TWI586353B - Pharmaceutical preparations containing calcium antagonists and angiotensin II receptor antagonists - Google Patents

Pharmaceutical preparations containing calcium antagonists and angiotensin II receptor antagonists Download PDF

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TWI586353B
TWI586353B TW102136759A TW102136759A TWI586353B TW I586353 B TWI586353 B TW I586353B TW 102136759 A TW102136759 A TW 102136759A TW 102136759 A TW102136759 A TW 102136759A TW I586353 B TWI586353 B TW I586353B
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disintegrant
mass
angiotensin
antagonist
calcium
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TW201427661A (en
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Yukiko Tanaka
Ichirou Hara
Hiroyuki Higuchi
Tomoya Onoshita
Akiko Teramoto
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Ea Pharma Co Ltd
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Description

含有鈣拮抗劑及血管張力素II受體拮抗劑之醫藥製劑 Medicinal preparation containing calcium antagonist and angiotensin II receptor antagonist

本發明係關於含有鈣拮抗劑及血管張力素II受體拮抗劑作為有效成分之醫藥製劑。 The present invention relates to a pharmaceutical preparation containing a calcium antagonist and an angiotensin II receptor antagonist as an active ingredient.

高血壓係指血壓變得持續較正常範圍更高的狀態。高血壓係生活習慣所導致的疾病之一,若高血壓狀態持續,則會併發動脈硬化症、或缺血性心臟病、腦中風等。 Hypertension refers to a state in which blood pressure continues to be higher than the normal range. One of the diseases caused by high blood pressure living habits, if the state of hypertension persists, it may be complicated by atherosclerosis, or ischemic heart disease, or stroke.

目前,為了治療高血壓患者,使用有高血壓治療劑(降血壓劑)的血壓控制乃一般所廣泛進行。高血壓治療劑方面,一般使用有鈣拮抗劑(CCB)、血管張力素交換酵素抑制劑、血管張力素II受體拮抗劑(ARB)等。 At present, in order to treat patients with hypertension, blood pressure control using a therapeutic agent for hypertension (hypertensive agent) is generally carried out widely. In the treatment of hypertension, calcium antagonists (CCB), angiotensin exchange enzyme inhibitors, and angiotensin II receptor antagonists (ARB) are generally used.

鈣拮抗劑(CCB),已知有藉由抑制Ca2+透過離子通道攝入細胞內,使平滑肌之收縮減弱化,而發揮降血壓作用。鈣拮抗劑,係目前在日本最為廣泛運用的降血壓劑,由於嚴重的副作用少,且價格僅次於利尿劑而為低價,因此一般推薦作為第一選擇藥物。 Calcium antagonists (CCB) are known to exert a blood pressure lowering effect by inhibiting the absorption of Ca 2+ into the cells through the ion channel and attenuating the contraction of smooth muscle. Calcium antagonists, which are currently the most widely used antihypertensive agents in Japan, are generally recommended as the first choice because they have few serious side effects and are second only to diuretics and are low in price.

血管張力素II受體拮抗劑(ARB),已知有藉由對於血 管張力素II受體產生特異性拮抗,而抑制經腎素-血管張力素系統所產生之具有強的昇壓作用之血管張力素II的生理作用,而發揮降血壓作用。 Angiotensin II receptor antagonist (ARB), known to be used for blood The tensin II receptor produces specific antagonism, and inhibits the physiological action of angiotensin II, which has a strong pressor action by the renin-angiotensin system, and exerts a blood pressure lowering effect.

如上所述,鈣拮抗劑與血管張力素II受體拮抗劑,係指藉由不同的機制而獲得降血壓作用。因而,對於以單劑投予不太能觀察到症狀之改善的高血壓患者而言,在提高治療效果的目的下,亦嘗試有將鈣拮抗劑與血管張力素II受體拮抗劑合併使用(專利文獻1)。 As described above, a calcium antagonist and an angiotensin II receptor antagonist mean that a blood pressure lowering effect is obtained by a different mechanism. Therefore, for hypertensive patients who are less likely to observe an improvement in symptoms in a single dose, the use of a calcium antagonist in combination with an angiotensin II receptor antagonist has also been attempted for the purpose of improving the therapeutic effect ( Patent Document 1).

[先前技術文獻] [Previous Technical Literature] [專利文獻] [Patent Literature]

[專利文獻1]日本特開2008-44871號公報 [Patent Document 1] Japanese Patent Laid-Open Publication No. 2008-44871

然而,兩藥劑皆欠缺保存安定性,且鈣拮抗劑係具有對於光會進行經時性分解的問題點。另一方面,血管張力素II受體拮抗劑,係具有若在高的溫度條件下進行保存,則溶出速度會異常地降低的問題點。因此,鈣拮抗劑製劑係需要在遮光條件下進行保存,血管張力素II受體拮抗劑製劑係需要留意溫度以進行保存。 However, both agents lack storage stability, and calcium antagonists have problems with temporal decomposition of light. On the other hand, an angiotensin II receptor antagonist has a problem that the dissolution rate is abnormally lowered when stored under a high temperature condition. Therefore, calcium antagonist preparations need to be preserved under shading conditions, and angiotensin II receptor antagonist preparations require attention to temperature for preservation.

若僅將兩藥劑合併使用,則只要分別以不同的方法將兩藥劑個別地進行保存即可,因此,上述缺點並非大問題。 If only two drugs are used in combination, it is only necessary to separately store the two drugs in different ways. Therefore, the above disadvantages are not a big problem.

然而,於摻合劑的情況中,由於無法將兩藥劑個別地 進行保存,因此無法以併用藥的方式解決問題。因而,必須一面經常留意溫度與光兩者一面進行保存。 However, in the case of a blending agent, since the two agents cannot be individually Save it, so you can't solve the problem by using it together. Therefore, it is necessary to always pay attention to both the temperature and the light for preservation.

此外,鈣拮抗劑及血管張力素II受體拮抗劑之原料藥(drug substance),皆具有對水之溶解度低,且即使投予原料藥,直至展現效果為止亦耗費時間的問題。例如,作為鈣拮抗劑之一的西尼地平(Cilnidipine),係在室溫時對水之溶解度為數ng/mL,作為血管張力素II受體拮抗劑之一的纈沙坦(Valsartan),係對水之溶解度為0.17mg/mL左右。因此,目前市售之鈣拮抗劑製劑及血管張力素II受體拮抗劑製劑,皆為了提高溶出速度而精心設計。 Further, the drug substance of the calcium antagonist and the angiotensin II receptor antagonist has a low solubility in water, and it takes time even if the drug substance is administered until the effect is exhibited. For example, Cilnidipine, one of the calcium antagonists, has a solubility in water of several ng/mL at room temperature, and is one of the angiotensin II receptor antagonists, Valsartan. The solubility in water is about 0.17 mg/mL. Therefore, currently available calcium antagonist preparations and angiotensin II receptor antagonist preparations are carefully designed to increase the dissolution rate.

然而,市售之鈣拮抗劑製劑、與血管張力素II受體拮抗劑製劑,由於分別以個別的方法提昇溶出速度,因此不易以一種醫藥製劑(摻合劑)實現兩者之溶出輪廓。 However, commercially available calcium antagonist preparations and angiotensin II receptor antagonist preparations are difficult to achieve a dissolution profile by a single pharmaceutical preparation (admixture) because the dissolution rate is increased by an individual method.

本發明係鑑於上述問題點而完成者,其目的為提供一種血管張力素II受體拮抗劑之保存安定性高,藉此得以緩和保存條件之醫藥製劑。再者,目的為提供一種醫藥製劑(摻合劑),其係可實現與市售之鈣拮抗劑製劑及血管張力素II受體拮抗劑製劑各自的溶出輪廓(elution profile)接近之溶出輪廓。 The present invention has been made in view of the above problems, and an object thereof is to provide a pharmaceutical preparation which has high storage stability of an angiotensin II receptor antagonist and thereby alleviates storage conditions. Further, it is an object of the invention to provide a pharmaceutical preparation (admixture) which achieves a dissolution profile close to the elution profile of each of a commercially available calcium antagonist preparation and an angiotensin II receptor antagonist preparation.

為了解決上述課題,本發明係採用了以下的構造。 In order to solve the above problems, the present invention adopts the following configuration.

(1)一種醫藥製劑,其特徵為含有作為有效成分之鈣拮抗劑及血管張力素II受體拮抗劑、與5質量%以 上之崩解劑,且至少鈣拮抗劑為固體分散體之形態。 (1) A pharmaceutical preparation characterized by containing a calcium antagonist as an active ingredient and an angiotensin II receptor antagonist, and 5% by mass The above disintegrant, and at least the calcium antagonist is in the form of a solid dispersion.

(2)如上述(1)所記載之醫藥製劑,其中鈣拮抗劑為顆粒之形態,且血管張力素II受體拮抗劑係以覆蓋含有該鈣拮抗劑之顆粒的一部分或全部的方式存在。 (2) The pharmaceutical preparation according to the above (1), wherein the calcium antagonist is in the form of particles, and the angiotensin II receptor antagonist is present in such a manner as to cover a part or all of the particles containing the calcium antagonist.

(3)如上述(2)所記載之醫藥製劑,其中崩解劑被包含於前述顆粒中。 (3) The pharmaceutical preparation according to the above (2), wherein the disintegrating agent is contained in the particles.

(4)如上述(2)或(3)所記載之醫藥製劑,其中崩解劑,係以與前述血管張力素II受體拮抗劑一起覆蓋前述顆粒的一部分或全部的方式存在。 (4) The pharmaceutical preparation according to the above (2) or (3), wherein the disintegrating agent is present so as to cover a part or all of the particles together with the angiotensin II receptor antagonist.

(5)如上述(1)~(4)中任一項所記載之醫藥製劑,其中崩解劑,係由交聯羧甲基纖維素鈉(croscarmellose sodium)、交聯羧甲基纖維素鈣、低取代度羥丙基纖維素、羧甲基澱粉鈉、交聯聚維酮及α化澱粉所成之群中選出的至少1種。 (5) The pharmaceutical preparation according to any one of the above (1), wherein the disintegrating agent is croscarmellose sodium or croscarmellose calcium. At least one selected from the group consisting of low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, crospovidone, and gelatinized starch.

(6)如上述(1)~(5)中任一項所記載之醫藥製劑,其中前述鈣拮抗劑,係由西尼地平(Cilnidipine)、安洛待平(Amlodipine)、尼伐地平(Nilvadipine)、尼非待平(Nifedipine)、阿折地平(Azelnidipine)、尼索地平(Nisoldipine)、尼卡地平(Nicardipine)、尼莫地平(Nimodipine)、尼川待平(Nitrendipine)及曼尼待平(Manidipine)所成之群中選出的至少1種。 (6) The pharmaceutical preparation according to any one of the above (1), wherein the calcium antagonist is Cilinidipine, Amlodipine, Nilvadipine (Nilvadipine) ), Nifedipine, Azelnidipine, Nisoldipine, Nicardipine, Nimodipine, Nitrindipine, and Manitipine At least one selected from the group (Manidipine).

(7)如上述(6)所記載之醫藥製劑,其中前述鈣拮抗劑為西尼地平(Cilnidipine)。 (7) The pharmaceutical preparation according to the above (6), wherein the calcium antagonist is cilnidipine.

(8)如上述(1)~(7)中任一項所記載之醫藥製劑,其中前述血管張力素II受體拮抗劑,係由纈沙坦(Valsartan)、坎地 沙坦(Candesartan)、艾比沙坦(Irbesartan)、氯沙坦(losartan)、替米沙坦(Telmisartan)、奧美沙坦(Olmesartan)、艾比沙坦(Irbesartan)及依普沙坦(Eprosartan)所成之群中選出的至少1種。 (8) The pharmaceutical preparation according to any one of the above (1), wherein the angiotensin II receptor antagonist is valsartan or valer. Candesartan, Irbesartan, losartan, telmisartan, olmesartan, Irbesartan and Eprosartan At least one selected from the group.

(9)如上述(8)所記載之醫藥製劑,其中前述血管張力素II受體拮抗劑為纈沙坦(Valsartan)。 (9) The pharmaceutical preparation according to the above (8), wherein the angiotensin II receptor antagonist is valsartan.

(10)如上述(1)~(9)中任一項所記載之醫藥製劑,其中鈣拮抗劑與血管張力素II受體拮抗劑之質量比為1:1~1:32。 (10) The pharmaceutical preparation according to any one of the above (1), wherein the mass ratio of the calcium antagonist to the angiotensin II receptor antagonist is 1:1 to 1:32.

(11)如上述(1)~(10)中任一項所記載之醫藥製劑,其係含有塗佈被膜,該塗佈被膜係含有由黃色三氧化二鐵、三氧化二鐵及黑氧化鐵所成之群中選出的至少1種之著色劑。 (11) The pharmaceutical preparation according to any one of the above aspects, comprising a coating film containing yellow ferric oxide, ferric oxide and black iron oxide At least one coloring agent selected from the group formed.

(12)如上述(11)所記載之醫藥製劑,其中前述著色劑的比例,相對於塗佈被膜100質量份為0.1~5質量份之範圍內。 (12) The pharmaceutical preparation according to the above (11), wherein the ratio of the coloring agent is in the range of 0.1 to 5 parts by mass based on 100 parts by mass of the coating film.

(13)如上述(11)或(12)所記載之醫藥製劑,其中前述塗佈被膜係進一步含有氧化鈦。 (13) The pharmaceutical preparation according to the above (11) or (12), wherein the coating film system further contains titanium oxide.

(14)如上述(1)~(13)中任一項所記載之醫藥製劑,其係錠劑、膠囊劑、細粒劑或顆粒之形態。 (14) The pharmaceutical preparation according to any one of the above (1) to (13), which is in the form of a tablet, a capsule, a fine granule or a granule.

(15)如上述(14)所記載之醫藥製劑,其係錠劑之形態。 (15) The pharmaceutical preparation according to the above (14), which is in the form of a tablet.

(16)如上述(1)~(15)中任一項所記載之醫藥製劑,其係降血壓劑。 (16) The pharmaceutical preparation according to any one of the above (1) to (15) which is a blood pressure lowering agent.

本發明之醫藥製劑,係可提昇血管張力素II受體拮抗劑之保存安定性。此外,該醫藥製劑係可實現與 市售之鈣拮抗劑製劑及血管張力素II受體拮抗劑各自的溶出輪廓(elution profile)接近之溶出輪廓。 The pharmaceutical preparation of the present invention can enhance the preservation stability of an angiotensin II receptor antagonist. In addition, the pharmaceutical preparation can be achieved with The elution profile of each of the commercially available calcium antagonist formulations and the angiotensin II receptor antagonist is close to the dissolution profile.

以下,對於用以實施本發明之形態進行說明。 Hereinafter, embodiments for carrying out the invention will be described.

本發明之醫藥製劑,其特徵為含有作為有效成分之鈣拮抗劑及血管張力素II受體拮抗劑、與5質量%以上之崩解劑,且至少鈣拮抗劑為固體分散體之形態。 The pharmaceutical preparation of the present invention is characterized in that it contains a calcium antagonist and an angiotensin II receptor antagonist as an active ingredient, and a disintegrant of 5% by mass or more, and at least a calcium antagonist is in the form of a solid dispersion.

此外,本發明之醫藥製劑,較佳為含有含鈣拮抗劑之顆粒與血管張力素II受體拮抗劑,更佳為血管張力素II受體拮抗劑以覆蓋含有鈣拮抗劑之顆粒的一部分或全部的方式存在。如此之醫藥製劑係可列舉例如:血管張力素II受體拮抗劑覆蓋含鈣拮抗劑之顆粒的周圍而成之顆粒、細粒、或將1或複數含鈣拮抗劑之顆粒與血管張力素II受體拮抗劑的混合物進行製錠所得之錠劑等。 Further, the pharmaceutical preparation of the present invention preferably comprises a calcium-containing antagonist-containing granule and an angiotensin II receptor antagonist, more preferably an angiotensin II receptor antagonist to cover a part of the granule containing the calcium antagonist or All the way there is. Such a pharmaceutical preparation may, for example, be an angiotensin II receptor antagonist covering a particle surrounded by a calcium-containing antagonist, a fine particle, or a particle of 1 or a plurality of calcium-containing antagonists and angiotensin II. A mixture of receptor antagonists is used to prepare tablets and the like obtained by tableting.

此外,本發明之醫藥製劑,較佳為血管張力素II受體拮抗劑以覆蓋含有鈣拮抗劑之顆粒的一部分或全部的方式存在,且至少鈣拮抗劑為固體分散體之形態。血管張力素II受體拮抗劑與鈣拮抗劑一同為固體分散體之形態亦可。 Further, in the pharmaceutical preparation of the present invention, preferably, the angiotensin II receptor antagonist is present in such a manner as to cover a part or all of the particles containing the calcium antagonist, and at least the calcium antagonist is in the form of a solid dispersion. The angiotensin II receptor antagonist may be in the form of a solid dispersion together with the calcium antagonist.

於本說明書及請求項之範圍中,「固體分散體」係意味著:於惰性載體之中藥物呈單分子狀分散的固體。於固體分散體內,藥物係以非晶質之狀態存在於載體 中。惰性載體係只要是高分子化合物則可無特別限制地使用,可列舉例如:結合劑、懸浮劑、界面活性劑等之高分子化合物。懸浮劑係可列舉:阿拉伯膠、黃原膠、海藻酸鈉等。界面活性劑係可列舉:聚氧乙烯硬化蓖麻油、月桂基硫酸鈉、聚氧乙烯-聚氧丙二醇等。 In the context of the present specification and claims, "solid dispersion" means that the drug is a monomolecularly dispersed solid in an inert carrier. In a solid dispersion, the drug is present in the carrier in an amorphous state. in. The inert carrier is not particularly limited as long as it is a polymer compound, and examples thereof include a polymer compound such as a binder, a suspending agent, and a surfactant. Examples of the suspending agent include gum arabic, xanthan gum, sodium alginate, and the like. Examples of the surfactant include polyoxyethylene hardened castor oil, sodium lauryl sulfate, polyoxyethylene-polyoxypropylene glycol, and the like.

固體分散體,例如,可使用使藥物及載體成分溶解於有機溶劑的溶液,經造粒之後,使其乾燥而得到。 The solid dispersion can be obtained, for example, by using a solution in which a drug and a carrier component are dissolved in an organic solvent, followed by granulation and drying.

<鈣拮抗劑> <calcium antagonist>

鈣拮抗劑,係藉由抑制Ca2+透過離子通道攝入細胞內,使平滑肌之收縮減弱化,而展現血壓之下降作用的藥物。 A calcium antagonist is a drug that exhibits a decrease in blood pressure by inhibiting the absorption of Ca 2+ through an ion channel and attenuating the contraction of smooth muscle.

本發明所使用的鈣拮抗劑係以1,4-二氫吡啶衍生物為佳,以由西尼地平(Cilnidipine)、安洛待平(Amlodipine)、尼伐地平(Nilvadipine)、尼非待平(Nifedipine)、阿折地平(Azelnidipine)、尼索地平(Nisoldipine)、尼卡地平(Nicardipine)、尼莫地平(Nimodipine)、尼川待平(Nitrendipine)及曼尼待平(Manidipine)所成之群中選出的至少1種為更佳。此等當中,係以西尼地平(Cilnidipine;化學名:(±)-2-methoxyethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate)為特佳。 The calcium antagonist used in the present invention is preferably a 1,4-dihydropyridine derivative, which is composed of cilnidipine, Amlodipine, Nilvadipine, and Nifedi. (Nifedipine), Azelnidipine, Nisoldipine, Nicardipine, Nimodipine, Nitrindipine, and Manidipine At least one selected from the group is better. Among these, it is cilnidipine (chemical name: (±)-2-methoxyethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate) is particularly preferred.

西尼地平(Cilnidipine),係作為將L型鈣通道及N型鈣通道一同阻滯之L/N型鈣拮抗劑的周知之化合物,且能夠藉由周知之製造方法來進行製造。此外,亦能夠取得市 售之該製劑。再者,西尼地平(Cilnidipine)亦可藉由從該製劑萃取等而取得。 Cilnidipine is a well-known compound which is an L/N type calcium antagonist which blocks an L-type calcium channel and an N-type calcium channel together, and can be manufactured by a well-known manufacturing method. In addition, the city can also be obtained. The preparation is sold. Further, Cilnidipine can also be obtained by extraction from the preparation or the like.

鈣拮抗劑亦可因應需要,而作為藥理上所容許之鹽、水合物、溶劑合物。藥理學上所容許之鹽係可列舉例如:與無機酸之鹽(鹽酸鹽、氫溴酸鹽、磷酸鹽、硫酸鹽等)、與有機酸之鹽(乙酸鹽、琥珀酸鹽、馬來酸鹽、富馬酸鹽、蘋果酸鹽、酒石酸鹽等)等。進而,於本發明中所使用的鈣拮抗劑亦可因應需要,而適當的使用其之光學活性體。 Calcium antagonists can also be used as pharmacologically acceptable salts, hydrates, and solvates, as needed. Pharmacologically acceptable salts include, for example, salts with inorganic acids (hydrochloride, hydrobromide, phosphate, sulfate, etc.), and salts with organic acids (acetate, succinate, Malay). Acid salt, fumarate, malate, tartrate, etc.). Further, the calcium antagonist used in the present invention may suitably use an optically active substance thereof as needed.

鈣拮抗劑,相對於醫藥製劑100質量%,較佳為含有0.1~10質量%,更佳為含有0.5~5質量%。 The calcium antagonist is preferably contained in an amount of 0.1 to 10% by mass, more preferably 0.5 to 5% by mass based on 100% by mass of the pharmaceutical preparation.

<血管張力素II受體拮抗劑> <Angiotensin II receptor antagonist>

血管張力素II受體拮抗劑,係指藉由與作為昇壓物質之血管張力素II拮抗,阻礙血管張力素II與血管張力素II受體結合,而展現血壓之下降作用的藥物。血管張力素II受體拮抗劑係可列舉例如:纈沙坦(Valsartan)、坎地沙坦(Candesartan)、氯沙坦(losartan)、替米沙坦(Telmisartan)、奧美沙坦(Olmesartan)、艾比沙坦(Irbesartan)、依普沙坦(Eprosartan)等。其中,係以纈沙坦(化學名:(-)-N-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-N-valeryl-L-valine)為特佳。 An angiotensin II receptor antagonist is a drug which exhibits a blood pressure lowering effect by blocking angiotensin II binding to angiotensin II receptor by antagonizing angiotensin II as a blood pressure-reducing substance. Examples of the angiotensin II receptor antagonist include valsartan, candesartan, losartan, telmisartan, olmesartan, and olmesartan. Irbesartan, Eprosartan, etc. Among them, valsartan (chemical name: (-)-N-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-N-valeryl-L-valine) is particularly preferred.

血管張力素II受體拮抗劑亦可因應需要,而作為藥理上所容許之鹽、水合物、溶劑合物。藥理學上所容許之 鹽係可列舉例如:與無機酸之鹽(鹽酸鹽、氫溴酸鹽、磷酸鹽、硫酸鹽等)、與有機酸之鹽(乙酸鹽、琥珀酸鹽、馬來酸鹽、富馬酸鹽、蘋果酸鹽、酒石酸鹽等)等。進而,於本發明中所使用的血管張力素II受體拮抗劑亦可因應需要,而適當的使用其之光學活性體。 Angiotensin II receptor antagonists may also be pharmacologically acceptable salts, hydrates, and solvates, as needed. Pharmacologically permissible Examples of the salt system include salts with inorganic acids (hydrochloride, hydrobromide, phosphate, sulfate, etc.) and salts with organic acids (acetate, succinate, maleate, fumaric acid). Salt, malate, tartrate, etc.). Further, the angiotensin II receptor antagonist used in the present invention may suitably use an optically active substance thereof as needed.

血管張力素II受體拮抗劑係可將1種單獨使用,亦可將2種以上組合使用。 The angiotensin II receptor antagonist may be used alone or in combination of two or more.

血管張力素II受體拮抗劑,相對於醫藥製劑100質量%,較佳為含有5~50質量%,更佳為含有10~40質量%。 The angiotensin II receptor antagonist is preferably contained in an amount of 5 to 50% by mass, more preferably 10 to 40% by mass based on 100% by mass of the pharmaceutical preparation.

此外,鈣拮抗劑與血管張力素II受體拮抗劑之質量比,係以1:1~1:32之範圍內為佳,以1:4~1:16之範圍內為更佳。 Further, the mass ratio of the calcium antagonist to the angiotensin II receptor antagonist is preferably in the range of 1:1 to 1:32, and more preferably in the range of 1:4 to 1:16.

<崩解劑> <Disintegrant>

崩解劑係意味著:當服用或者放入水中時,會被水浸濕,而使製劑崩壞的添加物。 The disintegrant means an additive which is wetted by water when taken or placed in water to cause the preparation to collapse.

於本發明之醫藥製劑中所含有的崩解劑,較佳為交聯羧甲基纖維素鈉、交聯羧甲基纖維素鈣、低取代度羥丙基纖維素、羧甲基澱粉鈉、交聯聚維酮及α化澱粉,更佳為交聯羧甲基纖維素鈉、低取代度羥丙基纖維素、羧甲基澱粉鈉及交聯聚維酮,再更佳為交聯羧甲基纖維素鈉、低取代度羥丙基纖維素,特佳為交聯羧甲基纖維素鈉。崩解劑係可將1種單獨使用,亦可將2種以上組合使用。 The disintegrant contained in the pharmaceutical preparation of the present invention is preferably croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, Cross-linked povidone and alpha-starch, more preferably croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch and crospovidone, more preferably cross-linked carboxylate Sodium methylcellulose, low-substituted hydroxypropylcellulose, particularly preferably croscarmellose sodium. One type of the disintegrator may be used alone or two or more types may be used in combination.

崩解劑,相對於醫藥製劑100質量%,合計為含有5質量%以上,較佳為含有5~35質量%,更佳為6~30質量%之範圍內。 The disintegrating agent is contained in an amount of 5% by mass or more, preferably 5 to 35% by mass, and more preferably 6 to 30% by mass based on 100% by mass of the pharmaceutical preparation.

崩解劑,係以與鈣拮抗劑一同包含於顆粒中為佳。此外,崩解劑,較佳為以與血管張力素II受體拮抗劑一起覆蓋前述顆粒的一部分或全部的方式存在。於含有鈣拮抗劑之顆粒中所含有的崩解劑(第1崩解劑)、和與血管張力素II受體拮抗劑一同存在於顆粒周圍的崩解劑(第2崩解劑),係可為同一崩解劑,亦可為彼此不同種類之崩解劑。雖可僅第1崩解劑及第2崩解劑中任一者包含於醫藥製劑中,但以第1崩解劑與第2崩解劑兩者皆包含於醫藥製劑中為佳。 The disintegrant is preferably contained in the granule together with the calcium antagonist. Further, the disintegrant is preferably present in such a manner as to cover a part or all of the aforementioned particles together with the angiotensin II receptor antagonist. a disintegrant (first disintegrant) contained in a granule containing a calcium antagonist, and a disintegrant (second disintegrant) existing around the granule together with an angiotensin II receptor antagonist They may be the same disintegrant or different types of disintegrants from each other. Although only one of the first disintegrant and the second disintegrator may be contained in the pharmaceutical preparation, it is preferred that both the first disintegrant and the second disintegrant are contained in the pharmaceutical preparation.

第1崩解劑,相對於醫藥製劑100質量%,較佳為含有1~15質量%,更佳為1~10質量%。 The first disintegrant is preferably contained in an amount of from 1 to 15% by mass, more preferably from 1 to 10% by mass, based on 100% by mass of the pharmaceutical preparation.

第2崩解劑,相對於醫藥製劑100質量%,較佳為含有1~30質量%,更佳為2~25質量%。 The second disintegrator is preferably contained in an amount of 1 to 30% by mass, and more preferably 2 to 25% by mass based on 100% by mass of the pharmaceutical preparation.

<結合劑> <Bonding agent>

本發明之醫藥製劑亦可含有結合劑。結合劑係可使用各種類者,並無特別限定,可列舉例如水溶性高分子。其中,較佳為羥丙基纖維素、羥丙基甲基纖維素鄰苯二甲酸酯、甲基纖維素、羥丙基甲基纖維素乙酸酯丁二酸酯、羧甲基乙基纖維素、羧甲基纖維素鈉、羥乙基纖維素、羥乙基甲基纖維素、乙酸鄰苯二甲酸纖維素,更佳為羥丙基纖 維素、羥丙基甲基纖維素鄰苯二甲酸酯。 The pharmaceutical preparation of the present invention may also contain a binding agent. The binder can be used in various types, and is not particularly limited, and examples thereof include a water-soluble polymer. Among them, preferred are hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl Cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, cellulose acetate phthalate, more preferably hydroxypropylcellulose Vitamin, hydroxypropyl methylcellulose phthalate.

結合劑,相對於醫藥製劑100質量%,較佳為含有1~90質量%,更佳為3~40質量%,再更佳為5~20質量%。 The binder is preferably from 1 to 90% by mass, more preferably from 3 to 40% by mass, even more preferably from 5 to 20% by mass, based on 100% by mass of the pharmaceutical preparation.

使用結合劑時,該結合劑較佳為包含於含有鈣拮抗劑之顆粒內。 When a binding agent is used, the binding agent is preferably contained in a particle containing a calcium antagonist.

<潤滑劑> <Lubricant>

本發明之醫藥製劑亦可含有潤滑劑。潤滑劑係可使用各種類者,並無特別限定,可列舉例如:硬脂酸鎂、硬脂酸、硬脂酸鈣、碳酸鎂。潤滑劑,相對於醫藥製劑100質量%,較佳為含有0.5~2質量%。 The pharmaceutical preparation of the present invention may also contain a lubricant. The lubricant can be used in various types, and is not particularly limited, and 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 based on 100% by mass of the pharmaceutical preparation.

使用潤滑劑時,該潤滑劑,較佳為以與血管張力素II受體拮抗劑一起覆蓋前述顆粒的一部分或全部的方式存在。 When a lubricant is used, the lubricant preferably exists to cover a part or all of the particles together with an angiotensin II receptor antagonist.

<賦形劑> <excipient>

本發明之醫藥製劑亦可含有賦形劑。賦形劑係可使用各種類者,並無特別限定,可列舉例如:乳糖水合物、白糖、葡萄糖、還原麥芽糖、甘露醇、山梨糖醇等之糖類、玉米澱粉、馬鈴薯澱粉、部分α化澱粉、糊精、支鏈澱粉等之澱粉類及其衍生物、結晶纖維素、微結晶纖維素等之纖維素類、聚乙二醇、偏矽酸鋁酸鎂之1種或2種以上之混合物。其中,較佳為乳糖水合物、甘露醇、部分α化澱 粉、結晶纖維素,更佳為乳糖水合物、結晶纖維素。 The pharmaceutical preparation of the present invention may also contain an excipient. The excipients can be used in various types, and are not particularly limited, and examples thereof include lactose hydrate, white sugar, glucose, reduced maltose, mannitol, sorbitol, sugar, corn starch, potato starch, and partially gelatinized starch. And a mixture of starch or a derivative thereof such as dextrin and amylopectin, cellulose such as crystalline cellulose or microcrystalline cellulose, polyethylene glycol, or magnesium metasilicate aluminate, or a mixture of two or more thereof . Among them, preferred are lactose hydrate, mannitol, and partial α-deposit Powder, crystalline cellulose, more preferably lactose hydrate, crystalline cellulose.

賦形劑係可將1種單獨使用,亦可將2種以上組合使用。此外,使用賦形劑時,於含有鈣拮抗劑之顆粒內所含有的賦形劑(第1賦形劑)、和以與血管張力素II受體拮抗劑一起覆蓋前述顆粒的一部分或全部之方式存在的賦形劑(第2賦形劑),係可為同一,亦可為不同。亦可僅第1賦形劑及第2賦形劑中任一者包含於醫藥製劑中。 One type of the excipients may be used alone or two or more types may be used in combination. Further, when an excipient is used, an excipient (first excipient) contained in a granule containing a calcium antagonist, and a part or all of the granules are covered with an angiotensin II receptor antagonist. The excipient (second excipient) present in the form may be the same or different. Only one of the first excipient and the second excipient may be included in the pharmaceutical preparation.

第1賦形劑,相對於醫藥製劑100質量%,較佳為含有1~40質量%,更佳為1~30質量%。 The first excipient is preferably 1 to 40% by mass, and more preferably 1 to 30% by mass based on 100% by mass of the pharmaceutical preparation.

第2賦形劑,相對於醫藥製劑100質量%,較佳為含有1~40質量%,更佳為5~30質量%。 The second excipient is preferably contained in an amount of 1 to 40% by mass, more preferably 5 to 30% by mass based on 100% by mass of the pharmaceutical preparation.

<流動化劑> <mobile agent>

本發明之醫藥製劑亦可含有流動化劑。流動化劑係可使用各種類者,並無特別限定,可列舉例如:含水二氧化矽、輕質矽酸酐(light anhydrous silicic acid)、滑石。其中,更佳為含水二氧化矽。 The pharmaceutical preparation of the present invention may also contain a fluidizing agent. The fluidizing agent can be used in various types, and is not particularly limited, and examples thereof include aqueous cerium oxide, light anhydrous silicic acid, and talc. Among them, more preferred is aqueous cerium oxide.

流動化劑,相對於醫藥製劑100質量%,較佳為含有1~10質量%,更佳為1~5質量%。 The fluidizing agent is preferably contained in an amount of from 1 to 10% by mass, more preferably from 1 to 5% by mass, based on 100% by mass of the pharmaceutical preparation.

使用流動化劑時,該流動化劑,較佳為以與血管張力素II受體拮抗劑一起覆蓋前述顆粒的一部分或全部的方式存在。 When a fluidizing agent is used, the fluidizing agent preferably exists to cover a part or all of the particles together with the angiotensin II receptor antagonist.

<塗佈被膜> <Coated film>

此外,本發明之醫藥製劑,係以其表面具有塗佈被膜為佳。塗佈被膜之質量比例雖只要因應目的而調製即可,但相對於醫藥製劑100質量%,較佳為1~10質量%,更佳為3~8質量%。 Further, the pharmaceutical preparation of the present invention preferably has a coating film on its surface. The mass ratio of the coating film may be adjusted according to the purpose, but it is preferably 1 to 10% by mass, and more preferably 3 to 8% by mass based on 100% by mass of the pharmaceutical preparation.

塗佈被膜,例如,可藉由使用盤塗佈裝置(pan coating device)、滾筒式塗佈裝置、流動塗佈裝置等,來塗佈已將塗佈劑溶解於水中的塗佈液,而形成於醫藥製劑表面。 The coating film is coated, for example, by coating a coating liquid in which a coating agent has been dissolved in water by using a pan coating device, a roll coating device, a flow coating device, or the like. On the surface of pharmaceutical preparations.

塗佈劑係可列舉:羥丙基甲基纖維素、MACROGOL 6000等。 Examples of the coating agent include hydroxypropylmethylcellulose, MACROGOL 6000, and the like.

<著色劑> <colorant>

塗佈被膜,較佳為含有黃色三氧化二鐵、三氧化二鐵及黑氧化鐵等之氧化鐵系之著色劑。上述著色劑係可將1種單獨使用,亦可將2種以上組合使用。 The coating film is preferably an iron oxide-based coloring agent containing yellow ferric oxide, ferric oxide, and black iron oxide. One type of the coloring agent may be used alone or two or more types may be used in combination.

前述著色劑,相對於塗佈被膜100質量份,較佳為以0.1~5質量份之比例含有,更佳為以0.25~1質量份之比例含有。 The coloring agent is preferably contained in an amount of 0.1 to 5 parts by mass, more preferably 0.25 to 1 part by mass, based on 100 parts by mass of the coating film.

藉由具有含上述著色劑之塗佈被膜,而可提昇醫藥製劑中所含有的鈣拮抗劑之光安定性。亦即,不僅無在高溫保存時溶出速度會降低之血管張力素II受體拮抗劑的問題點,亦可改善容易光分解之鈣拮抗劑的問題點。 By having a coating film containing the above coloring agent, the light stability of the calcium antagonist contained in the pharmaceutical preparation can be improved. That is, not only the problem of the angiotensin II receptor antagonist which has a reduced dissolution rate at the time of high-temperature storage, but also the problem of the calcium antagonist which is easily photodecomposed can be improved.

此外,塗佈被膜,係除上述氧化鐵系之著色劑以外,亦可進一步含有氧化鈦等之其他的著色劑。含有氧化鈦 時,氧化鈦,相對於塗佈被膜100質量份,較佳為含有5~25質量份,更佳為含有10~20質量份。 Further, the coating film may further contain other coloring agents such as titanium oxide in addition to the iron oxide-based coloring agent. Containing titanium oxide The titanium oxide is preferably contained in an amount of 5 to 25 parts by mass, more preferably 10 to 20 parts by mass, per 100 parts by mass of the coating film.

本發明之醫藥製劑,較佳為固體製劑,更佳為錠劑、膠囊劑、細粒劑或顆粒之形態,特佳為錠劑之形態。此外,錠劑之形狀並無特別限制,可列舉例如:圓形、橢圓形(除正圓形以外之所有的長圓形:橢圓形、蛋形、橢圓體形、卵圓形等)、菱形、三角形等。設有割線時,割線的形狀可為平溝型、U字溝型、V字溝型中任一種,錠劑為橢圓形狀時,係以沿著短軸形成為佳。 The pharmaceutical preparation of the present invention is preferably a solid preparation, more preferably in the form of a tablet, a capsule, a fine granule or a granule, and particularly preferably in the form of a tablet. Further, the shape of the tablet is not particularly limited, and examples thereof include a circular shape and an elliptical shape (all oblong circles other than a perfect circular shape: an elliptical shape, an egg shape, an ellipsoid shape, an oval shape, etc.), a rhombus shape, and the like. Triangles, etc. When the secant line is provided, the shape of the secant line may be any one of a flat groove type, a U-groove type, and a V-shaped groove type, and when the tablet is an elliptical shape, it is preferably formed along the short axis.

本發明之醫藥製劑,較佳為在基於盛液法之溶出試驗中,鈣拮抗劑會在試驗開始15分鐘後,其之48~78質量%溶解於水中。相同地,較佳為在基於盛液法之溶出試驗中,鈣拮抗劑會在試驗開始90分鐘後,其之75質量%以上溶解於水中。 In the pharmaceutical preparation of the present invention, it is preferred that in the dissolution test based on the liquid-containing method, the calcium antagonist is dissolved in water after 15 minutes from the start of the test, 48 to 78% by mass. Similarly, it is preferred that in the dissolution test based on the liquid-containing method, the calcium antagonist is dissolved in water at 90% by mass or more after 90 minutes from the start of the test.

此外,較佳為在基於盛液法之溶出試驗中,血管張力素II受體拮抗劑會在試驗開始15分鐘後,其之75質量%以上溶解於水中。相同地,較佳為在基於盛液法之溶出試驗中,血管張力素II受體拮抗劑會在試驗開始30分鐘後,其之85質量%以上溶解於水中。 Further, it is preferred that the angiotensin II receptor antagonist is dissolved in water 15 minutes after the start of the test in the dissolution test by the liquid-containing method. Similarly, it is preferred that the angiotensin II receptor antagonist is dissolved in water 30 minutes after the start of the test in the dissolution test by the liquid-containing method.

若溶出率為上述範圍內,則可達成與市售之鈣拮抗劑製劑、血管張力素II受體拮抗劑製劑各自的溶出輪廓(elution profile)接近之溶出輪廓。因而,可得到發揮與併用投予2種製劑之情況相同的效果之醫藥製劑(摻合劑)。 When the dissolution rate is within the above range, a dissolution profile close to the elution profile of each of the commercially available calcium antagonist preparation and the angiotensin II receptor antagonist preparation can be achieved. Therefore, a pharmaceutical preparation (admixture) which exhibits the same effects as those in the case where two kinds of preparations are administered in combination can be obtained.

<製造方法> <Manufacturing method>

本發明之醫藥製劑,係可利用該領域以往所周知的方法進行製造。例如,可利用乾式造粒法、濕式造粒法、直接製錠法等之方法進行製造。更具體而言,例如,可藉由將鈣拮抗劑予以顆粒化,於所得到的含鈣拮抗劑之顆粒中,混合血管張力素II受體拮抗劑,藉由乾式造粒法造粒之後,進行製錠,而製造。 The pharmaceutical preparation of the present invention can be produced by a method known in the art. For example, it can be produced by a method such as a dry granulation method, a wet granulation method, or a direct tableting method. More specifically, for example, by granulating a calcium antagonist, an angiotensin II receptor antagonist is mixed in the obtained calcium-containing antagonist particle, and after granulation by a dry granulation method, Making ingots and making them.

<用途> <Use>

本發明之醫藥製劑,由於具有降血壓作用,因此作為高血壓患者治療用之降血壓劑為有用。 The pharmaceutical preparation of the present invention is useful as a blood pressure lowering agent for the treatment of hypertensive patients because of its hypotensive effect.

<投予對象> <subject to target>

本發明之醫藥製劑的投予對象係可列舉:小鼠、大鼠、倉鼠、兔、貓、狗、牛、羊、猴、人類等之哺乳動物。尤其,人類為投予對象較佳。 The pharmaceutical preparation of the present invention may be administered to mammals such as mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, and humans. In particular, humans are preferred for the subject of administration.

[實施例] [Examples]

以下,雖藉由實施例更詳細地說明本發明,但本發明並不受此等例子所限定。實施例中,只要無特別說明,則「%」係意味著質量%。 Hereinafter, the present invention will be described in more detail by way of examples, but the invention is not limited by these examples. In the examples, "%" means mass% unless otherwise specified.

[實施例1] [Example 1]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而 得到表1記載之西尼地平(Cilnidipine)顆粒。 By granulation by agitation using an organic solvent (dichloromethane and methanol) The cilnidipine granules described in Table 1 were obtained.

於上述之西尼地平(Cilnidipine)顆粒中混合表2所示的成分,並藉由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠(Uncoated tablets)(崩解劑添加量:22.5mg/錠,每1粒裸錠為9%)。 The components shown in Table 2 were mixed in the above-mentioned Cilnidipine granules, and by dry granulation, granulation, and tableting, Cilnidipine/Valsartan admixture was obtained. Uncoated tablets (addition amount of disintegrant: 22.5 mg/ingot, 9% per one naked ingot).

對於以上述方式所得到的裸錠,使用盤型塗佈機,塗佈表3之處方,而得到薄膜包覆錠。於該錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦(Valsartan)之比例:15.2%、第1崩解劑之比例:4.8%,第2崩解劑之比例:3.8%(崩解劑合計:8.6%) With respect to the bare ingot obtained in the above manner, a disc coater was used and the surface of the table 3 was applied to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.2%, the ratio of the first disintegrant: 4.8%, and the ratio of the second disintegrant : 3.8% (total disintegrator: 8.6%)

[實施例2] [Embodiment 2]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而得到表1記載之西尼地平(Cilnidipine)顆粒。於所得到的西尼地平(Cilnidipine)顆粒中混合表4所示的成分,並藉由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠(崩解劑添加量:52.5mg/錠,每1粒裸錠為21%)。對於所得到的裸錠,使用盤型塗佈機,塗佈表3之處方,而得到薄膜包覆錠。於錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦(Valsartan)之比例:15.2%、第1崩解劑之比例:4.8%,第2崩解劑之比例:15.2%(崩解劑合計:20.0%) The cilnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The components shown in Table 4 were mixed with the obtained Cilnidipine granules, and cilnidipine/Valsartan admixture was obtained by dry granulation, granulation, and tableting. The bare ingot (addition amount of disintegrant: 52.5 mg/ingot, 21% per one naked ingot). With respect to the obtained bare ingot, a disc coater was applied and the surface of Table 3 was applied to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.2%, the ratio of the first disintegrant: 4.8%, the ratio of the second disintegrant: 15.2% (total disintegrator: 20.0%)

[實施例3] [Example 3]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而得到表1記載之西尼地平(Cilnidipine)顆粒。於所得到的西尼地平(Cilnidipine)顆粒中混合表5所示的成分,並藉由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠(崩解劑添加量:12.5mg/錠,每1粒裸錠為29%)。對於所得到的裸錠,使用盤型塗佈機,塗佈表3之處方,而得到薄膜包覆錠。於錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦(Valsartan)之比例:15.2%、第1崩解劑之比例:4.8%,第2崩解劑之比例:22.9%(崩解劑合計:27.6%) The cilnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The components shown in Table 5 were mixed with the obtained Cilnidipine granules, and Cilinidipine/Valsartan admixture was obtained by dry granulation, granulation, and tableting. The bare ingot (addition amount of disintegrant: 12.5 mg/ingot, 29% per one bare ingot). With respect to the obtained bare ingot, a disc coater was applied and the surface of Table 3 was applied to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.2%, the ratio of the first disintegrant: 4.8%, the ratio of the second disintegrant: 22.9% (total disintegrator: 27.6%)

[比較例1] [Comparative Example 1]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而得到表1記載之西尼地平(Cilnidipine)顆粒。於所得到的西尼地平(Cilnidipine)顆粒中混合表6所示的成分,並藉 由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠(崩解劑添加量:12.5mg/錠,每1粒裸錠為5%)。對於所得到的裸錠,使用盤型塗佈機,塗佈表3之處方,而得到薄膜包覆錠。於錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦(Valsartan)之比例:15.2%、第1崩解劑之比例:4.8%,第2崩解劑之比例:0.0%(崩解劑合計:4.8%) The cilnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). Mixing the ingredients shown in Table 6 with the obtained cilnidipine granules, and borrowing A dry ingot, a granule, and a tablet for the incorporation of Cilnidipine/Valsartan admixture (addition amount of disintegrant: 12.5 mg/ingot, 5 per ingot) %). With respect to the obtained bare ingot, a disc coater was applied and the surface of Table 3 was applied to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.2%, the ratio of the first disintegrant: 4.8%, the ratio of the second disintegrant: 0.0% (total disintegrator: 4.8%)

[試驗例1] [Test Example 1]

針對纈沙坦(Valsartan)之溶出試驗,係按照第十六改正日本藥典之事項所記載的溶出試驗法(盛液法),以每分鐘50次旋轉,使用900mL之水作為試驗液,進行試驗。採取從試驗開始15分鐘、30分鐘後之試驗液,藉由液體層析法進行試驗,來計算出纈沙坦(Valsartan)之溶出率。 The dissolution test for valsartan was carried out in accordance with the dissolution test method (liquid method) described in the sixteenth revision of the Japanese Pharmacopoeia, using 50 mL of rotation per minute and using 900 mL of water as the test solution. . The test solution after 15 minutes and 30 minutes from the start of the test was tested by liquid chromatography to calculate the dissolution rate of valsartan.

[試驗例2] [Test Example 2]

針對西尼地平(Cilnidipine)之溶出試驗,係按照第十六改正日本藥典之事項所記載的溶出試驗法(盛液法),以 每分鐘50次旋轉,使用添加了0.1w/v%聚山梨醇酯80之溶出試驗第2液900mL作為試驗液,進行試驗。採取從試驗開始15分鐘、90分鐘後之試驗液,藉由液體層析法進行試驗,來計算出西尼地平(Cilnidipine)之溶出率。 The dissolution test for cilnidipine is based on the dissolution test method (liquid method) described in the sixteenth revision of the Japanese Pharmacopoeia. The test was carried out by rotating 500 times per minute and using 900 mL of the second test solution of the dissolution test containing 0.1 w/v% of polysorbate 80 as a test liquid. The test solution of 15 minutes and 90 minutes from the start of the test was tested by liquid chromatography to calculate the dissolution rate of cilnidipine.

[試驗例3] [Test Example 3]

在氣密狀態下以溫度60℃之條件保管1個月,按照試驗例1的方式來計算出溶出率。 The solution was stored in an airtight state at a temperature of 60 ° C for one month, and the dissolution rate was calculated in the same manner as in Test Example 1.

<結果> <Result>

對於實施例1~3、比較例1,按照試驗例1及2來計算出溶出率(%)。 With respect to Examples 1 to 3 and Comparative Example 1, the dissolution rate (%) was calculated in accordance with Test Examples 1 and 2.

另外,考慮作為西尼地平(Cilnidipine)之市售製劑的Atelec(註冊商標)錠及作為纈沙坦(Valsartan)之市售製劑的Diovan(註冊商標)錠之溶出速度而設定目標值,將西尼地平(Cilnidipine)、纈沙坦(Valsartan)之溶出率滿足所有目標值者評估為○,將其中一個不滿足者評估為×。 In addition, the target value is set in consideration of the dissolution rate of the Atelec (registered trademark) ingot as a commercially available preparation of cilnidipine and the Diovan (registered trademark) ingot as a commercial preparation of valsartan. The dissolution rate of Cilnidipine and Valsartan meets all target values and is evaluated as ○, and one of the unsatisfied persons is evaluated as ×.

其結果,針對實施例1~3,係由於西尼地平(Cilnidipine)及纈沙坦(Valsartan)皆顯示目標值之溶出率,因此確認為具有目的之溶出速度的製劑。但,針對比較例1,並未顯示目標值之溶出率,而確認出非為具有目的之溶出速度的製劑。 As a result, in Examples 1 to 3, since both Cilnidipine and Valsartan showed the dissolution rate of the target value, it was confirmed that the preparation had a desired dissolution rate. However, in Comparative Example 1, the dissolution rate of the target value was not shown, and it was confirmed that the preparation was not the intended dissolution rate.

使用實施例1、實施例2及Diovan錠40mg(市售品),按照試驗例3,來確認出安全性。其結果,針對實施例1及實施例2之處方的製劑,保存後亦保持高的溶出率。 Using Example 1, Example 2, and 40 mg of a Diovan ingot (commercial product), the safety was confirmed according to Test Example 3. As a result, the preparations of Examples 1 and 2 were maintained at a high dissolution rate after storage.

[實施例4] [Example 4]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而得到表10記載之西尼地平(Cilnidipine)顆粒。 The cilnidipine particles described in Table 10 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).

於上述之西尼地平(Cilnidipine)顆粒中混合表11所示的成分,並藉由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠。 The ingredients shown in Table 11 were mixed in the above-mentioned Cilnidipine granules, and by dry granulation, granulation, and tableting, Cilnidipine/Valsartan admixture was obtained. Bare ingots.

對於以上述方式所得到的裸錠,使用盤型塗佈機,塗佈表12之處方,而得到薄膜包覆錠。於該錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦(Valsartan)之比例:15.2%、第1崩解劑之比例:4.8%,第2崩解劑之比例:7.6%(崩解劑合計:12.4%)。氧化鐵系著色劑相對於塗佈被膜100質量份之比例:1.0質量份,氧化鈦之比例:14.8質量份。 The bare ingot obtained in the above manner was coated with a disk coater using a disk coater to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.2%, the ratio of the first disintegrant: 4.8%, and the ratio of the second disintegrant : 7.6% (total disintegrator: 12.4%). The ratio of the iron oxide-based coloring agent to 100 parts by mass of the coating film: 1.0 part by mass, and the ratio of titanium oxide: 14.8 parts by mass.

[比較例2] [Comparative Example 2]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而得到表10記載之西尼地平(Cilnidipine)顆粒。 The cilnidipine particles described in Table 10 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).

於所得到的西尼地平(Cilnidipine)顆粒中混合表11所示的成分,並藉由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠。 The components shown in Table 11 were mixed with the obtained cilnidipine granules, and cilnidipine/valsartan admixture was obtained by dry granulation, granulation, and tableting. Bare ingot.

對於所得到的裸錠,使用盤型塗佈機,塗佈表13之處方,而得到薄膜包覆錠。於該錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦(Valsartan)之比例:15.2%、第1崩解劑之比例:4.8%,第2崩解劑之比例:7.6%(崩解劑合計:12.4%)。氧化鐵系著色劑相對於塗佈被膜100質量份之比例:0.0質量份,氧化鈦之比例:15.0質量份。 With respect to the obtained bare ingot, a disk coating machine was used, and the surface of the table 13 was applied to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.2%, the ratio of the first disintegrant: 4.8%, and the ratio of the second disintegrant : 7.6% (total disintegrator: 12.4%). The ratio of the iron oxide-based coloring agent to 100 parts by mass of the coating film: 0.0 part by mass, and the ratio of titanium oxide: 15.0 parts by mass.

[實施例5] [Example 5]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而得到表14記載之西尼地平(Cilnidipine)顆粒。 The cilnidipine particles described in Table 14 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).

於上述之西尼地平(Cilnidipine)顆粒中混合表15所示的成分,並藉由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠。 The ingredients shown in Table 15 were mixed in the above-mentioned Cilnidipine granules, and by dry granulation, granulation, and tableting, Cilnidipine/Valsartan admixture was obtained. Bare ingots.

對於以上述方式所得到的裸錠,使用盤型塗佈機,塗佈表16之處方,而得到薄膜包覆錠。於該錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦(Valsartan)之比例:15.5%、第1崩解劑之比例:4.8%, 第2崩解劑之比例:15.4%(崩解劑合計:20.2%)。氧化鐵系著色劑相對於塗佈被膜100質量份之比例:0.25質量份,氧化鈦之比例:15.0質量份。 With respect to the bare ingot obtained in the above manner, a disk coating machine was used and the surface of the table 16 was applied to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.5%, and the ratio of the first disintegrant: 4.8%. The ratio of the second disintegrator: 15.4% (total disintegrator: 20.2%). The ratio of the iron oxide-based coloring agent to 100 parts by mass of the coating film: 0.25 parts by mass, and the ratio of titanium oxide: 15.0 parts by mass.

[實施例6] [Embodiment 6]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而得到表14記載之西尼地平(Cilnidipine)顆粒。於所得到的西尼地平(Cilnidipine)顆粒中混合表15所示的成分,並藉由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠。對於所得到的裸錠,使用盤型塗佈機,塗佈表17之處方,而得到薄膜包覆錠。於該錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦之比例:15.5%、第1崩解劑之比例:4.8%,第2崩解劑之比例:15.4%(崩解劑合計:20.2%)。氧化鐵系著色劑相對於塗佈被膜100質量份之比例:0.25質量份,氧化鈦之比例:15.0質量份。 The cilnidipine particles described in Table 14 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The components shown in Table 15 were mixed with the obtained Cilnidipine granules, and the cilnidipine/valsartan admixture was obtained by dry granulation, granulation, and tableting. Bare ingot. With respect to the obtained bare ingot, a disk coating machine was used, and the surface of the table 17 was applied to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.5%, the ratio of the first disintegrant: 4.8%, the ratio of the second disintegrant: 15.4% (Total disintegrant: 20.2%). The ratio of the iron oxide-based coloring agent to 100 parts by mass of the coating film: 0.25 parts by mass, and the ratio of titanium oxide: 15.0 parts by mass.

[實施例7] [Embodiment 7]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而得到表14記載之西尼地平(Cilnidipine)顆粒。於所得到的西尼地平(Cilnidipine)顆粒中混合表15所示的成分,並藉由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠。對於所得到的裸錠,使用盤型塗佈機,塗佈表18之處方,而得到薄膜包覆錠。於該錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦(Valsartan)之比例:15.5%、第1崩解劑之比例:4.8%,第2崩解劑之比例:15.4%(崩解劑合計:20.2%)。氧化鐵系著色劑相對於塗佈被膜100質量份之比例:0.25質量份,氧化鈦之比例:15.0質量份。 The cilnidipine particles described in Table 14 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The components shown in Table 15 were mixed with the obtained Cilnidipine granules, and the cilnidipine/valsartan admixture was obtained by dry granulation, granulation, and tableting. Bare ingot. With respect to the obtained bare ingot, a disk coating machine was used, and the surface of the table 18 was applied to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.5%, the ratio of the first disintegrant: 4.8%, and the ratio of the second disintegrant : 15.4% (total disintegrator: 20.2%). The ratio of the iron oxide-based coloring agent to 100 parts by mass of the coating film: 0.25 parts by mass, and the ratio of titanium oxide: 15.0 parts by mass.

[比較例3] [Comparative Example 3]

藉由使用有機溶劑(二氯甲烷及甲醇)的攪拌造粒,而得到表14記載之西尼地平(Cilnidipine)顆粒。於所得到的西尼地平(Cilnidipine)顆粒中混合表15所示的成分,並藉由乾式造粒、整粒、製錠,而得到西尼地平(Cilnidipine)/纈沙坦(Valsartan)摻合劑之裸錠。對於所得到的裸錠,使用盤型塗佈機,塗佈表19之處方,而得到薄膜包覆錠。於該錠劑中所含有的西尼地平(Cilnidipine)之比例:1.9%,纈沙坦(Valsartan)之比例:15.5%、第1崩解劑之比例:4.8%,第2崩解劑之比例:15.4%(崩解劑合計:20.2%)。氧化鐵系著色劑相對於塗佈被膜100質量份之比例:0.0質量份,氧化鈦之比例:15.0質量份。 The cilnidipine particles described in Table 14 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The components shown in Table 15 were mixed with the obtained Cilnidipine granules, and the cilnidipine/valsartan admixture was obtained by dry granulation, granulation, and tableting. Bare ingot. With respect to the obtained bare ingot, a disk coating machine was used, and the surface of the table 19 was applied to obtain a film-coated ingot. The ratio of cilnidipine contained in the tablet: 1.9%, the ratio of valsartan: 15.5%, the ratio of the first disintegrant: 4.8%, and the ratio of the second disintegrant : 15.4% (total disintegrator: 20.2%). The ratio of the iron oxide-based coloring agent to 100 parts by mass of the coating film: 0.0 part by mass, and the ratio of titanium oxide: 15.0 parts by mass.

[試驗例4] [Test Example 4]

實施在120萬Lux照射時之光安定性試驗,計算出西尼地平(Cilnidipine)類緣物質總量值。 The light stability test at 1.2 million Lux irradiation was carried out to calculate the total amount of linidipine (Cilnidipine) rim material.

<結果> <Result>

針對實施例4~7、比較例2及3,按照試驗例4來計算出西尼地平(Cilnidipine)類緣物質總量值。其結果,相較於僅添加了氧化鈦之比較例2及比較例3,實施例4~7,其西尼地平(Cilnidipine)類緣物質總量皆顯示低值,而確認出對於光為安定。 With respect to Examples 4 to 7, and Comparative Examples 2 and 3, the total amount of Cirnidipine-like material was calculated in accordance with Test Example 4. As a result, compared with Comparative Example 2 and Comparative Example 3 in which only titanium oxide was added, in Examples 4 to 7, the total amount of Cirnidipine-like material showed a low value, and it was confirmed that the light was stable. .

[產業上之可利用性] [Industrial availability]

本發明之醫藥製劑,係可提昇血管張力素II受體拮抗劑之保存安定性。此外,該醫藥製劑係可實現與市售之鈣拮抗劑製劑及血管張力素II受體拮抗劑各自的溶出輪廓接近之溶出輪廓。因而,產業上極為有用。 The pharmaceutical preparation of the present invention can enhance the preservation stability of an angiotensin II receptor antagonist. Further, the pharmaceutical preparation can achieve a dissolution profile close to the dissolution profile of each of the commercially available calcium antagonist preparation and the angiotensin II receptor antagonist. Therefore, the industry is extremely useful.

Claims (12)

一種醫藥摻合劑,其係含有作為有效成分之鈣拮抗劑及血管張力素II受體拮抗劑、與以第1崩解劑以及第2崩解劑之合計為5質量%以上之崩解劑之醫藥摻合劑,前述鈣拮抗劑為固體分散體之形態,前述鈣拮抗劑為西尼地平(Cilnidipine),前述血管張力素II受體拮抗劑為纈沙坦(Valsartan),第1崩解劑相對於醫藥製劑100質量%為含有1~15質量%之量,第2崩解劑相對於醫藥製劑100質量%為含有1~30質量%之量,並藉由將包含第1崩解劑及鈣拮抗劑之顆粒、血管張力素II受體拮抗劑以及第2崩解劑造粒,並打錠所得。 A pharmaceutical admixture containing a calcium antagonist and an angiotensin II receptor antagonist as an active ingredient, and a disintegrant of 5% by mass or more based on the total of the first disintegrant and the second disintegrant. a pharmaceutical admixture, wherein the calcium antagonist is in the form of a solid dispersion, the calcium antagonist is cilnidipine, the angiotensin II receptor antagonist is valsartan, and the first disintegrant is relatively 100% by mass of the pharmaceutical preparation is contained in an amount of 1 to 15% by mass, and the second disintegrant is contained in an amount of 1 to 30% by mass based on 100% by mass of the pharmaceutical preparation, and the first disintegrating agent and calcium are contained. The granules of the antagonist, the angiotensin II receptor antagonist, and the second disintegrant are granulated and obtained by tableting. 如請求項1所記載之醫藥摻合劑,其中第1崩解劑以及第2崩解劑分別獨立由交聯羧甲基纖維素鈉(croscarmellose sodium)、交聯羧甲基纖維素鈣、低取代度羥丙基纖維素、羧甲基澱粉鈉、交聯聚維酮及α化澱粉所成之群中選出的至少1種。 The pharmaceutical admixture according to claim 1, wherein the first disintegrant and the second disintegrant are independently replaced by croscarmellose sodium, croscarmellose calcium, and low substitution. At least one selected from the group consisting of hydroxypropylcellulose, sodium carboxymethyl starch, crospovidone, and gelatinized starch. 如請求項1或2所記載之醫藥摻合劑,其中,前述鈣拮抗劑以0.1~10質量%含有,且前述血管張力素II受體拮抗劑以5~50質量%含有。 The pharmaceutical admixture according to claim 1 or 2, wherein the calcium antagonist is contained in an amount of 0.1 to 10% by mass, and the angiotensin II receptor antagonist is contained in an amount of 5 to 50% by mass. 如請求項1或2所記載之醫藥摻合劑,其係以乾式造粒法將包含第1崩解劑及鈣拮抗劑之顆粒、血管張力素II受體拮抗劑以及第2崩解劑造粒,並打錠所得。 The pharmaceutical admixture according to claim 1 or 2, which granulates a granule comprising a first disintegrant and a calcium antagonist, an angiotensin II receptor antagonist, and a second disintegrant by a dry granulation method. And get the ingots. 如請求項1或2所記載之醫藥摻合劑,其中,崩解劑以第1崩解劑以及第2崩解劑合計為6~30質量%含有。 The pharmaceutical admixture according to claim 1 or 2, wherein the disintegrant is contained in an amount of from 6 to 30% by mass based on the total of the first disintegrant and the second disintegrant. 如請求項1或2所記載之醫藥摻合劑,其中鈣拮抗劑與血管張力素II受體拮抗劑之質量比為1:1~1:32。 The pharmaceutical admixture according to claim 1 or 2, wherein the mass ratio of the calcium antagonist to the angiotensin II receptor antagonist is 1:1 to 1:32. 如請求項1或2所記載之醫藥摻合劑,其係含有塗佈被膜,該塗佈被膜係含有由黃色三氧化二鐵、三氧化二鐵及黑氧化鐵所成之群中選出的至少1種之著色劑。 The pharmaceutical admixture according to claim 1 or 2, which further comprises a coating film containing at least 1 selected from the group consisting of yellow ferric oxide, ferric oxide and black iron oxide. Kind of coloring agent. 如請求項7所記載之醫藥摻合劑,其中前述著色劑的比例,相對於塗佈被膜100質量份為0.1~5質量份之範圍內。 The pharmaceutical admixture according to claim 7, wherein the ratio of the coloring agent is in the range of 0.1 to 5 parts by mass based on 100 parts by mass of the coating film. 如請求項7所記載之醫藥摻合劑,其中前述塗佈被膜係進一步含有氧化鈦。 The pharmaceutical admixture according to claim 7, wherein the coating film system further contains titanium oxide. 如請求項1或2所記載之醫藥摻合劑,其係錠劑、膠囊劑、細粒劑或顆粒之形態。 The pharmaceutical admixture according to claim 1 or 2, which is in the form of a tablet, a capsule, a fine granule or a granule. 如請求項10所記載之醫藥摻合劑,其係錠劑之形態。 The pharmaceutical admixture according to claim 10, which is in the form of a tablet. 如請求項1或2所記載之醫藥製劑,其係降血壓劑。 The pharmaceutical preparation according to claim 1 or 2, which is a blood pressure lowering agent.
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