JP2007284390A

JP2007284390A - Imidapril hydrochloride-containing tablet

Info

Publication number: JP2007284390A
Application number: JP2006114335A
Authority: JP
Inventors: Taichiro Togo; 太一郎東郷
Original assignee: Ohara Pharmaceutical Co Ltd
Current assignee: Ohara Pharmaceutical Co Ltd
Priority date: 2006-04-18
Filing date: 2006-04-18
Publication date: 2007-11-01

Abstract

<P>PROBLEM TO BE SOLVED: To provide tablets keeping imidapril hydrochloride stable therein for a long period. <P>SOLUTION: The tablets are each composed of imidapril hydrochloride and ingredients in terms of pharmaceutical preparation, wherein a lubricant as one of the ingredients contains no metal ion. Among the ingredients, as the lubricant, a hydrogenated oil, glycerol fatty acid ester, sucrose fatty acid ester, carnauba wax or white beeswax, as an excipient, lactose, D-mannitol, erythritol or trehalose, as a binder, polyvinyl alcohol(partially saponified product thereof), methyl cellulose or pullulan, and as an disintegrant, carmellose, can be preferably used. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

本発明は、塩酸イミダプリル（日本医薬品一般的名称）を長期間安定に含有することができる錠剤に関する。 The present invention relates to a tablet capable of stably containing imidapril hydrochloride (Japanese pharmaceutical generic name) for a long period of time.

塩酸イミダプリルは、ＡＣＥ阻害剤として高血圧症の患者にに使用されている有用な医薬であるが、空気中の湿気の影響を受けて加水分解し易い性質を有している。そこで、その保存安定性を改善した製剤がいくつか提案されている。 Imidapril hydrochloride is a useful drug used in hypertensive patients as an ACE inhibitor, but has a property of being easily hydrolyzed under the influence of moisture in the air. Therefore, several preparations with improved storage stability have been proposed.

特許第３２３２６８７号公報Japanese Patent No. 3232687 特開２００４−３４６０６６号公報JP 2004-346066 A

本発明の課題は、塩酸イミダプリルを長期間安定に保持することができる錠剤を提供することにある。 The subject of this invention is providing the tablet which can hold | maintain imidapril hydrochloride stably for a long period of time.

本発明者は、塩酸イミダプリルの錠剤化に関する検討過程で、滑沢剤として繁用されているステアリン酸マグネシウムを使用すると、塩酸イミダプリルが予想外に高い比率で加水分解することを見出した。ところが驚くべきことに、ステアリン酸マグネシウムに代えて硬化油を使用すると、顕著にその加水分解が抑えられ、長期保存可能な塩酸イミダプリル含有錠剤を得ることができることを見出した。そこで本発明者は、さらに検討を加え、本発明を完成した。 The present inventor has found that imidapril hydrochloride is hydrolyzed at an unexpectedly high rate when magnesium stearate, which is frequently used as a lubricant, is used in the process of studying tableting of imidapril hydrochloride. Surprisingly, however, it has been found that when hydrogenated oil is used in place of magnesium stearate, its hydrolysis is remarkably suppressed and a tablet containing imidapril hydrochloride which can be stored for a long period of time can be obtained. Therefore, the inventor further studied and completed the present invention.

すなわち、本発明によれば、
（１）塩酸イミダプリルと製剤上の添加物からなる錠剤であって、滑沢剤が金属イオンを含まないことを特徴とする錠剤、
（２）滑沢剤が、硬化油、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、カルナウバロウ又はサラシミツロウである前記（１）に記載の錠剤、
（３）製剤上の添加物として含んでいてもよい水溶性賦形剤が、乳糖、Ｄ−マンニトール、エリスリトール又はトレハロースである前記（１）に記載の錠剤、
（４）製剤上の添加物として含まれる結合剤がポリビニルアルコール（部分ケン化物）、メチルセルロース又はプルランである前記（１）に記載の錠剤、
（５）製剤上の添加剤として含まれる崩壊剤がカルメロースである前記（１）に記載の錠剤を提供することができる。 That is, according to the present invention,
(1) A tablet comprising imidapril hydrochloride and an additive on the preparation, wherein the lubricant does not contain a metal ion,
(2) The tablet according to (1), wherein the lubricant is hydrogenated oil, glycerin fatty acid ester, sucrose fatty acid ester, carnauba wax, or white beeswax,
(3) The tablet according to (1), wherein the water-soluble excipient that may be contained as an additive in the preparation is lactose, D-mannitol, erythritol, or trehalose,
(4) The tablet according to (1), wherein the binder contained as an additive on the preparation is polyvinyl alcohol (partially saponified product), methylcellulose, or pullulan,
(5) The tablet according to (1) above, wherein the disintegrant contained as an additive in the preparation is carmellose.

本発明の錠剤によれば、安定性に問題がある塩酸イミダプリルを長期間安定に保持できる。 According to the tablet of the present invention, imidapril hydrochloride having a problem in stability can be stably retained for a long period of time.

本発明の活性薬剤である塩酸イミダプリルは、白色の結晶であり、製剤化に際しては、その平均粒子径を１〜５０μｍ程度に粉末化したものが好適である。 Imidapril hydrochloride, which is the active agent of the present invention, is a white crystal and is preferably powdered to an average particle size of about 1 to 50 μm during formulation.

本発明における塩酸イミダプリルと製剤上の添加物との混合割合は、特に限定されないが、好ましい組成を示せば次の通りである。
塩酸イミダプリル１重量部
金属イオンを含まない滑沢剤０．０５〜３重量部
水溶性賦形剤５〜４０重量部
結合剤０．０５〜５重量部
崩壊剤０．０５〜５重量部
なお、本発明の錠剤は、前述の成分の他に、必要に応じ、着色剤、矯味剤等の製剤上の添加物を使用して製造してもよい。 The mixing ratio of imidapril hydrochloride and the additive on the preparation in the present invention is not particularly limited, but is as follows if a preferable composition is shown.
Imidapril hydrochloride 1 part by weight
Lubricant containing no metal ions 0.05-3 parts by weight
5-40 parts by weight of water-soluble excipient
0.05-5 parts by weight of binder
Disintegrant 0.05 to 5 parts by weight The tablet of the present invention may be produced by using additives on the preparation such as a coloring agent and a corrigent as necessary in addition to the above-mentioned components.

本発明の錠剤は、通常の方法、例えば第十四改正日本薬局方の製剤総則に記載されている方法により、容易に製造をすることができる。 The tablet of the present invention can be easily produced by a usual method, for example, a method described in the General Formulation of the 14th revised Japanese Pharmacopoeia.

実施例１
塩酸イミダプリル３０ｇ（平均粒子径：約２０μｍ）及び乳糖４３０．８ｇを流動層造粒機（パウレック製：ＭＰ−０１型）に入れ、５重量％のポリビニルアルコール（部分ケン化物）水溶液１９２ｇを噴霧し、流動層造粒法にて造粒した。これに硬化油９．６ｇを加え混合後、混合物をロータリー式打錠機（菊水製作所製：Ｖｉｒｇｏ型）で圧縮成型し、下記組成の錠剤を得た。
［成分］［１錠当たりの重量（ｍｇ）］
塩酸イミダプリル５．０
乳糖７１．８
ポリビニルアルコール（部分ケン化物）１．６
硬化油１．６
合計８０．０ Example 1
30 g of imidapril hydrochloride (average particle size: about 20 μm) and 430.8 g of lactose were put in a fluidized bed granulator (manufactured by POWREC: MP-01 type) and sprayed with 192 g of a 5 wt% aqueous solution of polyvinyl alcohol (partially saponified product). Then, it was granulated by a fluidized bed granulation method. 9.6 g of hardened oil was added thereto and mixed, and then the mixture was compression-molded with a rotary tableting machine (manufactured by Kikusui Seisakusho: Virgo type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imidapril hydrochloride 5.0
Lactose 71.8
Polyvinyl alcohol (partially saponified product) 1.6
Hardened oil 1.6
Total 80.0

実施例２
塩酸イミダプリル３０ｇ（平均粒子径：約２０μｍ）及び乳糖４３０．８ｇを流動層造粒機（パウレック製：ＭＰ−０１型）に入れ、５重量％ポリビニルアルコール（部分ケン化物）水溶液１９２ｇを噴霧し、流動層造粒法にて造粒した。これにグリセリン脂肪酸エステル９．６ｇを加え混合後、混合物をロータリー式打錠機（菊水製作所製：Ｖｉｒｇｏ型）で圧縮成型し、下記組成の錠剤を得た。
［成分］［１錠当たりの重量（ｍｇ）］
塩酸イミダプリル５．０
乳糖７１．８
ポリビニルアルコール（部分ケン化物）１．６
グリセリン脂肪酸エステル１．６
合計８０．０ Example 2
30 g of imidapril hydrochloride (average particle size: about 20 μm) and 430.8 g of lactose were placed in a fluidized bed granulator (manufactured by POWREC: MP-01 type) and sprayed with 192 g of a 5 wt% polyvinyl alcohol (partially saponified product) solution. Granulated by fluidized bed granulation. 9.6 g of glycerin fatty acid ester was added thereto and mixed, and then the mixture was compression-molded with a rotary tableting machine (manufactured by Kikusui Seisakusho: Virgo type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imidapril hydrochloride 5.0
Lactose 71.8
Polyvinyl alcohol (partially saponified product) 1.6
Glycerin fatty acid ester 1.6
Total 80.0

実施例３
塩酸イミダプリル３０ｇ（平均粒子径：約２０μｍ）及びＤ−マンニトール４３０．８ｇを流動層造粒機（パウレック製：ＭＰ−０１型）に入れ、５重量％プルラン水溶液１９２ｇを噴霧し、流動層造粒法にて造粒した。これに硬化油９．６ｇを加え混合後、混合物をロータリー式打錠機（菊水製作所製：Ｖｉｒｇｏ型）で圧縮成型し、下記組成の錠剤を得た。
［成分］［１錠当たりの重量（ｍｇ）］
塩酸イミダプリル５．０
Ｄ−マンニトール７１．８
プルラン１．６
硬化油１．６
合計８０．０ Example 3
30 g of imidapril hydrochloride (average particle size: about 20 μm) and 430.8 g of D-mannitol were placed in a fluidized bed granulator (manufactured by POWREC: MP-01 type), sprayed with 192 g of a 5% by weight pullulan aqueous solution, and fluidized bed granulated. Granulated by the method. 9.6 g of hardened oil was added thereto and mixed, and then the mixture was compression-molded with a rotary tableting machine (manufactured by Kikusui Seisakusho: Virgo type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imidapril hydrochloride 5.0
D-mannitol 71.8
Pullulan 1.6
Hardened oil 1.6
Total 80.0

実施例４
塩酸イミダプリル３０ｇ（平均粒子径：約２０μｍ）及び乳糖４１６．４ｇを流動層造粒機（パウレック製：ＭＰ−０１型）に入れ、５重量％ポリビニルアルコール（部分ケン化物）水溶液２８８ｇを噴霧し、流動層造粒法にて造粒した。これにカルメロース９．６ｇ及び硬化油９．６ｇを加え混合後、混合物をロータリー式打錠機（菊水製作所製：Ｖｉｒｇｏ型）で圧縮成型し、下記組成の錠剤を得た。
［成分］［１錠当たりの重量（ｍｇ）］
塩酸イミダプリル５．０
乳糖７１．８
ポリビニルアルコール（部分ケン化物）２．４
カルメロース１．６
硬化油１．６
合計８０．０ Example 4
30 g of imidapril hydrochloride (average particle size: about 20 μm) and 416.4 g of lactose were placed in a fluidized bed granulator (manufactured by POWREC: MP-01 type) and sprayed with 288 g of a 5 wt% aqueous solution of polyvinyl alcohol (partially saponified product). Granulated by fluidized bed granulation. Carmellose 9.6g and hydrogenated oil 9.6g were added and mixed to this, and the mixture was compression-molded with the rotary type tableting machine (Kikusui Seisakusho: Virgo type | mold), and the tablet of the following composition was obtained.
[Components] [Weight per tablet (mg)]
Imidapril hydrochloride 5.0
Lactose 71.8
Polyvinyl alcohol (partially saponified product) 2.4
Carmellose 1.6
Hardened oil 1.6
Total 80.0

比較例１
塩酸イミダプリル３０ｇ（平均粒子径：約２０μｍ）及び乳糖４３０．８ｇを流動層造粒機（パウレック製：ＭＰ−０１型）に入れ、５重量％ポリビニルアルコール（部分ケン化物）水溶液１９２ｇを噴霧し、流動層造粒法にて造粒した。これにステアリン酸マグネシウム９．６ｇを加え混合後、混合物をロータリー式打錠機（菊水製作所製：Ｖｉｒｇｏ型）で圧縮成型し、下記組成の錠剤を得た。
［成分］［１錠当たりの重量（ｍｇ）］
塩酸イミダプリル５．０
乳糖７１．８
ポリビニルアルコール（部分ケン化物）１．６
ステアリン酸マグネシウム１．６
合計８０．０ Comparative Example 1
30 g of imidapril hydrochloride (average particle size: about 20 μm) and 430.8 g of lactose were placed in a fluidized bed granulator (manufactured by POWREC: MP-01 type) and sprayed with 192 g of a 5 wt% polyvinyl alcohol (partially saponified product) solution. Granulated by fluidized bed granulation. 9.6 g of magnesium stearate was added thereto and mixed, and then the mixture was compression-molded with a rotary tableting machine (manufactured by Kikusui Seisakusho: Virgo type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Imidapril hydrochloride 5.0
Lactose 71.8
Polyvinyl alcohol (partially saponified product) 1.6
Magnesium stearate 1.6
Total 80.0

試験例１（苛酷試験での錠剤中の塩酸イミダプリル残存率）
（１）試験方法
実施例１〜４の錠剤及び比較例１で得た錠剤について各ＯＯ錠をとり、それぞれ開放した硝子瓶に収容し、恒温槽に入れ、温度６０℃、相対湿度７５％の条件下に保存した。保存開始から７日経過後、各錠剤中の塩酸イミダプリルの残存量を高速液体クロマトグラフィーにより測定した。その測定結果から、それぞれ残存百分率（％）を算出し、下記の結果を得た。
保存開始時（％）７日経過後（％）
実施例１９９．８９９．６
実施例２９９．７９９．５
実施例３９９．４９９．４
実施例４９９．７９９．４
比較例１９９．９９３．９
以上の結果から、本発明に係る実施例１〜４の錠剤は、比較例１の錠剤と比べ、塩酸イミダプリルを極めて効果的に安定に保持し得ることが判った。 Test Example 1 (Imidapril hydrochloride remaining rate in tablets in severe test)
(1) Test method Each OO tablet was taken about the tablet of Examples 1-4 and the tablet obtained by the comparative example 1, each was accommodated in the open glass bottle, and it put into the thermostat, and the temperature of 60 degreeC and relative humidity of 75% are carried out. Stored under conditions. Seven days after the start of storage, the residual amount of imidapril hydrochloride in each tablet was measured by high performance liquid chromatography. From the measurement results, the remaining percentage (%) was calculated, and the following results were obtained.
Start of storage (%) After 7 days (%)
Example 1 99.8 99.6
Example 2 99.7 99.5
Example 3 99.4 99.4
Example 4 99.7 99.4
Comparative Example 1 99.9 93.9
From the above results, it was found that the tablets of Examples 1 to 4 according to the present invention can hold imidapril hydrochloride very effectively and stably as compared with the tablet of Comparative Example 1.

塩酸イミダプリルは、腎障害を伴なう高血圧症等の治療に有用な医薬であるが、安定性に問題がある。しかし、本発明によれば、塩酸イミダプリルを長期間安定に保持することができる錠剤を、医療現場に提供することができる。 Imidapril hydrochloride is a useful drug for the treatment of hypertension associated with renal disorder, but has a problem in stability. However, according to this invention, the tablet which can hold | maintain imidapril hydrochloride stably for a long term can be provided to a medical field.

Claims

塩酸イミダプリルと製剤上の添加物からなる錠剤であって、滑沢剤が金属イオンを含まないことを特徴とする錠剤。 A tablet comprising imidapril hydrochloride and a pharmaceutical additive, wherein the lubricant does not contain metal ions.

滑沢剤が、硬化油、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、カルナウバロウ又はサラシミツロウである請求項１に記載の錠剤。 The tablet according to claim 1, wherein the lubricant is hydrogenated oil, glycerin fatty acid ester, sucrose fatty acid ester, carnauba wax or honey beeswax.

製剤上の添加物として含んでいてもよい水溶性賦形剤が、乳糖、Ｄ−マンニトール、エリスリトール又はトレハロースである請求項１に記載の錠剤。 The tablet according to claim 1, wherein the water-soluble excipient that may be contained as an additive in the preparation is lactose, D-mannitol, erythritol, or trehalose.

製剤上の添加物として含まれる結合剤がポリビニルアルコール（部分ケン化物）、メチルセルロース又はプルランである請求項１に記載の錠剤。 The tablet according to claim 1, wherein the binder contained as an additive in the preparation is polyvinyl alcohol (partially saponified product), methylcellulose or pullulan.

製剤上の添加物として含まれる崩壊剤がカルメロースである請求項１に記載の錠剤。 The tablet according to claim 1, wherein the disintegrant contained as an additive in the preparation is carmellose.