JP4298212B2 - Method for producing high melting point type epinastine hydrochloride - Google Patents
Method for producing high melting point type epinastine hydrochloride Download PDFInfo
- Publication number
- JP4298212B2 JP4298212B2 JP2002095200A JP2002095200A JP4298212B2 JP 4298212 B2 JP4298212 B2 JP 4298212B2 JP 2002095200 A JP2002095200 A JP 2002095200A JP 2002095200 A JP2002095200 A JP 2002095200A JP 4298212 B2 JP4298212 B2 JP 4298212B2
- Authority
- JP
- Japan
- Prior art keywords
- epinastine hydrochloride
- epinastine
- alcohol
- producing
- melting point
- 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.)
- Expired - Fee Related
Links
Images
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】
【発明が属する技術分野】
アレルギー性疾患治療剤である塩酸エピナスチンの高融点型結晶の工業的製造法に関する。
【０００２】
【従来の技術】
塩酸エピナスチンは約２５０℃から２６３℃で融解する低融点型結晶と、約２７５℃から２８１℃で融解する高融点型結晶の２つの結晶多形が公知である。塩酸エピナスチンの製造法としては、幾つかの方法が知られている。
【０００３】
特開平３−６６３１１号公報ではメタノール中で懸濁したエピナスチンを塩化水素を含有するエーテルで処理し、エーテルで沈殿させることにより塩酸エピナスチンが得られる。この欠点は、低融点型結晶が含まれる点にあることがＷＯ ０１／４０２２９で報告されている。
【０００４】
ＷＯ ０１／４０２２９ではエピナスチンを水に懸濁し、塩酸を用いpHを定められた非常に狭い範囲内に調製し塩酸エピナスチンの高融点型結晶を沈殿させることにより得られる。この種の操作は極めて複雑で、工業的生産に適していない。
【０００５】
【発明が解決しようとする課題】
通常、結晶多形が存在する化合物は結晶形によって種々の性質が相違する。よって、結晶多形が存在する化合物を医薬品として用いる場合、安定性、溶解度、溶解速度などの性質の違いによって吸収や製剤化の問題となることが多く知られている。塩酸エピナスチンが医薬品として要求される均一な品質及び一定の作用効果を確保するためには、単一の結晶性の化合物を常に一定して提供することが必要である。
【０００６】
これまでの製造法では一定の品質が得られない、操作が複雑である等の欠点があり、工業的生産に適しているとは言えなかった。本発明は、従来の技術の欠点がない工業規模で利用できる塩酸エピナスチンの高溶解型結晶の製造法を提供する。
【０００７】
【課題を解決するための手段】
本発明者らは、従来の技術の欠点の改善を目指して鋭意研究を進めてきた。その結果、本発明の製造法が塩酸エピナスチンの高融点型結晶を常に一定して得られることを見出し、本発明をなすに至った。
【０００８】
本発明は、より具体的には図１に示すように示差熱分析(DSC)において融解ピーク：約２７５℃から２８１℃を有することにより特徴付けられる塩酸エピナスチンの高融点型結晶の製造法である。
【０００９】
【発明の実施の形態】
塩酸エピナスチンの高融点型結晶の製造法について、具体的に述べる。なお、本発明におけるエピナスチンとは、塩酸エピナスチンの遊離体、すなわち３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ〔ｃ，ｆ〕イミダゾ〔１，５−ａ〕アゼピンを意味する。
【００１０】
１）塩酸エピナスチンをアルコールに加熱溶解し、エーテル系溶媒またはエステル系溶媒を加え、結晶化することにより製造する。アルコールとしてはエタノール、１−プロパノール、２−プロパノールがあげられる。エーテル系溶媒としてはイソプロピルエーテル、ｔ−ブチルメチルエーテル、テトラヒドロフランなどがあげられ、ｔ−ブチルメチルエーテル、テトラヒドロフランが医薬品の安全性の点から好ましい。エステル系溶媒としては酢酸エチル、酢酸ブチルがあげられ、安価な酢酸エチルが好ましい。
【００１１】
２）塩酸エピナスチンをアルコールに溶解し結晶化することにより製造する。アルコールとしては炭素数３〜４のアルコールがあげられ、具体的には１−プロパノール、２−プロパノール、１−ブタノール、２−ブタノールが用いられ、特に１−プロパノールが収率の点から好ましい。
【００１２】
３）塩酸エピナスチンをジメチルホルムアミドに溶解し結晶化することにより製造する。
【００１３】
４）塩酸エピナスチンをアルコールに加熱溶解し、アセトニトリルを加え、結晶化することにより製造する。アルコールとしてはメタノール、エタノール、１−プロパノール、２−プロパノールがあげられる。
【００１４】
５）塩酸エピナスチンをジメチルスルホキシドに加熱溶解し、アセトンを加え、結晶化することにより製造する。
【００１５】
６）エピナスチンをアルコールに懸濁し塩化水素/アルコールを加え加熱溶解後、減圧下にて濃縮して得られた塩酸エピナスチンを用い上記１）〜５）の方法により製造する。アルコールとしてはメタノール、エタノール、１−プロパノール、２−プロパノールがあげられる。
【００１６】
【実施例】
実施例によって本発明を具体的に説明するが、本発明がこれらの実施例のみに限定されるものではない。
【００１７】
[実施例１]
塩酸エピナスチン1gをエタノール2mlに加熱溶解した。ここにテトラヒドロフラン20mlを加え、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチン高融点型結晶0.6gを得た。
【００１８】
[実施例２]
塩酸エピナスチン15gをエタノール60mlに加熱溶解した。ここにt-ブチルメチルエーテル150mlを加え、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチン高融点型結晶13gを得た。
【００１９】
[実施例３]
塩酸エピナスチン15gをエタノール45mlに加熱溶解した。ここに酢酸エチル225mlを加え、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチン高融点型結晶11gを得た。
【００２０】
[実施例４]
塩酸エピナスチン30gを1-プロパノール90mlに加熱溶解した。室温まで30分間かけて冷却後、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチン高融点型結晶24gを得た。
【００２１】
[実施例５]
塩酸エピナスチン１gをジメチルホルムアミド５mlに加熱溶解した。氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチン高融点型結晶0.8gを得た。
【００２２】
[実施例６]
塩酸エピナスチン3gをメタノール3mlに加熱溶解した。ここにアセトニトリル10mlを加え、約1/5量の溶媒を減圧下留去した。残留混合物にアセトニトリル2mlを加え氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチンの高融点型結晶1.6gを得た。
【００２３】
[実施例７]
塩酸エピナスチン１gをジメチルスルホキシド２mlに加熱溶解した。ここにアセトン５mlを加え、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチン高融点型結晶0.7gを得た。
【００２４】
[実施例８]
エピナスチン52gをエタノール240mlに懸濁した。攪拌下、13%-塩化水素/エタノール 64gを加え40℃で加熱溶解した。これに、活性炭3gを添加し40℃で30分間攪拌した後、不溶物をろ去し、ろ液を減圧下にて濃縮した。残留物にエタノール125mlを加え加熱溶解後、冷却し室温まで戻した。ここにテトラヒドロフラン1200mlを加え、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチンの高融点型結晶36gを得た。
【００２５】
[実施例９]
エピナスチン5gをエタノール23mlに懸濁した。攪拌下、18%-塩化水素/エタノール 4.4gを加え40℃で加熱溶解した。これに、活性炭0.3gを添加し40℃で30分間攪拌した後、不溶物をろ去し、ろ液を減圧下にて濃縮した。残留物にエタノール23mlを加え加熱溶解後、冷却し室温まで戻した。ここにt-ブチルメチルエーテル57mlを加え、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチンの高融点型結晶4.9gを得た。
【００２６】
[実施例１０]
エピナスチン5gをエタノール23mlに懸濁した。攪拌下、18%-塩化水素/エタノール 4.4gを加え40℃で加熱溶解した。これに、活性炭0.3gを添加し40℃で30分間攪拌した後、不溶物をろ去し、ろ液を減圧下にて濃縮した。残留物にエタノール17mlを加え加熱溶解後、冷却し室温まで戻した。ここに酢酸エチル86mlを加え、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチンの高融点型結晶4.1gを得た。
【００２７】
[実施例１１]
エピナスチン5gをエタノール23mlに懸濁した。攪拌下、18%-塩化水素/エタノール 4.4gを加え40℃で加熱溶解した。これに、活性炭0.3gを添加し40℃で30分間攪拌した後、不溶物をろ去し、ろ液を減圧下にて濃縮した。残留物に１−プロパノール17mlを加え加熱溶解後、冷却し室温まで戻し、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチンの高融点型結晶4.6gを得た。
【００２８】
[実施例１２]
エピナスチン82gをエタノール380mlに懸濁した。攪拌下、19%-塩化水素/エタノール 66.1gを加え40℃で加熱溶解した。これに、活性炭4gを添加し40℃で30分間攪拌した後、不溶物をろ去し、ろ液を減圧下にて濃縮した。残留物にジメチルホルムアミド470mlを加え加熱溶解後、冷却し室温まで戻し、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチンの高融点型結晶67gを得た。
【００２９】
[実施例１３]
エピナスチン2.5gをメタノール10mlに懸濁した。攪拌下、18%-塩化水素/メタノール 2.2gを加え40℃で加熱溶解後、減圧下にて濃縮した。残留物にメタノール3mlを加え加熱溶解後、アセトニトリル10mlを加え、約1/5量の溶媒を減圧下留去した。残留混合物にアセトニトリル2mlを加え氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチンの高融点型結晶1.4gを得た。
【００３０】
[実施例１４]
エピナスチン5gをエタノール23mlに懸濁した。攪拌下、18%-塩化水素/エタノール 4.4gを加え40℃で加熱溶解した。これに、活性炭0.3gを添加し40℃で30分間攪拌した後、不溶物をろ去し、ろ液を減圧下にて濃縮した。残留物にジメチルスルホキシド10mlを加え加熱溶解後、冷却し室温まで戻した。ここにアセトン25mlを加え、氷冷攪拌下、析出した結晶をろ別・乾燥し、塩酸エピナスチンの高融点型結晶4gを得た。
【００３１】
【発明の効果】
本発明の製造法によれば、塩酸エピナスチンの高融点型結晶を簡単な操作で容易に製造することができるという効果が奏される。
【００３２】
【図面の簡単な説明】
【図１】塩酸エピナスチンの高融点型結晶の示差熱分析(DSC)である。[0001]
[Technical field to which the invention belongs]
The present invention relates to an industrial production method of a high melting point crystal of epinastine hydrochloride, which is a therapeutic agent for allergic diseases.
[0002]
[Prior art]
Epinastine hydrochloride is known in two crystal polymorphs: a low-melting-type crystal that melts at about 250 to 263 ° C. and a high-melting-type crystal that melts at about 275 to 281 ° C. Several methods are known for producing epinastine hydrochloride.
[0003]
In JP-A-3-66311, epinastine hydrochloride suspended in methanol is treated with ether containing hydrogen chloride and precipitated with ether to obtain epinastine hydrochloride. It has been reported in WO 01/40229 that this drawback lies in the inclusion of low melting point type crystals.
[0004]
In WO 01/40229, it is obtained by suspending epinastine in water, adjusting the pH within a very narrow range using hydrochloric acid, and precipitating high-melting-type crystals of epinastine hydrochloride. This type of operation is extremely complex and not suitable for industrial production.
[0005]
[Problems to be solved by the invention]
Usually, a compound having a crystalline polymorph has various properties depending on the crystalline form. Therefore, when a compound having a crystalline polymorph is used as a pharmaceutical, it is often known that absorption and formulation problems occur due to differences in properties such as stability, solubility, and dissolution rate. In order for epinastine hydrochloride to ensure the uniform quality and certain functions and effects required as a pharmaceutical product, it is necessary to always provide a single crystalline compound in a constant manner.
[0006]
The conventional production methods have such disadvantages that a certain quality cannot be obtained and the operation is complicated, so that it cannot be said to be suitable for industrial production. The present invention provides a process for producing highly soluble crystals of epinastine hydrochloride that can be used on an industrial scale without the disadvantages of the prior art.
[0007]
[Means for Solving the Problems]
The inventors of the present invention have been diligently researching to improve the drawbacks of the conventional techniques. As a result, it has been found that the production method of the present invention can always obtain a high melting point type crystal of epinastine hydrochloride, and has led to the present invention.
[0008]
More specifically, the present invention is a method for producing a high melting point type crystal of epinastine hydrochloride characterized by having a melting peak: about 275 ° C. to 281 ° C. in differential thermal analysis (DSC) as shown in FIG. .
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The production method of the high melting point type epinastine hydrochloride will be specifically described. In addition, the epinastine in this invention means the free form of epinastine hydrochloride, ie, 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine.
[0010]
1) It is manufactured by heating and dissolving epinastine hydrochloride in alcohol, adding an ether solvent or an ester solvent, and crystallization. Examples of the alcohol include ethanol, 1-propanol, and 2-propanol. Examples of the ether solvent include isopropyl ether, t-butyl methyl ether, tetrahydrofuran, and the like, and t-butyl methyl ether and tetrahydrofuran are preferable from the viewpoint of safety of pharmaceuticals. Examples of the ester solvent include ethyl acetate and butyl acetate, and inexpensive ethyl acetate is preferable.
[0011]
2) Manufactured by dissolving epinastine hydrochloride in alcohol and crystallizing. Examples of the alcohol include alcohols having 3 to 4 carbon atoms. Specifically, 1-propanol, 2-propanol, 1-butanol and 2-butanol are used, and 1-propanol is particularly preferable from the viewpoint of yield.
[0012]
3) Manufactured by dissolving epinastine hydrochloride in dimethylformamide and crystallizing.
[0013]
4) It is manufactured by heating and dissolving epinastine hydrochloride in alcohol, adding acetonitrile and crystallizing. Examples of the alcohol include methanol, ethanol, 1-propanol, and 2-propanol.
[0014]
5) It is manufactured by heating and dissolving epinastine hydrochloride in dimethyl sulfoxide, adding acetone and crystallizing.
[0015]
6) Epinastine is suspended in alcohol, hydrogen chloride / alcohol is added and dissolved by heating, and then epinastine hydrochloride obtained by concentrating under reduced pressure is used for the production according to the methods 1) to 5). Examples of the alcohol include methanol, ethanol, 1-propanol, and 2-propanol.
[0016]
【Example】
EXAMPLES The present invention will be specifically described with reference to examples, but the present invention is not limited only to these examples.
[0017]
[Example 1]
1 g of epinastine hydrochloride was dissolved by heating in 2 ml of ethanol. Tetrahydrofuran (20 ml) was added thereto, and the crystals precipitated were collected by filtration and dried with ice-cooling to obtain 0.6 g of epinastine hydrochloride high melting point type crystals.
[0018]
[Example 2]
Epinastine hydrochloride (15 g) was dissolved in 60 ml of ethanol by heating. 150 ml of t-butyl methyl ether was added thereto, and the precipitated crystals were filtered and dried with stirring under ice cooling to obtain 13 g of epinastine hydrochloride high melting point type crystals.
[0019]
[Example 3]
Epinastine hydrochloride (15 g) was dissolved by heating in ethanol (45 ml). 225 ml of ethyl acetate was added thereto, and the precipitated crystals were filtered and dried with stirring under ice-cooling to obtain 11 g of epinastine hydrochloride high melting point crystals.
[0020]
[Example 4]
30 g of epinastine hydrochloride was dissolved by heating in 90 ml of 1-propanol. After cooling to room temperature over 30 minutes, the precipitated crystals were filtered and dried with ice-cooling and stirring to obtain 24 g of epinastine hydrochloride high melting point type crystals.
[0021]
[Example 5]
1 g of epinastine hydrochloride was dissolved in 5 ml of dimethylformamide by heating. Under ice-cooling and stirring, the precipitated crystals were filtered and dried to obtain 0.8 g of epinastine hydrochloride high melting point type crystals.
[0022]
[Example 6]
3 g of epinastine hydrochloride was dissolved by heating in 3 ml of methanol. 10 ml of acetonitrile was added thereto, and about 1/5 amount of the solvent was distilled off under reduced pressure. 2 ml of acetonitrile was added to the residual mixture, and the crystals that precipitated were filtered and dried with stirring under ice cooling to obtain 1.6 g of high-melting-point crystals of epinastine hydrochloride.
[0023]
[Example 7]
1 g of epinastine hydrochloride was dissolved by heating in 2 ml of dimethyl sulfoxide. Acetone (5 ml) was added thereto, and the precipitated crystals were filtered and dried with stirring under ice cooling to obtain 0.7 g of epinastine hydrochloride high melting point crystals.
[0024]
[Example 8]
Epinastine 52g was suspended in ethanol 240ml. Under stirring, 64% of 13% hydrogen chloride / ethanol was added and dissolved by heating at 40 ° C. To this was added 3 g of activated carbon, and the mixture was stirred at 40 ° C. for 30 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. 125 ml of ethanol was added to the residue and dissolved by heating, then cooled and returned to room temperature. Tetrahydrofuran (1200 ml) was added thereto, and the crystals precipitated were filtered and dried under ice-cooling and stirring to obtain 36 g of high-melting-point crystals of epinastine hydrochloride.
[0025]
[Example 9]
Epinastine (5 g) was suspended in ethanol (23 ml). Under stirring, 4.4 g of 18% hydrogen chloride / ethanol was added and dissolved by heating at 40 ° C. To this was added 0.3 g of activated carbon, and the mixture was stirred at 40 ° C. for 30 minutes. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. 23 ml of ethanol was added to the residue and dissolved by heating, and then cooled and returned to room temperature. To this was added 57 ml of t-butyl methyl ether, and the crystals precipitated were collected by filtration and dried with ice-cooling to obtain 4.9 g of high-melting-type crystals of epinastine hydrochloride.
[0026]
[Example 10]
Epinastine (5 g) was suspended in ethanol (23 ml). Under stirring, 4.4 g of 18% hydrogen chloride / ethanol was added and dissolved by heating at 40 ° C. To this was added 0.3 g of activated carbon, and the mixture was stirred at 40 ° C. for 30 minutes. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. 17 ml of ethanol was added to the residue and dissolved by heating, then cooled and returned to room temperature. 86 ml of ethyl acetate was added thereto, and the crystals precipitated were filtered and dried under ice-cooling and stirring to obtain 4.1 g of a high melting point crystal of epinastine hydrochloride.
[0027]
[Example 11]
Epinastine (5 g) was suspended in ethanol (23 ml). Under stirring, 4.4 g of 18% hydrogen chloride / ethanol was added and dissolved by heating at 40 ° C. To this was added 0.3 g of activated carbon, and the mixture was stirred at 40 ° C. for 30 minutes. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. 17 ml of 1-propanol was added to the residue, dissolved by heating, cooled and returned to room temperature, and the crystals precipitated were filtered and dried with stirring under ice cooling to obtain 4.6 g of high-melting-point crystals of epinastine hydrochloride.
[0028]
[Example 12]
Epinastine 82g was suspended in ethanol 380ml. Under stirring, 66.1 g of 19% hydrogen chloride / ethanol was added and dissolved by heating at 40 ° C. 4 g of activated carbon was added thereto, and the mixture was stirred at 40 ° C. for 30 minutes. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. 470 ml of dimethylformamide was added to the residue, dissolved by heating, cooled and cooled to room temperature, and the crystals precipitated were filtered and dried with stirring under ice cooling to obtain 67 g of high-melting-point crystals of epinastine hydrochloride.
[0029]
[Example 13]
Epinastine (2.5 g) was suspended in methanol (10 ml). Under stirring, 2.2 g of 18% hydrogen chloride / methanol was added, and the mixture was heated and dissolved at 40 ° C., and then concentrated under reduced pressure. 3 ml of methanol was added to the residue and dissolved by heating, 10 ml of acetonitrile was added, and about 1/5 amount of the solvent was distilled off under reduced pressure. 2 ml of acetonitrile was added to the residual mixture, and the crystals precipitated were filtered and dried with stirring under ice cooling to obtain 1.4 g of high-melting-point crystals of epinastine hydrochloride.
[0030]
[Example 14]
Epinastine (5 g) was suspended in ethanol (23 ml). Under stirring, 4.4 g of 18% hydrogen chloride / ethanol was added and dissolved by heating at 40 ° C. To this was added 0.3 g of activated carbon, and the mixture was stirred at 40 ° C. for 30 minutes. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue, 10 ml of dimethyl sulfoxide was added and dissolved by heating, and then cooled and returned to room temperature. Acetone (25 ml) was added thereto, and the crystals precipitated were filtered and dried with stirring under ice-cooling to obtain 4 g of high-melting-point crystals of epinastine hydrochloride.
[0031]
【The invention's effect】
According to the production method of the present invention, there is an effect that a high melting point type crystal of epinastine hydrochloride can be easily produced by a simple operation.
[0032]
[Brief description of the drawings]
FIG. 1 is a differential thermal analysis (DSC) of a high melting point crystal of epinastine hydrochloride.
Claims (17)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002095200A JP4298212B2 (en) | 2002-03-29 | 2002-03-29 | Method for producing high melting point type epinastine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002095200A JP4298212B2 (en) | 2002-03-29 | 2002-03-29 | Method for producing high melting point type epinastine hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2003286287A JP2003286287A (en) | 2003-10-10 |
| JP4298212B2 true JP4298212B2 (en) | 2009-07-15 |
Family
ID=29238797
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002095200A Expired - Fee Related JP4298212B2 (en) | 2002-03-29 | 2002-03-29 | Method for producing high melting point type epinastine hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4298212B2 (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| DE102004054054A1 (en) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines |
| WO2006060615A1 (en) * | 2004-12-01 | 2006-06-08 | Teva Gyógyszergyár Zàrtköruen Muködo Rèszvènytàrsasàg | Non-hygroscopic and powdery amorphous pimecrolimus |
| JP4895510B2 (en) * | 2005-02-23 | 2012-03-14 | 株式会社トクヤマ | Method for producing variolamine |
| KR20070062504A (en) * | 2005-06-22 | 2007-06-15 | 테바 파마슈티컬 인더스트리즈 리미티드 | Polymorph of Tegase Road Maleate |
| PE20080251A1 (en) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | USES OF DPP IV INHIBITORS |
| KR101452915B1 (en) | 2006-05-04 | 2014-10-21 | 베링거 인겔하임 인터내셔날 게엠베하 | Polymorphism |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| PE20140960A1 (en) | 2008-04-03 | 2014-08-15 | Boehringer Ingelheim Int | FORMULATIONS INVOLVING A DPP4 INHIBITOR |
| UY32030A (en) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN" |
| KR20190016601A (en) | 2008-08-06 | 2019-02-18 | 베링거 인겔하임 인터내셔날 게엠베하 | Treatment for diabetes in patients inappropriate for metformin therapy |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| AU2009331471B2 (en) | 2008-12-23 | 2015-09-03 | Boehringer Ingelheim International Gmbh | Salt forms of organic compound |
| AR074990A1 (en) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY |
| KR20120107080A (en) | 2009-11-27 | 2012-09-28 | 베링거 인겔하임 인터내셔날 게엠베하 | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
| KR101927068B1 (en) | 2010-05-05 | 2018-12-10 | 베링거 인겔하임 인터내셔날 게엠베하 | Sequential Combination Therapy by the Weight Reducing Treatment Followed by the DPP-4 Inhibitor |
| KR20220025926A (en) | 2010-06-24 | 2022-03-03 | 베링거 인겔하임 인터내셔날 게엠베하 | Diabetes therapy |
| AR083878A1 (en) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | VASOPROTECTORA AND CARDIOPROTECTORA ANTIDIABETIC THERAPY, LINAGLIPTINA, TREATMENT METHOD |
| CN103781788B (en) | 2011-07-15 | 2016-08-17 | 勃林格殷格翰国际有限公司 | Quinazoline, its preparation and the purposes in pharmaceutical composition thereof being substituted |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| WO2013171166A1 (en) | 2012-05-14 | 2013-11-21 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp-4 inhibitor for use in the treatment of sirs and/or sepsis |
| JP6224084B2 (en) | 2012-05-14 | 2017-11-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Xanthine derivatives as DPP-4 inhibitors for the treatment of glomerular epithelial cell related disorders and / or nephrotic syndrome |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| CN104098575B (en) * | 2013-04-15 | 2016-06-01 | 四川科瑞德凯华制药有限公司 | Brilliant type of a kind of Epinastine Hydrochloride and its production and use |
| JP6615109B2 (en) | 2014-02-28 | 2019-12-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Medical use of DPP-4 inhibitors |
| MX390363B (en) | 2016-06-10 | 2025-03-20 | Boehringer Ingelheim Int | Combinations of linagliptin and metformin |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3008944A1 (en) * | 1980-03-08 | 1981-09-24 | C.H. Boehringer Sohn, 6507 Ingelheim | DIBENZIMIDAZOAZEPINE, THEIR PRODUCTION AND USE |
| DE4102148A1 (en) * | 1991-01-25 | 1992-07-30 | Boehringer Ingelheim Kg | METHOD FOR PRODUCING 3-AMINO-9,13B-DIHYDRO-1H-DIBENZ- (C, F) IMIDAZOLE (1,5-A) AZEPINE HYDROCHLORIDE |
| CA2184802C (en) * | 1995-10-10 | 2007-07-31 | Karl-Heinz Bender | Process for manufacture of imidazo benzodiazepine derivatives |
| JPH1053576A (en) * | 1996-06-07 | 1998-02-24 | Eisai Co Ltd | Polymorphic crystal of donepezil hydrochloride and its production |
| JP3563643B2 (en) * | 1999-08-23 | 2004-09-08 | 沢井製薬株式会社 | Imidazoline compounds, intermediates thereof, and methods for producing them, and methods for producing azepine compounds and salts thereof |
| DE19958460A1 (en) * | 1999-12-03 | 2001-06-07 | Boehringer Ingelheim Pharma | Process for the preparation of epinastine hydrochloride in high-melting crystal modification |
| GB0013407D0 (en) * | 2000-06-02 | 2000-07-26 | Astrazeneca Ab | Forms of a chemical compound |
-
2002
- 2002-03-29 JP JP2002095200A patent/JP4298212B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2003286287A (en) | 2003-10-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4298212B2 (en) | Method for producing high melting point type epinastine hydrochloride | |
| CA1131660A (en) | METHOD FOR RESOLVING RACEMIC 6-METHOXY-.alpha.-METHYL-2-NAPHTHALENEACETIC ACID INTO ITS ENANTIOMERS | |
| WO2017050171A1 (en) | Crystal form of pyrroloquinoline quinone sodium salt and preparation method and use thereof | |
| JP3946954B2 (en) | Racemate resolution of 2-hydroxypropionic acid | |
| CN102675395A (en) | Polymorphic form of ulipristal acetate and preparation method thereof | |
| JP2005506969A (en) | Novel modification of trometamol salt of R-thioctic acid and its production | |
| HU185941B (en) | Process for optical separating mixture of d- and l-bracket-6-methoxy-2-naphtyl-bracket closed-propionic acids | |
| TW200940485A (en) | Preparing method of tamibarotene crystal form II | |
| EP3762384A1 (en) | Crystalline forms of venetoclax | |
| WO2020029762A1 (en) | PREPARATION METHOD FOR FUSED TRICYCLIC γ-AMINO ACID DERIVATIVE AND INTERMEDIATE THEREOF | |
| CN116199729B (en) | Avermectin crystal form B and preparation method thereof | |
| JP2000086690A (en) | Purification of roxithromycin | |
| CN109293631B (en) | Preparation method of 3-amino-N- (2, 6-dioxo-3-piperidyl) -phthalimide compound | |
| JP4514017B2 (en) | Method for producing epinastine hydrochloride | |
| CN116589463B (en) | High-purity apixaban and preparation method thereof | |
| JPS6320817B2 (en) | ||
| JP5419570B2 (en) | Method for purifying 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine | |
| JP3256376B2 (en) | Crystal of suplatast tosilate and method for producing the same | |
| JP2920617B2 (en) | Purification method of 4-hydroxypiperidine | |
| CN108250255A (en) | A kind of method for improving trichloro-cane-6-ethyl ester crystallization yield | |
| JPS63218655A (en) | Optical resolution of n-carbamoylmethionine | |
| CN106957311B (en) | Solvate of raltitrexed and preparation method thereof | |
| JPS58188862A (en) | Preparation of n-acylcarnosine | |
| KR20030008708A (en) | Method of preparing optically active mandelic acid | |
| KR820001179B1 (en) | Method for resolving racemic 6-methoxy-2 methyl-2-naphthalene acetic acid into its enantiomers |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20050318 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20070725 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20081028 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20081222 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20090414 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20090415 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 4298212 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120424 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120424 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130424 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140424 Year of fee payment: 5 |
|
| LAPS | Cancellation because of no payment of annual fees |