JPS6089479A - Production of stable pipethanate hydrochloride pharmaceutical - Google Patents
Production of stable pipethanate hydrochloride pharmaceuticalInfo
- Publication number
- JPS6089479A JPS6089479A JP58197886A JP19788683A JPS6089479A JP S6089479 A JPS6089479 A JP S6089479A JP 58197886 A JP58197886 A JP 58197886A JP 19788683 A JP19788683 A JP 19788683A JP S6089479 A JPS6089479 A JP S6089479A
- Authority
- JP
- Japan
- Prior art keywords
- hydrochloride
- drying
- aluminum silicate
- starch hydrolyzate
- pipesanate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は安定な塩酸ビペサネート製剤の製造方法に関す
るものである。更に詳しくは、塩酸ビペサネートの水溶
液にケイ酸アルミニウム及びでん粉加水分解物を加えて
、造粒乾燥することを特長とする安定な塩酸ビペサネー
ト製剤の製造方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing stable bipesanate hydrochloride formulations. More specifically, the present invention relates to a method for producing a stable bipesanate hydrochloride preparation, which is characterized by adding aluminum silicate and starch hydrolyzate to an aqueous solution of bipesanate hydrochloride, followed by granulation and drying.
本発明の目的物の主成分である塩酸ピペサネートは第6
級アミンの塩酸塩であって、有用なコリン遮断剤として
主に制酸剤と配合されて常用される水溶性医薬品である
。槽造的にはベンジル酸とピペリジンエタノールとのエ
ステルであるところから、この結晶は水分、熱、塩基性
物質によって分解をうけやすいことが知られており、従
って塩基性の薬物である制酸剤と配合された製剤の場合
特に分解されやすく、その製剤の有効期間が短いことが
大きな欠点である。Pipesanate hydrochloride, which is the main component of the object of the present invention, is the 6th
It is a water-soluble drug that is a useful cholinergic blocker and is commonly used in combination with antacids. Because it is an ester of benzylic acid and piperidine ethanol, it is known that this crystal is easily decomposed by moisture, heat, and basic substances, and is therefore used as an antacid, which is a basic drug. A major drawback is that preparations formulated with these drugs are particularly susceptible to decomposition and have a short shelf life.
従来から不安定な水溶性医薬品の安定化法として公知な
合成又は天然の高分子膜や蝋状物質による被覆法は、操
作が繁雑であったり、被覆膜が不均一なため安定な製品
を完全に得ることを得ず、又、ケイ酸又はケイ酸塩ヒド
ロゲルによる包蔵化法は、ヒドロゲルという特殊なもの
を調製して用いることや乾燥効率が悪いなどの欠点があ
る。又、シクロデキストリンによって包接化合物となす
方法にあっては製造コストが高く、工業的に生産が不適
当であったりして安定生産をみていないのが現状である
。Coating methods with synthetic or natural polymer membranes or waxy substances, which have been known as methods for stabilizing unstable water-soluble pharmaceuticals, are complicated to operate and the coating is uneven, making it difficult to obtain stable products. Furthermore, the encapsulation method using silicic acid or silicate hydrogel has drawbacks such as the need to prepare and use a special hydrogel and poor drying efficiency. Furthermore, in the method of forming an clathrate compound using cyclodextrin, the manufacturing cost is high, and production is not suitable for industrial use, so that stable production is not currently possible.
本発明者らは上記の欠点を改善し、本発明の水溶性医薬
品である塩酸ビペサネート製剤を安定化し、そして更に
好ましくは安価に大量生産を可能ならしめる目的で鋭意
研究を重ねた結果ケイ酸アルミニウム及びでん粉加水分
解物のいづれも、夫々単独で用いては塩酸ビベサネート
を安定化することはできないが、両者が共存すれば塩酸
ビペサネートが極めて安定になるという驚くべき事実を
発見し、本発明を完成させるに至った。The present inventors have conducted intensive research to improve the above-mentioned drawbacks, stabilize the water-soluble pharmaceutical bipesanate hydrochloride formulation of the present invention, and more preferably enable mass production at low cost.As a result, aluminum silicate The inventors discovered the surprising fact that bipesanate hydrochloride cannot be stabilized when used alone and starch hydrolyzate, but bipesanate hydrochloride becomes extremely stable when both are used together, and the present invention was completed based on this discovery. I ended up letting it happen.
本発明を実施するに当たっては、塩酸ピペサネートの水
溶液に最初にケイ酸アルミニウムとでん粉加水分解物を
加えるが、両者の注加法は同時、順次のいづれでもよく
、本発明の効果に影響を及ぼさない。得られた混合液を
混和均一攪拌したのち、次いで得られたスラリー状混和
物を造粒乾燥するに際しては押出成形ののちマルメライ
ザーで造粒して棚式乾燥する方法、流動床造粒乾燥、噴
霧造粒乾燥等いづれの造粒乾燥法によっても良いが、大
量に安定生産が可能である点で、造粒と乾燥を同時に行
うことのできる噴霧乾燥が好ましい。In carrying out the present invention, aluminum silicate and starch hydrolyzate are first added to an aqueous solution of pipesanate hydrochloride, but both may be added simultaneously or sequentially without affecting the effects of the present invention. After mixing and uniformly stirring the obtained mixture, the obtained slurry mixture is then granulated and dried by extrusion molding, granulation with a marmerizer, and shelf drying, fluidized bed granulation drying, Although any granulation and drying method such as spray granulation drying may be used, spray drying is preferred because it allows stable production in large quantities and allows granulation and drying to be performed simultaneously.
本発明に使用されているケイ酸アルミニウムは日本薬局
方天然又は合成ケイ酸アルミニウムであって、表面酸性
点が多く、シかも吸着能を高めるための大きな微細構造
を有するので好適である。又でん粉加水分解物は、でん
粉を原料に酵素によって加水分解して得られるグルコー
ス残基を基本骨格にもつ、DexstroseE!qu
ivalent値口でん粉の品位の表示であって直接還
元糖(ぶどう糖として)/全固形物×100で表す。以
下DE値・と略称する。The aluminum silicate used in the present invention is natural or synthetic aluminum silicate according to the Japanese Pharmacopoeia, and is suitable because it has many acidic points on the surface and a large fine structure for increasing the adsorption ability. In addition, starch hydrolyzate is DexstroseE!, which has a basic skeleton of glucose residues obtained by hydrolyzing starch with enzymes. qu
ivalent value is an indication of the quality of starch and is expressed as direct reducing sugar (as glucose)/total solids x 100. Hereinafter, it will be abbreviated as DE value.
〕が2′〜66の値を有するものであり、好ましくは吸
湿性の低い性質をもつ2〜20のり、[C値をもつもの
であって、DE値をほとんど有せずグルコース残基の環
状構造をもつのが特長のシクロデキストリンはこれに該
当しない。] has a value of 2' to 66, preferably 2 to 20, which has a property of low hygroscopicity, and has a [C value, has almost no DE value and has a cyclic structure of glucose residues. This does not apply to cyclodextrin, which is characterized by its structure.
本発明に用いる塩酸ビペサネートの水溶液の濃度は1〜
5 w/v%であり、後に行う造粒乾燥の方法に関係し
て濃度を選ぶ。即ち造粒後乾燥するときは1〜6%、同
時に造粒乾燥を行う工程を選ぶときは2〜5%にする。The concentration of the aqueous solution of bipesanate hydrochloride used in the present invention is 1 to
5 w/v%, and the concentration is selected in relation to the method of granulation and drying that will be carried out later. That is, it should be 1 to 6% when drying after granulation, and 2 to 5% when selecting a process in which granulation and drying are performed at the same time.
又、本発明に用いるケイ酸アルミニウム、でん粉加水分
解物の塩酸ピペサネートに対する配合比は、ケイ酸アル
ミニウム粉末の細孔径、細孔容積、比表面積等の表面物
性によって決まるが、塩酸ピペサネート1部に対し、ケ
イ酸アルミニウム粉末5〜50部、でん粉加水分解物1
〜5部を用いると良い。又、湿式造粒乾燥の乾燥温度は
乾燥法により異なるが、゛製剤にかかる品温が50〜6
0 が好ましい。In addition, the blending ratio of aluminum silicate and starch hydrolyzate used in the present invention to pipesanate hydrochloride is determined by the surface properties of the aluminum silicate powder, such as pore diameter, pore volume, and specific surface area. , 5 to 50 parts of aluminum silicate powder, 1 part of starch hydrolyzate
It is recommended to use ~5 parts. In addition, the drying temperature for wet granulation drying varies depending on the drying method.
0 is preferred.
本発明で得られた安定な塩酸ピペサネート製剤はそのま
ま単味の製剤として用いることもできるが、制酸剤との
配合剤とした場合でも長期にわたり安定性を保つことが
できる。The stable pipesanate hydrochloride preparation obtained in the present invention can be used as it is as a single preparation, but it can also maintain stability for a long period of time even when combined with an antacid.
本発明の実施例1〜4、参考例1〜2で得られた製剤を
試験製剤として用い、次の安定性試験を行い、結果を表
工、夏に示した。The following stability tests were conducted using the formulations obtained in Examples 1 to 4 and Reference Examples 1 to 2 of the present invention as test formulations, and the results were presented in Omoteko and Natsu.
安定性試験
[試験工〕試験製剤1.09をポリセロ包材40X6C
1+mk:密封し、40’、75%RH及び50°の条
件下で6ケ月加速試験し、製剤中の塩酸ピペサネートの
残存量から水分、熱の同製剤に及ぼす影響を調べた。Stability test [Testing process] Test formulation 1.09 was wrapped in polycello packaging material 40X6C.
1+mk: The product was sealed and subjected to an accelerated test for 6 months under the conditions of 40', 75% RH and 50°, and the effects of moisture and heat on the product were investigated based on the residual amount of pipesanate hydrochloride in the product.
結果を表工に示した。The results were shown to the surface engineer.
[試験1工]試験製剤0.19と塩基性物質である日本
薬局方沈降炭酸カルシウム又は日本薬局方炭酸マグネシ
ウムの0.9gを混合した後ポリセロ包材40 X 6
0 mmに密封し、以下「試験工」と同様に行って塩基
性物質の存在下での水分、熱の製剤に及ぼす影響を調べ
た。[Test 1] After mixing 0.19 g of the test preparation and 0.9 g of Japanese Pharmacopoeia precipitated calcium carbonate or Japanese Pharmacopoeia magnesium carbonate, which is a basic substance, polycello packaging material 40 x 6
The test tube was sealed to a diameter of 0 mm, and the effects of moisture and heat on the preparation in the presence of a basic substance were investigated in the same manner as in the "Experimental Engineering" section below.
その結果を表エエに示した。The results are shown in Table A.
\
本発明における安定化の機構についての考察は以下の如
くであるが、本発明はこの考察に拘束されるものではな
い。\ Although the consideration regarding the stabilization mechanism in the present invention is as follows, the present invention is not limited to this consideration.
試験製剤を用いた安定性試験結果から、参考例1の単に
ケイ酸アルミニウム粉末と塩酸ピペサネート水溶液を混
和し、当該スラリーを乾燥させた試験製剤は、安定性試
験の6ケ月後には水分、熱の影響から製造直後の1/2
〜1/6量しか塩酸ピペサネートは存在せず、又、塩基
性物質が存在すれば更に結果は悪くなる。この結果は、
塩酸ピベサネートが乾燥工程中にケイ酸アルミニウムの
粉体表面に晶出するため、完全な吸着包蔵がなされてい
ないことを示している。From the stability test results using the test formulation, it was found that the test formulation of Reference Example 1, which was prepared by simply mixing aluminum silicate powder and pipesanate hydrochloride aqueous solution and drying the slurry, was free from moisture and heat 6 months after the stability test. 1/2 immediately after manufacturing due to influence
Only ~1/6 of the amount of pipesanate hydrochloride is present, and the results are even worse if basic substances are present. This result is
This shows that pivesanate hydrochloride crystallizes on the surface of the aluminum silicate powder during the drying process, so complete adsorption and encapsulation is not achieved.
又一方、参考例2の単にでん粉加水分解物と塩酸ビペサ
ネート水溶液とを混和し、当該スラリーを乾燥させた試
験製剤も、上記安定性試験結果と同様塩酸ピペサネート
は製造直後の1/2〜1/6量しか残存していない。こ
の結果は、でん粉加水分解物が包接力、吸着力をもって
いないため、でん粉加水分解物が塩酸ビペサネートを被
覆保護しないことを示していると思われる。On the other hand, in the test formulation of Reference Example 2 in which the starch hydrolyzate and the bipesanate hydrochloride aqueous solution were simply mixed and the slurry was dried, the pipesanate hydrochloride was 1/2 to 1/2 the same as the above stability test results. Only 6 quantities remain. This result seems to indicate that the starch hydrolyzate does not cover and protect bipesanate hydrochloride because the starch hydrolyzate does not have inclusion or adsorption power.
一方、実施例1〜4で得られた試験製剤の加速虐待条件
下での安定性試験を行っても、製剤中の塩酸ビペサネー
トの残存量は製造直後と6ケ月後とほとんど変わらず、
従って水、熱や塩基性物質の影響を全く受けない。この
ことは水溶性の塩酸ビペサネート、微細構造を有するケ
イ酸アルミニウム粉末と水易溶性のでん粉加水分解物の
王者のあるところで、10〜100A細孔を有するケイ
酸アルミニウムに塩酸ピペサネー)(分子径7 XX2
oλ)が表面吸着されそのものを乾燥工程の間にでん
粉加水分解物が保護コロイド状の被覆膜で覆い、水分、
熱や塩基性物質による影響から塩酸ビペサネートを保護
安定化するものと考えられる。On the other hand, even when the test formulations obtained in Examples 1 to 4 were subjected to stability tests under accelerated abuse conditions, the residual amount of bipesanate hydrochloride in the formulations was almost the same immediately after production and after 6 months.
Therefore, it is completely unaffected by water, heat, and basic substances. This means that water-soluble bipesanate hydrochloride, aluminum silicate powder with a fine structure, and easily water-soluble starch hydrolyzate are the kings, and aluminum silicate with 10-100A pores is mixed with pipesanate hydrochloride (molecular diameter 7 XX2
oλ) is adsorbed on the surface, and during the drying process, the starch hydrolyzate is covered with a protective colloid-like coating film, and moisture,
It is thought to protect and stabilize bipesanate hydrochloride from the effects of heat and basic substances.
以下実施例を示す。Examples are shown below.
実施例1
塩酸ピペサネー、) 50 gに60°の温湯1.67
1を加えて6W/v%溶液となし、その溶液に日本薬局
方合成ケイ酸アルミニウム650りを加えて均一に混和
し、次いでDI値2のでん粉加水分解物1259を加え
練合し、42メツシユ篩を用いて造粒後、50°で棚式
乾燥して細粒を得た。得!785 g。Example 1 Pipesanate hydrochloride,) 50 g of 60° warm water 1.67 g
1 was added to make a 6W/v% solution, 650 ml of Japanese Pharmacopoeia synthetic aluminum silicate was added to the solution, and mixed uniformly. Next, starch hydrolyzate 1259 with a DI value of 2 was added and kneaded, and 42 mesh After granulation using a sieve, the mixture was dried on a shelf at 50° to obtain fine granules. Benefit! 785g.
実施例2
塩酸ピペサネート500gに60°の温湯16.71を
加え3w/v%溶液となし、その溶液に日本薬局方合成
ケイ酸アルミニウム5.5kg及びDII2O3でん粉
加水分解物2.25〜を同時に加えて均一に混和し、当
該スラリーを、入熱温度210°で噴%乾燥して細粒を
得た。得量7.76PC9゜
実施例6
実施例2で用いたと同一の塩酸ピベサネート3w/v%
水溶液16.77に、日本薬局方天然ケイ酸アルミニウ
ム6.5kgとDE値8のでん粉加水分解物1.25に
9を同時に加えて均一に混和し、当該スラリーを入熱温
度220°で噴霧乾燥して細粒を得た。得量7.82k
g。Example 2 16.71 g of 60° warm water was added to 500 g of pipesanate hydrochloride to make a 3 w/v% solution, and 5.5 kg of Japanese Pharmacopoeia synthetic aluminum silicate and 2.25 ~ of DII2O3 starch hydrolyzate were simultaneously added to the solution. The slurry was spray-dried at a heat input temperature of 210° to obtain fine particles. Yield 7.76PC9゜Example 6 Pibesanate hydrochloride same as used in Example 2 3w/v%
To the aqueous solution 16.77, 6.5 kg of Japanese Pharmacopoeia natural aluminum silicate and 1.25 starch hydrolyzate with a DE value of 8 and 9 were simultaneously added and mixed uniformly, and the slurry was spray-dried at a heat input temperature of 220°. Fine grains were obtained. Earned amount 7.82k
g.
実施例4
実施例1で用いたと同一の塩酸ピペサネート3w/v%
水溶液1.671に、DI値19のでん粉加水分解物2
50gを加えて均一に混和し次いで、日本薬局方天然ケ
イ酸アルミニウム5259を加えて練合し、20メツシ
ユ篩を用いて造粒乾燥後、50°で棚式乾燥して細粒を
得た。得量7689゜
参考例1
実施例2で用いたと同一の塩酸ピペサネート3w/v%
水溶液16.7/に、日本薬局方合成ケイ酸アルミニウ
ム7.75kgを加えて均一に混和し、当該スラリーを
入熱温度210°で噴霧乾燥して細粒を得た。畳量7.
8kg0参考例2
実施例1で用いたと同一の塩酸ビベサネート5*/v%
水溶液1.671に、DID値19のでん粉加水分解物
250りを加えて練合し、42メツシユ篩を用いて造粒
後50°で棚式乾燥して細粒を得た。得量2829゜
特許出願人 富士化学工業株式会社
7−i−3−
手続補正書(方式)
%式%
1、事件の表示 昭和58年特願第197886号2、
)A明の名称 安定な塩酸ビペサネート製剤の製造方法
3、補正をする者
特許出願人
トヤマケン ナカニイカフグンカミイチマチョコホウオ
ンジ住所 富山県中新用郡上市町横法音寺
55番地Example 4 Same pipesanate hydrochloride as used in Example 1 3w/v%
Starch hydrolyzate with DI value of 19 2 in aqueous solution 1.671
50 g of the mixture was added and mixed uniformly, and then Japanese Pharmacopoeia Natural Aluminum Silicate 5259 was added and kneaded. After granulation drying using a 20 mesh sieve, the mixture was dried on a shelf at 50° to obtain fine granules. Amount obtained: 7689° Reference Example 1 Pipesanate hydrochloride, the same as used in Example 2, 3 w/v%
7.75 kg of Japanese Pharmacopoeia synthetic aluminum silicate was added to 16.7 kg of the aqueous solution and mixed uniformly, and the slurry was spray-dried at a heat input temperature of 210° to obtain fine particles. Amount of tatami 7.
8kg0 Reference Example 2 Same vibesanate hydrochloride as used in Example 1 5*/v%
250 g of a starch hydrolyzate having a DID value of 19 was added to 1.671 g of an aqueous solution and kneaded, granulated using a 42 mesh sieve and dried on a shelf at 50° to obtain fine granules. Obtained amount 2829゜ Patent applicant Fuji Chemical Industry Co., Ltd. 7-i-3- Procedural amendment (method) % formula % 1. Indication of case Patent application No. 197886 of 1988 2.
) Name of Amei Process for producing stable bipesanate hydrochloride preparation 3, person making the amendment Patent applicant Ken Toyama Nakanikafugunkamiichimachocohouonji Address 55 Yokohoonji, Nakashinyo Gujo City, Toyama Prefecture
Claims (1)
ム及びでん粉加水分解物を加え造粒乾燥することを特長
とする安定な塩酸ピペサネート製剤の製造方法。 (2) 塩酸ピペサネート1部に対し、ケイ酸アルミニ
ウム5〜50部、でん粉加水分解物1〜5部を使用する
特許請求の範囲第1項記載の安定な塩酸ピペサネートの
製造方法。 (8)でん粉加水分解物のDFi値(但し、DE値はで
ん粉糖の品位の表示であって、直接還元糖(ぶどう糖と
して)/全固形分×100で表される)が2〜66であ
る特許請求の範囲第1項記載の安定な塩酸ビペサネート
製剤の製造方法。[Scope of Claims] (1) A method for producing a stable pipesanate hydrochloride preparation, which comprises adding aluminum silicate and starch hydrolyzate to an aqueous solution of pipesanate hydrochloride and granulating and drying. (2) The method for producing stable pipesanate hydrochloride according to claim 1, wherein 5 to 50 parts of aluminum silicate and 1 to 5 parts of starch hydrolyzate are used for 1 part of pipesanate hydrochloride. (8) The DFi value of the starch hydrolyzate (however, the DE value is an indication of the quality of starch sugar and is expressed as direct reducing sugar (as glucose)/total solids x 100) is 2 to 66. A method for producing a stable bipesanate hydrochloride formulation according to claim 1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP58197886A JPS6089479A (en) | 1983-10-21 | 1983-10-21 | Production of stable pipethanate hydrochloride pharmaceutical |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP58197886A JPS6089479A (en) | 1983-10-21 | 1983-10-21 | Production of stable pipethanate hydrochloride pharmaceutical |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6089479A true JPS6089479A (en) | 1985-05-20 |
JPH0329046B2 JPH0329046B2 (en) | 1991-04-23 |
Family
ID=16381929
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP58197886A Granted JPS6089479A (en) | 1983-10-21 | 1983-10-21 | Production of stable pipethanate hydrochloride pharmaceutical |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS6089479A (en) |
-
1983
- 1983-10-21 JP JP58197886A patent/JPS6089479A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPH0329046B2 (en) | 1991-04-23 |
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