, the angiotensin II receptor antagonist is mixed and granulated without using water, The production method according to (3) above, wherein a granule containing a calcium antagonist and an angiotensin II receptor antagonist is obtained by granulating a calcium antagonist together with an angiotensin II receptor antagonist without using water.
(5) In the granulation step, a calcium antagonist and an angiotensin II receptor antagonist are separately granulated without using water to obtain a calcium antagonist-containing granule and an angiotensin II receptor antagonist-containing granule, (1) The manufacturing method as described in (2).
(6) The production method according to any one of (3) to (5), further including a step of compression molding the granule obtained after the granulation step.
(7) The manufacturing method in any one of said (1)-(6) in which a calcium antagonist contains a 1, 4- dihydropyridine derivative.
(8) The 1,4-dihydropyridine derivative is at least one selected from the group consisting of cilnidipine, amlodipine, nilvadipine, nifedipine, azelnidipine, nisoldipine, nicardipine, nimodipine, nitrendipine and manidipine as described in (7) above Production method.
(9) The above-mentioned (1) to (8), 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 manufacturing method in any one.
(10) Any of the above (2) to (9), wherein the organic solvent is at least one selected from the group consisting of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone and diethyl ether The manufacturing method as described in.
(11) The production according to any one of (1) to (10) above, wherein the calcium antagonist and the angiotensin II receptor antagonist contained in the pharmaceutical preparation are in a mass ratio of 1: 1 to 1:32. Method.
(12) The production method according to any one of (1) to (11), wherein a disintegrant is used in the granulation step.
(13) In the dissolution test based on the paddle method, 25 to 55 mass% of the calcium antagonist is dissolved in water 7 minutes after the start of the test, and 75 mass% or more of the angiotensin II receptor antagonist is 15 minutes after the start of the test. The manufacturing method in any one of said (1)-(12) which has the elution profile which melt | dissolves in water.
(14) In a dissolution test based on the paddle method, 75 mass% or more of the calcium antagonist is dissolved in water 90 minutes after the start of the test, and 85 mass% or more of the angiotensin II receptor antagonist is water 30 minutes after the start of the test. The manufacturing method in any one of said (1)-(13) which has the elution profile which melt | dissolves in.
(15) The production method according to any one of (1) to (14), wherein the pharmaceutical preparation is an antihypertensive agent.
本発明の方法により製造された医薬製剤は、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することができる。 The pharmaceutical preparation produced by the method of the present invention can realize an elution profile close to the elution profile of each of the commercially available calcium antagonist preparation and angiotensin II receptor antagonist preparation.
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.
本発明の医薬製剤の製造方法は、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の製造方法であって、水を用いることなくカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を一緒に又は別々に造粒する造粒工程を含むことを特徴とする。
本発明の製造方法により得られる医薬製剤は、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が好ましい。カルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬が固体分散体の形態にあってもよい。
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。
The method for producing a pharmaceutical preparation of the present invention is a method for producing a pharmaceutical preparation comprising a calcium antagonist and an angiotensin II receptor antagonist as active ingredients, wherein the calcium antagonist and the angiotensin II receptor antagonist are added without using water. It is characterized by including a granulation step of granulating together or separately.
The pharmaceutical preparation obtained by the production method of the present invention preferably has at least a calcium antagonist in the form of a solid dispersion. The calcium antagonist and angiotensin II receptor antagonist may be in the form of a solid dispersion.
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.
［造粒工程］
本発明の製造方法は、水を用いることなくカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を一緒に又は別々に造粒する工程（造粒工程）を含む。したがって、本発明では、カルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬が水に溶解することなく造粒される。
また、造粒工程では、水を用いることなく有機溶媒を用いてカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を一緒に又は別々に造粒することが好ましい。さらには、カルシウム拮抗薬及び／又はアンジオテンシンＩＩ受容体拮抗薬とともに、崩壊剤を用いて上記造粒を行うことが好ましい。
[Granulation process]
The production method of the present invention includes a step of granulating a calcium antagonist and an angiotensin II receptor antagonist together or separately without using water (granulation step). Therefore, in the present invention, the calcium antagonist and the angiotensin II receptor antagonist are granulated without dissolving in water.
In the granulation step, it is preferable to granulate the calcium antagonist and the angiotensin II receptor antagonist together or separately using an organic solvent without using water. Furthermore, it is preferable to perform the granulation using a disintegrant together with a calcium antagonist and / or an angiotensin II receptor antagonist.
水を用いることなくカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を一緒に造粒する方法としては、流動層造粒機を用いて、水を用いることなくカルシウム拮抗薬をアンジオテンシンＩＩ受容体拮抗薬に噴霧することにより造粒する方法を挙げることができる。前記噴霧は、カルシウム拮抗薬を有機溶媒に溶解して得られる溶液を、アンジオテンシンＩＩ受容体拮抗薬に噴霧することが好ましい。造粒後、例えば、整粒機により整粒し、流動層乾燥機を用いて乾燥してもよい。上記方法により、カルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を含む顆粒を得ることができる。 As a method of granulating a calcium antagonist and an angiotensin II receptor antagonist together without using water, a fluidized bed granulator is used to convert the calcium antagonist into an angiotensin II receptor antagonist without using water. The method of granulating by spraying can be mentioned. The spraying is preferably performed by spraying a solution obtained by dissolving a calcium antagonist in an organic solvent onto an angiotensin II receptor antagonist. After granulation, for example, the particles may be sized using a sizing machine and dried using a fluidized bed dryer. By the said method, the granule containing a calcium antagonist and an angiotensin II receptor antagonist can be obtained.
また、水を用いることなくカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を一緒に造粒する方法として、水を用いずに（好ましくは有機溶媒を用いて）カルシウム拮抗薬を造粒してカルシウム拮抗薬含有顆粒を得た後、アンジオテンシンＩＩ受容体拮抗薬を該顆粒と水を用いずに混合して造粒する方法を挙げることもできる。造粒後、例えば、整粒機により整粒し、流動層乾燥機を用いて乾燥してもよい。上記方法により、カルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を含む顆粒を得ることができる。
アンジオテンシンＩＩ受容体拮抗薬とカルシウム拮抗薬含有顆粒との混合物を造粒する方法としては、例えば、乾式造粒機を用いた造粒法が挙げられる。該方法では、カルシウム拮抗薬を含む顆粒の一部また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てなる形態で、カルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を含む顆粒を得ることができる。得られた顆粒において、カルシウム拮抗薬を含む顆粒中及び該顆粒の外側の両方に崩壊剤が存在することが好ましい。
In addition, as a method of granulating a calcium antagonist and an angiotensin II receptor antagonist together without using water, the calcium antagonist is granulated without using water (preferably using an organic solvent) and calcium antagonist. An example is a method in which an angiotensin II receptor antagonist is mixed and granulated without using the water after obtaining the drug-containing granule. After granulation, for example, the particles may be sized using a sizing machine and dried using a fluidized bed dryer. By the said method, the granule containing a calcium antagonist and an angiotensin II receptor antagonist can be obtained.
Examples of a method for granulating a mixture of an angiotensin II receptor antagonist and a calcium antagonist-containing granule include a granulation method using a dry granulator. In the method, a granule containing a calcium antagonist and an angiotensin II receptor antagonist is obtained in a form in which an angiotensin II receptor antagonist is present so as to cover part or all of the granule containing a calcium antagonist. be able to. In the obtained granule, it is preferable that a disintegrant is present both in the granule containing the calcium antagonist and on the outside of the granule.
水を用いることなくカルシウム拮抗薬及びアンジオテンシンＩＩ受容体拮抗薬を別々に造粒する方法としては、カルシウム拮抗薬を水を用いずに造粒し、これとは別にアンジオテンシンＩＩ受容体拮抗薬を水を用いずに造粒する方法を挙げることができる。造粒後、例えば、整粒機により整粒し、流動層乾燥機を用いて乾燥してもよい。上記方法により、カルシウム拮抗薬含有顆粒とアンジオテンシンＩＩ受容体拮抗薬含有顆粒とを含む混合物を得ることができる。 As a method of granulating a calcium antagonist and an angiotensin II receptor antagonist separately without using water, the calcium antagonist is granulated without using water, and an angiotensin II receptor antagonist is separately added to water. The method of granulating without using can be mentioned. After granulation, for example, the particles may be sized using a sizing machine and dried using a fluidized bed dryer. By the above method, a mixture containing calcium antagonist-containing granules and angiotensin II receptor antagonist-containing granules can be obtained.
＜カルシウム拮抗薬＞
カルシウム拮抗薬とは、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は、１，４−ジヒドロピリジン誘導体を含むことが好ましい。１，４−ジヒドロピリジン誘導体としては、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。
<Calcium antagonist>
A calcium antagonist is a drug that exhibits a blood pressure lowering action by suppressing the uptake of Ca 2+ into cells via ion channels and attenuating the contraction of smooth muscle.
The calcium antagonist used in the present invention preferably contains a 1,4-dihydropyridine derivative. The 1,4-dihydropyridine derivative is preferably at least one selected from the group consisting of cilnidipine, amlodipine, nilvadipine, nifedipine, azelnidipine, nisoldipine, nicardipine, nimodipine, nitrendipine and manidipine. 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.
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。
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、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 angiotensin II receptor antagonists include valsartan, candesartan, irbesartan, losartan, telmisartan, olmesartan, irbesartan, and eprosartan. 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. .
＜有機溶媒＞
造粒工程で使用できる有機溶媒としては、例えば、ジクロロメタン、ジクロロエタン、クロロホルム、メタノール、エタノール、プロパノール、イソプロパノール、アセトン又はジエチルエーテルを挙げることができる。これらの中でも、ジクロロメタン、メタノール、エタノール、プロパノール、イソプロパノールからなる群から選択される少なくとも１種の有機溶媒を使用することが好ましい。有機溶媒は、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。
有機溶媒の量は、カルシウム拮抗薬又はカルシウム拮抗薬とアンジオテンシンＩＩ受容体拮抗薬とを造粒できる限り特に制限はなく、造粒方法に応じて適宜調節すればよい。
<Organic solvent>
Examples of the organic solvent that can be used in the granulation step include dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone, and diethyl ether. Among these, it is preferable to use at least one organic solvent selected from the group consisting of dichloromethane, methanol, ethanol, propanol, and isopropanol. An organic solvent may be used individually by 1 type, and may be used in combination of 2 or more type.
The amount of the organic solvent is not particularly limited as long as the calcium antagonist or the calcium antagonist and the angiotensin II receptor antagonist can be granulated, and may be appropriately adjusted according to the granulation method.
＜崩壊剤＞
本発明の製造方法では、造粒工程において、崩壊剤を用いることが好ましく、崩壊剤とカルシウム拮抗薬及び／又はアンジオテンシンＩＩ受容体拮抗薬と混合させて得られた混合物を用いて造粒を行うことがより好ましい。また、崩壊剤をカルシウム拮抗薬及び／又はアンジオテンシンＩＩ受容体拮抗薬とともに有機溶媒に溶解させて造粒を行うことが好ましい。
崩壊剤をとしては、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、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、クロスポビドン、低置換度カルボキシメチルスターチナトリウム及びアルファー化デンプンが好ましく、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、カルメロース、カルメロースナトリウム、クロスポビドン及び低置換度カルボキシメチルスターチナトリウムがより好ましく、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>
In the production method of the present invention, it is preferable to use a disintegrant in the granulation step, and granulation is performed using a mixture obtained by mixing the disintegrant with a calcium antagonist and / or an angiotensin II receptor antagonist. It is more preferable. Moreover, it is preferable to perform granulation by dissolving a disintegrant in an organic solvent together with a calcium antagonist and / or an angiotensin II receptor antagonist.
As the disintegrant, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, low-substituted carboxymethyl starch sodium and pregelatinized starch are preferred, More preferred are croscarmellose sodium, low-substituted hydroxypropylcellulose, carmellose, carmellose sodium, crospovidone and low-substituted carboxymethyl starch sodium, croscarmellose sodium and low-substituted hydroxypropylcellulose are more preferred, and croscarmellose. Loose 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５質量％以上含まれることが好ましく、５〜３５質量％の範囲内で含まれることがより好ましく、６〜３０質量％の範囲内であることがさらにより好ましい。また、カルシウム拮抗薬を造粒する場合には、崩壊剤は１〜１５質量％の範囲内で含まれることが好ましく、１〜１０質量％の範囲内であることがより好ましい。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造粒する場合には、１〜３０質量％の崩壊剤を混合物に添加することが好ましく、２〜２５質量％の崩壊剤を混合物に添加することがより好ましい。 The disintegrant is preferably contained in an amount of 5% by mass or more based on 100% by mass of the pharmaceutical preparation, more preferably in the range of 5 to 35% by mass, and in the range of 6 to 30% by mass. Even more preferred. Moreover, when granulating a calcium antagonist, it is preferable that a disintegrating agent is contained in the range of 1-15 mass%, and it is more preferable that it is in the range of 1-10 mass%. When granulating a mixture of a calcium antagonist-containing granule and an angiotensin II receptor antagonist, it is preferable to add 1-30% by mass of a disintegrant to the mixture, and 2-25% by mass of the disintegrant is mixed. It is more preferable to add to.
＜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。
また、崩壊剤、結合剤以外に、滑沢剤、賦形剤、流動化剤などをカルシウム拮抗薬及び／又はアンジオテンシンＩＩ受容体拮抗薬に加えてもよい。
<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.
In addition to the disintegrant and the binder, a lubricant, an excipient, a fluidizing agent and the like may be added to the calcium antagonist and / or the angiotensin II receptor antagonist.
ここで、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。
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。
Here, 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, Examples include potato starch, partially pregelatinized starch, starches such as 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.
It is preferable that 1-40 mass% is contained with respect to 100 mass% of pharmaceutical preparations, and 1-30 mass% is more preferable.
［圧縮成形工程］
本発明の医薬製剤の製造方法は、造粒工程で得られた顆粒を圧縮成形する工程を含んでいてもよい。
圧縮成形は、公知の方法を用いて行えばよく、例えば、ステアリン酸マグネシウム、タルク、ステアリン酸、ステアリン酸カルシウム又は炭酸マグネシウムを添加・混合し、打錠機にて圧縮成形すればよい。
圧縮成形して得られる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。
[Compression molding process]
The manufacturing method of the pharmaceutical formulation of this invention may include the process of compression-molding the granule obtained at the granulation process.
The compression molding may be performed using a known method. For example, magnesium stearate, talc, stearic acid, calcium stearate or magnesium carbonate may be added and mixed, and compression molding may be performed with a tableting machine.
The shape of the tablet obtained by compression molding is not particularly limited. For example, round shape, oval shape (any oval shape except for a perfect circle: oval shape, oval shape, oval barrel shape, oval shape, etc.), rhombus, triangle, etc. . 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.
［その他の工程］
本発明の医薬製剤の製造方法は、圧縮成形工程後に、更にコーティング処理を施す工程を設けてもよい。コーティング処理に用いられ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。コーティング処理は、従来知られている方法を用いればよく、例えば、コーティング剤を水などの溶媒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、医薬製剤表面にコーティングすればよい。コーティング液には、コーティング剤の他に、黄色三二酸化鉄、三二酸化鉄、黒酸化鉄、酸化チタン、食用青色１号、食用黄色４号、食用赤色２号などの着色剤を添加してもよい。これらの着色剤を添加することにより、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。
[Other processes]
The method for producing a pharmaceutical preparation of the present invention may further include a step of performing a coating treatment after the compression molding step. Examples of the coating agent used for the coating treatment include hypromellose and tuna gogol 6000. For the coating treatment, a conventionally known method may be used. For example, a coating solution obtained by dissolving a coating agent in a solvent such as water is used as a pharmaceutical preparation using a pan coding device, a drum type coating device, a fluid coating device, or the like. What is necessary is just to coat the surface. In addition to the coating agent, coloring agents such as yellow ferric oxide, ferric oxide, black iron oxide, titanium oxide, edible blue No. 1, edible yellow No. 4, and edible red No. 2 may be added to the coating liquid. Good. By adding these colorants, the photostability of the calcium antagonist can be improved.
本発明の方法により得られる医薬製剤は、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。
本発明の方法により得られる医薬製剤は、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７分後にその２５〜５５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。
The pharmaceutical preparation obtained by the method 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.
In the dissolution test based on the paddle method, the pharmaceutical preparation obtained by the method of the present invention preferably has a calcium antagonist dissolved in water in an amount of 25 to 55 mass% after 7 minutes from 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.
＜用途＞
本発明の製造方法により得られる医薬製剤は、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 obtained by the production method of the present invention has an antihypertensive action, it is useful as an antihypertensive agent for treating hypertensive patients.
＜投与対象＞
本発明の製造方法により得られる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 obtained by the production method 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。 EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these examples.
［実施例１］
メタケイ酸アルミン酸マグネシウム（２２．４ｋｇ）、結晶セルロース（６．４１ｋｇ）、乳糖水和物（４．８６ｋｇ）、クロスカルメロースナトリウム（５．１０ｋｇ）を攪拌造粒機に入れ混合した。その後、メタノール（２８．３ｋｇ）及びジクロロメタン（８．５ｋｇ）にシルニジピン（２．０４ｋｇ）、マクロゴール４００（１．４３ｋｇ）及びヒドロキシプロピルセルロース（８．１６ｋｇ）を溶解した結合液を投入し造粒した。造粒後、整粒機（コーミル）により整粒（スクリーン：１．６ｍｍ）し、流動層乾燥機を用い排気温度６０℃以下にて９０分間乾燥してＡ顆粒を得た。
次に、メタケイ酸アルミン酸マグネシウム（５２．４ｋｇ）、結晶セルロース（１４．９５ｋｇ）、クロスカルメロースナトリウム（１１．９０ｋｇ）を攪拌造粒機に入れ混合した。その後、メタノール（５７．８ｋｇ）及びジクロロメタン（５７．８ｋｇ）にシルニジピン（４．７６ｋｇ）、マクロゴール４００（３．３３ｋｇ）及びヒプロメロースフタル酸エステル（１９．０４ｋｇ）を溶解した結合液を投入し造粒した。造粒後、整粒機（コーミル）により整粒（スクリーン：１．６ｍｍ）し、流動層乾燥機を用い排気温度６０℃以下にて９０分間乾燥してＢ顆粒を得た。
上記で得られたＡ顆粒とＢ顆粒を混合し、表１に示す処方のシルニジピン顆粒を得た。
[Example 1]
Magnesium aluminate metasilicate (22.4 kg), crystalline cellulose (6.41 kg), lactose hydrate (4.86 kg) and croscarmellose sodium (5.10 kg) were placed in a stirring granulator and mixed. Thereafter, a binder solution in which cilnidipine (2.04 kg), macrogol 400 (1.43 kg) and hydroxypropylcellulose (8.16 kg) are dissolved in methanol (28.3 kg) and dichloromethane (8.5 kg) is added and granulated. did. After granulation, the mixture was sized (screen: 1.6 mm) with a sizing machine (Comil) and dried for 90 minutes at an exhaust temperature of 60 ° C. or lower using a fluidized bed dryer to obtain A granules.
Next, magnesium aluminate metasilicate (52.4 kg), crystalline cellulose (14.95 kg) and croscarmellose sodium (11.90 kg) were placed in a stirring granulator and mixed. Then, a binding solution in which cilnidipine (4.76 kg), Macrogol 400 (3.33 kg) and hypromellose phthalate (19.04 kg) were dissolved in methanol (57.8 kg) and dichloromethane (57.8 kg) was added. Then granulated. After granulation, it was sized (screen: 1.6 mm) with a sizing machine (Comil) and dried for 90 minutes at an exhaust temperature of 60 ° C. or less using a fluidized bed dryer to obtain B granules.
The A granules and B granules obtained above were mixed to obtain cilnidipine granules having the formulation shown in Table 1.
上記のシルニジピン顆粒（２９６６．４ｇ）、バルサルタン（９６９．６ｋｇ）、結晶セルロース（９３６ｇ）、クロスカルメロースナトリウム（９６０ｇ）、含水二酸化ケイ素（９６ｇ）及びステアリン酸マグネシウム（２４ｇ）を混合機を用いて２０分間混合し、混合末を得た。得られた混合末を乾式造粒（ロール圧力：６Ｍｐａ）にてフレークとし、整粒機（コーミル）により整粒（スクリーン：１．６ｍｍ）し、表２に示す処方のシルニジピン・バルサルタン配合顆粒を得た。 Using a mixer, the above cilnidipine granules (2966.4 g), valsartan (969.6 kg), crystalline cellulose (936 g), croscarmellose sodium (960 g), hydrous silicon dioxide (96 g) and magnesium stearate (24 g) Mix for 20 minutes to obtain a mixed powder. The obtained mixed powder is made into flakes by dry granulation (roll pressure: 6 Mpa), sized by a granulator (Comil) (screen: 1.6 mm), and granulated cilnidipine / valsartan blends having the formulation shown in Table 2 are obtained. Obtained.
上記にて得たシルニジピン・バルサルタン配合顆粒に、表３に示す処方となるようにステアリン酸マグネシウムを添加・混合し、打錠機にて圧縮成形することにより表３に示す処方の錠剤を得た。錠剤中に含まれるシルニジピンの割合：２．０％、バルサルタンの割合：１６．０％、第１の崩壊剤の割合：５．０％、第２の崩壊剤の割合：１６．０％（崩壊剤合計：２１．０％） Magnesium stearate was added to and mixed with the silnidipine / valsartan blended granule obtained above so as to have the formulation shown in Table 3, and the tablets having the formulation shown in Table 3 were obtained by compression molding with a tableting machine. . The proportion of cilnidipine contained in the tablet: 2.0%, the proportion of valsartan: 16.0%, the proportion of the first disintegrant: 5.0%, the proportion of the second disintegrant: 16.0% (disintegration) Agent total: 21.0%)
［実施例２］
バルサルタン（４００ｇ）、結晶セルロース（３４０ｇ）及びクロスカルメロースナトリウム（４００ｇ）を流動層造粒機に入れ、メタノール（２８０ｇ）及びジクロロメタン（１１２０ｇ）にヒドロキシプロピルセルロース（１００ｇ）を溶解した結合液を噴霧（スプレー速度７０ｇ／ｍＬ、排気温度３０℃）して表４に示す処方のバルサルタン顆粒を得た。
[Example 2]
Valsartan (400 g), crystalline cellulose (340 g) and croscarmellose sodium (400 g) are put into a fluid bed granulator, and a combined solution in which hydroxypropyl cellulose (100 g) is dissolved in methanol (280 g) and dichloromethane (1120 g) is sprayed. (Spray speed 70 g / mL, exhaust temperature 30 ° C.) to obtain valsartan granules having the formulation shown in Table 4.
上記にて得たバルサルタン顆粒、実施例１にて得たシルニジピン顆粒及びステアリン酸マグネシウムを表５に示す処方となるように添加・混合し、打錠機にて圧縮成形することにより表５に示す処方の錠剤を得た。錠剤中に含まれるシルニジピンの割合：２．０％、バルサルタンの割合：１６．０％、第１の崩壊剤の割合：５．０％、第２の崩壊剤の割合：１６．０％（崩壊剤合計：２１．０％） The valsartan granule obtained above, the cilnidipine granule obtained in Example 1 and magnesium stearate were added and mixed so as to have the formulation shown in Table 5, and compression-molded with a tableting machine to show in Table 5. A prescription tablet was obtained. The proportion of cilnidipine contained in the tablet: 2.0%, the proportion of valsartan: 16.0%, the proportion of the first disintegrant: 5.0%, the proportion of the second disintegrant: 16.0% (disintegration) Agent total: 21.0%)
［実施例３］
バルサルタン（２００ｇ）、結晶セルロース（５５０ｇ）、クロスカルメロースナトリウム（２７５ｇ）、乳糖水和物（９０ｇ）を流動層造粒機に入れ、メタノール（１１２０ｇ）及びジクロロメタン（２８０ｇ）にシルニジピン（２５ｇ）、ヒドロキシプロピルセルロース（１００ｇ）を溶解した結合液を噴霧（スプレー速度７０ｇ／ｍＬ、排気温度３０℃）して表６に示す処方のシルニジピン・バルサルタン配合顆粒を得た。
[Example 3]
Valsartan (200 g), crystalline cellulose (550 g), croscarmellose sodium (275 g), lactose hydrate (90 g) were placed in a fluidized bed granulator, cilnidipine (25 g) in methanol (1120 g) and dichloromethane (280 g), A binding solution in which hydroxypropylcellulose (100 g) was dissolved was sprayed (spray rate 70 g / mL, exhaust temperature 30 ° C.) to obtain granules containing cilnidipine / valsartan having the formulation shown in Table 6.
上記にて得たシルニジピン・バルサルタン配合顆粒に表７に示す処方となるようにステアリン酸マグネシウムを添加・混合し、打錠機にて圧縮成形することにより表７に示す処方の錠剤を得た。錠剤中に含まれるシルニジピンの割合：２．０％、バルサルタンの割合：１６．０％、崩壊剤合計：２２．０％ Magnesium stearate was added to and mixed with the silnidipine / valsartan blend granule obtained above so that the formulation shown in Table 7 was obtained, and the tablets having the formulation shown in Table 7 were obtained by compression molding with a tableting machine. Ratio of cilnidipine contained in the tablet: 2.0%, ratio of valsartan: 16.0%, total disintegrant: 22.0%
［比較例１］
バルサルタン（４０ｇ）、シルニジピン（５ｇ）、結晶セルロース（１２３ｇ）、クロスカルメロースナトリウム（８０ｇ）及びステアリン酸マグネシウム（２ｇ）を添加・混合し、打錠機にて圧縮成形することにより表８に示す処方の錠剤を得た。錠剤中に含まれるシルニジピンの割合：２．０％、バルサルタンの割合：１６．０％、崩壊剤合計：３２．０％）
なお、バルサルタンについては、粒子径Ｄ９０が２０μｍ以下の原薬を使用した。
[Comparative Example 1]
Table 8 shows valsartan (40 g), cilnidipine (5 g), crystalline cellulose (123 g), croscarmellose sodium (80 g) and magnesium stearate (2 g) added and mixed, and compression molded with a tableting machine. A prescription tablet was obtained. (The ratio of cilnidipine contained in the tablet: 2.0%, the ratio of valsartan: 16.0%, the total disintegrant: 32.0%)
For valsartan, a drug substance having a particle diameter D90 of 20 μm or less was used.
［比較例２］
バルサルタン（２００ｇ）、シルニジピン（２５ｇ）、結晶セルロース（５５０ｇ）、クロスカルメロースナトリウム（２７５ｇ）及び乳糖水和物（９０ｇ）を流動層造粒機に入れ、水（１４００ｇ）にヒドロキシプロピルセルロース（１００ｇ）を溶解した結合液を噴霧（スプレー速度７０ｇ／ｍＬ、排気温度３０℃）して表６のシルニジピン・バルサルタン配合顆粒を得た。
その後、実施例３の方法により表７に示す処方の錠剤を得た。錠剤中に含まれるシルニジピンの割合：２．０％、バルサルタンの割合：１６．０％、崩壊剤合計：２２．０％
[Comparative Example 2]
Valsartan (200 g), cilnidipine (25 g), crystalline cellulose (550 g), croscarmellose sodium (275 g) and lactose hydrate (90 g) were placed in a fluid bed granulator, and hydroxypropyl cellulose (100 g) in water (1400 g). ) Was dissolved (spray speed 70 g / mL, exhaust temperature 30 ° C.) to obtain granules containing cilnidipine / valsartan shown in Table 6.
Then, the tablet of the prescription shown in Table 7 was obtained by the method of Example 3. Ratio of cilnidipine contained in the tablet: 2.0%, ratio of valsartan: 16.0%, total disintegrant: 22.0%
［比較例３］
バルサルタン（４８４．８ｇ）、結晶セルロース（３７８ｇ）、クロスカルメロースナトリウム（４８０ｇ）及びヒドロキシプロピルセルロース（１５０ｇ）を攪拌造粒機に入れ、水（２１００ｇ）を投入し造粒した。造粒後、整粒機（コーミル）により整粒（スクリーン：１．６ｍｍ）し、流動層乾燥機を用い排気温度６０℃以下にて４５分間乾燥して表９に示す処方のバルサルタン顆粒を得た。
[Comparative Example 3]
Valsartan (484.8 g), crystalline cellulose (378 g), croscarmellose sodium (480 g) and hydroxypropylcellulose (150 g) were placed in a stirring granulator, and water (2100 g) was added for granulation. After granulation, it is sized (screen: 1.6 mm) with a sizing machine (Comil) and dried for 45 minutes at an exhaust temperature of 60 ° C. or less using a fluidized bed dryer to obtain valsartan granules with the formulation shown in Table 9. It was.
上記にて得たバルサルタン顆粒、実施例１にて得たシルニジピン顆粒及びステアリン酸マグネシウムを表９に示す処方となるように添加・混合し、打錠機にて圧縮成形することにより表１０に示す処方の錠剤を得た。錠剤中に含まれるシルニジピンの割合：２．０％、バルサルタンの割合：１６．０％、第１の崩壊剤の割合：５．０％、第２の崩壊剤の割合：１６．０％（崩壊剤合計：２１．０％） The valsartan granule obtained above, the cilnidipine granule obtained in Example 1 and magnesium stearate were added and mixed so as to have the formulation shown in Table 9, and compression-molded with a tableting machine and shown in Table 10 A prescription tablet was obtained. The proportion of cilnidipine contained in the tablet: 2.0%, the proportion of valsartan: 16.0%, the proportion of the first disintegrant: 5.0%, the proportion of the second disintegrant: 16.0% (disintegration) Agent total: 21.0%)
［試験例１］
実施例１〜３、比較例１〜３の錠剤中のバルサルタンの粒度を測定した。バルサルタンの粒度分布測定については、５０ｍｇのバルサルタンを分散溶液（シリコンオイル：０．２％スパン８５含有ｎ−ヘプタン／６０：４０ｖ／ｖ）に分散した後、Ｍａｌｖｅｒｎ Ｐａｒｔｉｃｌｅ ｓｉｚｅ ａｎａｌｙｚｅｒを用いて粒度を測定し、Ｄ９０を算出した。
[Test Example 1]
The particle size of valsartan in the tablets of Examples 1 to 3 and Comparative Examples 1 to 3 was measured. For the particle size distribution measurement of valsartan, 50 mg of valsartan was dispersed in a dispersion solution (silicon oil: n-heptane containing 0.2% span 85/60: 40 v / v), and then the particle size was measured using Malvern Particle size analyzer. D90 was calculated.
［試験例２］
顆粒の粒度分布測定については、自動乾式音波ふるい分け測定器ロボットシフターＲＰＳ−９５Ｃにて、目開き８５０μｍ、５００μｍ、３５５μｍ、２５０μｍ、１８０μｍ、１５０μｍ、１０６μｍ及び７５μｍの篩を用いて粒度分布を測定し、Ｄ１０、Ｄ５０、Ｄ９０を算出した。
[Test Example 2]
For granule particle size distribution measurement, the particle size distribution was measured with an automatic dry sonic sieving measuring instrument robot shifter RPS-95C using a sieve having openings of 850 μm, 500 μm, 355 μm, 250 μm, 180 μm, 150 μm, 106 μm and 75 μm, D10, D50, and D90 were calculated.
［試験例３］
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、シルニジピンの溶出率を算出した。
なお、実施例１、２及び比較例１については、１錠を用い、実施例３及び比較例２については２錠を用いて実施した。
[Test Example 3]
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 elution rate of cilnidipine.
For Examples 1 and 2 and Comparative Example 1, one tablet was used, and for Example 3 and Comparative Example 2, two tablets were used.
［試験例４］
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７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。
なお、実施例１、２及び比較例１については、１錠を用い、実施例３及び比較例２については２錠を用いて実施した。
[Test Example 4]
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 7 and 90 minutes after the start of the test were collected and tested by liquid chromatography to calculate the elution rate of cilnidipine.
For Examples 1 and 2 and Comparative Example 1, one tablet was used, and for Example 3 and Comparative Example 2, two tablets were used.
＜結果＞
バルサルタンの粒度を測定した結果、実施例１〜３、比較例１〜３に使用したバルサルタンの粒度は、すべてＤ９０が２０μｍ以下であった。
実施例１のシルニジピン顆粒及びシルニジピン・バルサルタン配合顆粒について、試験例２に従い粒度分布を測定した。その結果を表１１に記載する。
<Result>
As a result of measuring the particle size of valsartan, the particle size of valsartan used in Examples 1 to 3 and Comparative Examples 1 to 3 was all D90 of 20 μm or less.
The particle size distribution of the cilnidipine granule and the cilnidipine valsartan combination granule of Example 1 was measured according to Test Example 2. The results are listed in Table 11.
実施例１〜３、比較例１〜３にて作成し錠剤を試験例３及び４に従い溶出率を確認した。その結果を表１２に記載する。
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基準値を設定し、シルニジピン、バルサルタンそれぞれの溶出率が基準値を満たすものを○、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、すべて基準値内の溶出率となったが、比較例１〜３については、基準値内の溶出率が得られなかった。
The elution rate was confirmed according to Test Examples 3 and 4 prepared in Examples 1-3 and Comparative Examples 1-3. The results are listed in Table 12.
The reference values were set in consideration of the dissolution rate of Atelec (registered trademark) tablets, which are commercially available cilnidipine, and Dioban (registered trademark) tablets, which are commercially available valsartan. Those satisfying the conditions were evaluated as ◯, and those not satisfying were evaluated as ×.
As a result, for Examples 1 to 3, the elution rate was within the reference value, but for Comparative Examples 1 to 3, the elution rate within the reference value was not obtained.
本発明の方法により製造された医薬製剤は、カルシウム拮抗薬の溶出速度を高め、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 produced by the method of the present invention can increase the dissolution rate of the calcium antagonist, and can realize an elution profile close to that of the commercially available calcium antagonist preparation and the angiotensin II receptor antagonist preparation. Therefore, it is very useful industrially.
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| KR101931489B1 (en) | 2018-12-24 |
| TW201427720A (en) | 2014-07-16 |
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