• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention provides a water-soluble internal liquid solution containing pamotidine and edetic acid or salts thereof.
    公开号:KR20040012685A
    申请号:KR10-2003-7006974
    申请日:2001-11-21
    公开日:2004-02-11
    发明作者:요시미 하시모또；노부요시 후루야；하루요시 고지마
    申请人:야마노우치세이야쿠 가부시키가이샤；
    IPC主号:
    专利说明:

    Water-Soluble Liquid Internal Medicine
    [2] Tablets and powders containing pamotidine as an active ingredient are widely used worldwide as therapeutic agents for ulcers and gastritis, but no oral solution has been released.
    [3] This is because pamotidine is a basic compound, solubility in acidic regions but low in stability, and extreme solubility in stable neutral regions. In addition, unlike injectables, taste is an important problem in oral solution, and considering the taste, it cannot be made weakly basic or basic.
    [4] Japanese Patent Publication No. 63-65047 (or CA1184495) contains 1 mg / ml injectable aqueous solution of pamotididine obtained when L-aspartic acid is added as compared to maleic acid, fumaric acid, tartaric acid, citric acid, and phthalic acid (pH). 5.3) shows excellent stability.
    [5] In addition, US Patent No. 5,650, 421 discloses an injection solution in which pamotidine or a salt thereof is 0.1 to 0.8 mg / ml, and the pH of the injection solution adjusted to pH 5.7 to 6.4 by addition of an acid such as L-aspartic acid is left at room temperature for one year. The fact that it has the stability which is 95% or more is described.
    [6] Japanese Unexamined Patent Publication No. 11-193233 discloses pamotidine as a stable injection of pamotidine, solubilizing pamotidine with a water-soluble non-aqueous solvent such as polyethylene glycol, propylene glycol, ethanol, glycerin, and further adding lactic acid to the water-soluble non-aqueous solvent. Pamotidine at a high concentration (about 1 mg / ml to about 40 mg / ml) by coexisting acidic substances such as L-aspartic acid, L-glutamic acid, benzoic acid, citric acid, malic acid, ascorbic acid, gluconic acid, acetic acid, nicotinic acid, etc. Injectables having a pH of about 5.5 to about 7.5 are disclosed and are described as being able to stabilize pamotidine in solution over a long time at room temperature.
    [7] However, in order to apply the stabilization technique of the injections described in these publications to the oral solution as it is, there have been problems as described above.
    [8] In other words, in order to pass the drug approval screening criteria and to withstand market circulation, the residual rate after one year of storage at room temperature is required to be about 97%, and this is converted to the residual rate after two months of storage under the conditions of 40 ° C.
    [9] The stability by addition of L-aspartic acid described in Japanese Patent Publication (S) 63-65047 or US Patent 5,650,421 is insufficient as shown in Test Example 1 below.
    [10] In the examples of Japanese Patent Application Laid-Open No. 11-193233, the injection of pamotidine concentration of 1 mg / ml lowers the residual rate after 9 months storage to 96.6% under 40 ° C, but the bitter taste As the oral liquid of pamotidine present, it is preferable that the concentration be about 1 mg / ml in consideration of taste, and the method described in this publication is not suitable. In addition, Japanese Patent Laid-Open No. 11-193233 discloses that it is preferable to treat the product so that it does not come into contact with oxygen, such as venting nitrogen gas into the manufacturing liquid or filling the ampoule space with nitrogen gas. Nitrogen substitution is performed also in all the Examples. Nitrogen substitution is not desirable because it requires not only a process for this in the manufacturing process but also is expensive.
    [11] There is a need for the preparation of pamotidine water-soluble oral liquid preparations which can be manufactured in a cheap and simple manufacturing process and have long-term stability at room temperature that can withstand market circulation.
    [1] The present invention relates to a water-soluble oral solution of pamotidine.
    [12] As a result of studying various stabilization methods, the present inventors can simply add only edetic acid or salts thereof to obtain a very stable low concentration pamotidine oral solution having a pamotidine residual ratio of 97% or more after 12 months of storage at room temperature. The present invention was completed.
    [13] That is, the present invention relates to a water-soluble internal liquid solution containing pamotidine and edetic acid or salts thereof. Preferably, the present invention relates to a water-soluble oral solution having a pH of 5.5 to 7.0 containing pamotidine and edetic acid or salts thereof. More preferably, the water-soluble underwear having a pH of 5.5 to 7.0 containing pamotididine and edetic acid or salts thereof, and having a pamotididine concentration of 0.025 to 4 mg / ml (most preferably 0.2 to 2 mg / ml) It is about liquid preparation.
    [14] In the present invention, a stable water-soluble internal liquid solution is obtained only by adding edeic acid or a salt thereof and adjusting the pH without adding various additives. Particularly, nitrogen substitution is not necessary, and the manufacturing process can be simplified. . In addition, even at a low concentration solution of pamotidine concentration of 1 mg / ml or less, stability at room temperature sufficient to withstand market flowability, that is, stability at which the residual ratio after storage at room temperature for one year is 97% or more can be ensured.
    [15] Famotidine undergoes hydrolysis of the characteristic aminosulfonylamidino groups in its chemical structure to produce metabolites of aminocarbonyl groups or aminosulfonylaminocarbonyl groups. Also known are metabolites in which sulfinyl groups in the chemical structure are oxidized to form sulfoxides. Edeic acid or a salt thereof in the present invention not only inhibits the production of metabolites by oxidation of pamotidine as an antioxidant, but also significantly inhibits the production of metabolites by hydrolysis of pamotidine. A high level of stability is achieved in room temperature storage of motidine.
    [16]
    [17] The present invention will be described in more detail.
    [18] In the water-soluble oral solution of the present invention, the concentration of pamotidine is preferably 0.025 mg / ml to 4 mg / ml, more preferably 0.2 mg / ml to 2 mg / ml. This is because the usual dosage of pamotididine is 5 mg to 20 mg, which is the usual dosage as 2.5 ml to 200 ml of oral solution.
    [19] As a raw material for producing the water-soluble internal liquid solution of the present invention, an acid addition salt of pamotidine may be used instead of pamotidine. Examples of acid addition salts of pamotididine include salts with hydrochloric acid, hydrobromic acid, hydrogen iodide, sulfuric acid, fumaric acid, maleic acid, succinic acid, tartaric acid, and picric acid.
    [20] Edeic acid is another name also called ethylenediaminetetraacetic acid.
    [21] In the present invention, examples of the salt of edetic acid include disodium salt, disodium calcium salt, tetrasodium salt, and the like, and also include hydrates such as dihydrate and tetrahydrate.
    [22] As addition amount of edetic acid or its salt, a stabilizing effect is confirmed at 0.02 weight part or more with respect to 1 weight part of pamotididine, and although there is no upper limit in particular, it is the saturated solution concentration of edetic acid or its salt. Preferably it is 0.02-2 weight part with respect to 1 weight part of pamotididine.
    [23] The water-soluble oral solution of the present invention is dissolved by adding edetic acid or its salt, purified water and excipient to pamotididine or its salt, and then adjusted to the range of pH 5.5 to 7.0 with an acidic substance or a basic substance.
    [24] This invention can contain the various additives normally used for a water-soluble internal liquid solution. For example, sweeteners, preservatives, acidulants, flavoring agents, copulation agents, thickeners, pH adjusters and the like. Examples of sweeteners include sugars such as sucrose and glucose syrup, sugar alcohols such as mannitol, sorbitol and xylitol, sodium cyclamate, sodium saccharin, aspartame, sucralose, acesulfame potassium and stevia, glycyrrhizin and the like. Salts, honey, and the like. Specific examples of preservatives include alkyl parabens such as methyl paraben and propyl paraben, and benzoic acids such as sodium benzoate. Specific examples of the acidulant include citric acid, ascorbic acid and malic acid. Examples of the fragrance include refined oils such as menthol, camphor and peppermint oil, mint oil and cinnamon oil, and orange and drink flavors. Refined oils, such as aminoacetic acid, lemon oil, and orange oil, are mentioned as a mating agent. Cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium chondroitin sulfate, agar powder, gelatin, guar gum, xanthan gum, etc. Can be mentioned. Specifically as a pH adjuster, acidic substances, such as citric acid, malic acid, lactic acid, tartaric acid, adipic acid, and its salts are mentioned.
    [25] In addition, the oral liquid solution of the present invention may contain an active ingredient other than pamotidine. For example, an antacid, a gastric mucosal defense factor strengthening agent, a digestive tract activator, a vitamin, a herbal medicine, and a antagonist are mentioned. Specific examples of the antacid include cimetidine, ranitidine, nizatidine, roxatidine acetate, lansoprazole, sodium labeprazole, omeprazole, scofolia extract, belladonna extract, isopropamide iodide, scopolamine hydrobromide, and oxyhydrochloric acid. Phencyclimine, dicyclomine hydrochloride, meticene hydrochloride, methyl bromide hydrobromide, methyl scopolamine bromide, methyl hydroxyhisocybamine bromide, methylbenactin, pyrenezepine hydrochloride, and the like. Examples of gastric mucosal defense factor enhancers include sucralate, sodium ecarbate, hydrochloric acid lactose, benexate hydrochloride betadex, enprosteel, ornoprosteel, gefarnate, sofalcone, thiamine, cobalt, chlorophyll complex, teflon, Hydroxyfeed, flaunotol, proglumid, polar prezink, maleic acid isoglodine, misoprostol, malic clevoprid, levamifeed, aceglutamide aluminum, urogastron, azulene derivatives, Aldioxa, glycyrrhizin acid and salts thereof, licorice extract, L-glutamine, salts of copper chlorophyllin, histidine hydrochloride, methylmethioninesulfonium chloride, porcine gastric wall digestion and the like; Examples of the digestive tract activator include maleic acid trimerbutin, citric acid mosfrid, cisapride, etopri hydrochloride, metoclopramide, domperidone and the like; Examples of vitamins include vitamin B 1 ; B 2 ; C and its derivatives and salts thereof, vitamin E, vitamin D and the like; Examples of the herbal medicines include red oak bag, soft chopped rice, licorice, aloe, fennel, yeonmyeongcho, gentian, cinnamon, jaja, lumber, ginseng, hops and homica. Carnitine chloride, betanechol chloride, betaine hydrochloride, glutamic acid hydrochloride etc. are mentioned as a healthy agent.
    [26] Although this invention is demonstrated in more detail based on an Example and a test example below, this invention is not limited to these Examples.
    [27] <Test Example 1>
    [28] 90 ml of purified water was warmed to 40 ° C to dissolve 200 mg of stabilizer and pamotidine in the following table, and after cooling, an appropriate amount of 1% citric acid solution and purified water were added to prepare 200 ml of an aqueous oral solution preparation having a pH of 6.5. . When these preparations were stored for 4 weeks under the conditions of 50 ° C, the residual ratio of pamotididine is as shown in the following table.
    [29] StabilizerResidual rate (%) Calcium Dibasic Sodium 100 mg96.5 Aspartic acid80 mg93.0 160 mg92.4
    [30] The pamotidine residual ratio of the aqueous solution oral solution using aspartic acid as a stabilizer was 92 to 93%, whereas the pamotidine residual ratio of the aqueous solution oral solution using edetate as a stabilizer was 96.5%. In addition, the residual rate of the edetate-containing water-soluble internal liquid agent was slightly short of 97% because of severe storage conditions at 50 ° C for 4 weeks.
    [31] <Example 1>
    [32] 900 ml of purified water was warmed to 40 ° C to dissolve 1 g of disodium edetic acid and 1 g of famotidine, add 2.5 g of mannitol, and after cooling, to make 1000 ml. The pH of this water-soluble internal liquid preparation was 6.7, and when it preserve | saved for 2 months on 40 degreeC conditions, the residual ratio of pamotididine was 97.4%.
    [33] <Example 2>
    [34] 900 ml of purified water was warmed to 40 ° C. to dissolve 1 g of disodium edetic acid and 1 g of famotidine, and after cooling, purified water was added to make 1000 ml. PH of this water-soluble oral solution preparation was 6.7, and when it preserve | saved for 2 months on 40 degreeC conditions, the residual ratio of pamotididine was 97.5%.
    [35] <Example 3>
    [36] 90 ml of purified water was warmed to 40 ° C. to dissolve 100 mg of calcium didetate and 100 mg of famotidine, and after cooling, an appropriate amount of 1% citric acid solution and purified water were added to prepare 100 ml of an aqueous oral solution prepared at pH 6.0. Prepared. When this preparation was stored for 12 months under room temperature conditions, the famotidine residual ratio was 98.0%.
    [37] <Example 4>
    [38] 90 ml of purified water was warmed to 40 ° C. to dissolve 100 mg of calcium didetate and 100 mg of famotidine, and after cooling, an appropriate amount of 1% citric acid solution and purified water were added to prepare 100 ml of an aqueous oral solution having a pH of 6.25. Prepared. When this preparation was preserve | saved for 12 months under room temperature conditions, the residual rate of pamotididine was 97.7%.
    [39] Example 5
    [40] 90 ml of purified water was warmed to 40 ° C. to dissolve 100 mg of sodium didetate and 100 mg of famotidine, and after cooling, 100 ml of an aqueous oral solution prepared at pH 6.5 was added by adding an appropriate amount of 1% citric acid solution and purified water. Prepared. When this preparation was preserve | saved for 12 months under room temperature conditions, the residual rate of pamotididine was 98.7%.
    [41] <Example 6>
    [42] 90 ml of purified water was warmed to 40 ° C. to dissolve 44 mg of methylparaben, 6 mg of propylparaben, 100 mg of dicalcium edetate and 100 mg of famotidine, and after cooling, an appropriate amount of 1% citric acid solution and purified water were added. 100 ml of an aqueous oral solution preparation having a pH of 5.75 was prepared. When this preparation was preserve | saved for 12 months under room temperature conditions, the residual rate of pamotididine was 98.1%.
    [43] <Example 7>
    [44] 90 ml of purified water was warmed to 40 ° C. to dissolve 44 mg of methylparaben, 6 mg of propylparaben, 100 mg of dicalcium edetate and 100 mg of famotidine, and after cooling, an appropriate amount of 1% citric acid solution and purified water were added. 100 ml of an aqueous oral solution preparation having a pH of 6.25 was prepared. When this preparation was preserve | saved for 12 months under room temperature conditions, the residual rate of pamotididine was 98.0%.
    [45] <Example 8>
    [46] 90 ml of purified water was warmed to 40 ° C. to dissolve 44 mg of methylparaben, 6 mg of propylparaben, 100 mg of dicalcium edetate and 100 mg of famotidine, and after cooling, an appropriate amount of 1% citric acid solution and purified water were added. 100 ml of an aqueous oral solution preparation having a pH of 7.0 was prepared. When this preparation was preserve | saved for 12 months under room temperature conditions, the residual rate of pamotididine was 97.6%.
    [47] Example 9
    [48] 90 ml of purified water was warmed to 40 ° C to dissolve 44 mg of methylparaben, 6 mg of propylparaben, 10 mg of sodium edetic acid and 100 mg of famotidine, 15 mg of sucralose were added, and an appropriate amount of 1% after cooling. Lactic acid solution and purified water were added to prepare 100 ml of an aqueous oral solution preparation having a pH of 6.5. When this preparation was stored for 12 months under room temperature conditions, the residual ratio of pamotididine was 99.0%.
    [49] <Example 10>
    [50] 90 ml of purified water was warmed to 40 ° C. to dissolve 44 mg of methylparaben, 6 mg of propylparaben, 10 mg of sodium edetic acid and 50 mg of famotidine, 15 mg of sucralose were added and an appropriate amount of 1% after cooling Lactic acid solution and purified water were added to prepare 100 ml of an aqueous oral solution preparation having a pH of 6.5. When this preparation was preserve | saved for 12 months under room temperature conditions, the residual rate of pamotididine was 98.8%.
    [51] The water-soluble oral liquid preparation of the present invention can be produced by a simple and inexpensive process, and has sufficient stability to withstand market distribution even at low concentrations of pamotididine (1 mg / ml or less), that is, a residual rate after 12 months at room temperature is 97%. Sufficient stability above can be ensured.
    权利要求:
    Claims (5)
    [1" claim-type="Currently amended] A water-soluble oral solution containing pamotidine and edetic acid or salts thereof.
    [2" claim-type="Currently amended] The water-soluble oral solution according to claim 1, wherein the pH is 5.5 to 7.0.
    [3" claim-type="Currently amended] The water-soluble oral solution according to claim 1 or 2, wherein the pamotididine concentration is 0.025 to 4 mg / ml.
    [4" claim-type="Currently amended] The water-soluble oral solution according to claim 3, wherein the concentration of pamotidine is 0.2 to 2 mg / ml.
    [5" claim-type="Currently amended] The water-soluble internal liquid preparation of any one of Claims 1-4 which mix | blends 0.02-2 weight part of edetic acid or its salt with respect to 1 weight part of pamotididine.
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    同族专利:
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    CA2426925A1|2003-04-25|
    EP1336408A4|2005-01-19|
    JP4388743B2|2009-12-24|
    JPWO2002041892A1|2004-03-25|
    WO2002041892A1|2002-05-30|
    CN100453079C|2009-01-21|
    KR100765026B1|2007-10-09|
    US20040039036A1|2004-02-26|
    CN1476327A|2004-02-18|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-11-24|Priority to JP2000357701
    2000-11-24|Priority to JPJP-P-2000-00357701
    2001-11-21|Application filed by 야마노우치세이야쿠 가부시키가이샤
    2001-11-21|Priority to PCT/JP2001/010175
    2004-02-11|Publication of KR20040012685A
    2007-10-09|Application granted
    2007-10-09|Publication of KR100765026B1
    优先权:
    申请号 | 申请日 | 专利标题
    JP2000357701|2000-11-24|
    JPJP-P-2000-00357701|2000-11-24|
    PCT/JP2001/010175|WO2002041892A1|2000-11-24|2001-11-21|Water-soluble liquid internal medicine|
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