JP2009114142A - Tranexamic acid-containing oral liquid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral liquid preparation comprising tranexamic acid and a sweetening agent that accomplishes all of (1) stabilization of tranexamic acid, (2) prevention of formation of sugar cement (deposition of sugar on a container mouth) and (3) masking of the bitter taste of tranexamic acid. <P>SOLUTION: The oral liquid preparation comprises tranexamic acid and a sweetening agent, where the sweetening agent comprises a combination of reduced maltose syrup and sucralose. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a tranexamic acid-containing oral solution, and more particularly to (1) stabilization of tranexamic acid, (2) prevention of sugar cement, and (3) a tranexamic acid-containing oral solution that masks the bitter taste of tranexamic acid.

  Tranexamic acid is effective for tonsillitis and pharyngopharyngitis, and it is known that syrup (transamin syrup, Daiichi Sankyo) is available as an oral solution in dosage forms other than tablets. Patent Document 1 discloses an oral solution in which dihydrocodeine phosphate, dl-methylephedrine hydrochloride, guaifecin and Senegal extract are blended in addition to tranexamic acid as an oral solution in which other drugs are blended with tranexamic acid. Yes.

  Drugs blended in oral liquids often have bitterness, including tranexamic acid, and it is necessary to mask the bitterness when it is made into a liquid. In order to mask bitterness, oral liquid preparations are blended with sugars as sweeteners and taste-masking agents such as organic acids as sour agents.

However, by adding a sugar as a sweetener and an organic acid as a sour agent, destabilization of the drug is caused, and in the case of a multi-dose solution, a sugar as a sweetener precipitates when used for a certain period of time. There may be a problem that sugar deposited on the mouth adheres and the cap is difficult to close (referred to as sugar cement in the present specification). Therefore, it is difficult to simultaneously achieve (1) drug stabilization, (2) sugar cement prevention and (3) drug bitterness masking in an oral solution, particularly a multi-dose solution.
JP-A-9-286726

  It is an object of the present invention to provide a tranexamic acid-containing oral liquid preparation that masks (1) stabilization of tranexamic acid, (2) prevention of sugar cement, and (3) bitterness of tranexamic acid.

  As a result of intensive investigations to achieve the above object, the present inventors have found that an oral solution containing a combination of tranexamic acid, reduced maltose water candy and sucralose is (1) stabilization of tranexamic acid, (2) It has been found that sugar cement prevention and (3) bitterness masking of tranexamic acid can be achieved simultaneously, and the present invention has been completed.

That is, the present invention
[1] An oral solution containing tranexamic acid and a sweetener, wherein the sweetener is reduced maltose syrup and sucralose,

[2] The oral liquid preparation according to the above [1], containing 10 to 50 w / v% reduced maltose water candy,

[3] The oral solution according to [1] above, containing sucralose in an amount of 0.005 to 0.100 w / v%,

[4] A method for stabilizing a tranexamic acid-containing oral liquid, characterized by comprising tranexamic acid and reduced maltose water candy and sucralose as sweeteners,

[5] A method for preventing sugar cement of a tranexamic acid-containing multiple-dose oral liquid, comprising combining tranexamic acid with reduced maltose water candy and sucralose as sweeteners, and

[6] The present invention provides a bitterness masking method for tranexamic acid-containing oral solution, characterized by comprising tranexamic acid, and reduced maltose water candy and sucralose as sweetening agents.

  According to the present invention, (1) stabilization of tranexamic acid, (2) prevention of sugar cement in an oral solution containing tranexamic acid and a sweetener by combining tranexamic acid, reduced maltose water candy and sucralose And (3) bitterness masking of tranexamic acid can be achieved simultaneously.

  The oral solution of the present invention contains reduced maltose water candy and sucralose as sweetening agents. The amount of reduced maltose water candy is 10 to 50 w / v%, preferably 15 to 45 w / v%, more preferably 20 to 40 w / v% based on the oral liquid content.

  The amount of sucralose is 0.005-0.100 w / v% based on the oral solution content, preferably 0.010-0.080 w / v%, more preferably 0.020-0.060 w / v. %.

  The oral solution of the present invention preferably has a pH range of 2 to 12 where tranexamic acid is stable in a single aqueous solution (0.5% Briton-Robinson buffer).

  The oral solution of the present invention can contain other medicinal ingredients in addition to tranexamic acid, such as antipyretic analgesic / anti-inflammatory agents, antihistamines, antitussive expectorants, bronchodilators, vitamins, antacids, stomachic drugs, Examples include digestive agents, antipruritic agents, and mucosal repair agents. Additives that are usually blended in this type of oral solution may also be blended, such as sour agents, preservatives or preservatives, surfactants, solubilizers, emulsifiers, solvents, fragrances, and coloring agents. Can be mentioned.

  Antipyretic analgesic and anti-inflammatory agents include, for example, acetaminophen, ibuprofen, etenzaamide, phenacetin, mefenamic acid, aspirin, choline salicylate, sodium salicylate, salicylic acid amide, antipyrine, phenylbutazone, sulpyrine, diclofenac sodium, aluminoprofen, ketoprofen, Naproxen, loxoprofen sodium, tinolidine hydrochloride, epilysole, thiaramide hydrochloride, indomethacin, acemetacin, graphenin, pentazocine and piroxicam may be mentioned, and these may be used alone or in combination of two or more.

  Examples of the antihistamine include chlorpheniramine maleate, mequitazine, promethazine, diphenhydramine hydrochloride and carbinoxamine maleate, and these may be used alone or in combination of two or more.

  Examples of the antitussive expectorant or bronchodilator include, for example, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, tipepidine hibenzate, dl-methylephedrine hydrochloride, guaifenesin, senegal extract, carbocysteine , Bromhexine hydrochloride, trimethquinol hydrochloride, cloperastine hydrochloride, theophylline, aminophylline and noscapine, and the like, which may be used alone or in combination of two or more.

Examples of vitamins include vitamin Cs (ascorbic acid, calcium ascorbate, sodium ascorbate, etc.), vitamins E (dl-α-tocopherol calcium succinate, d-α-tocopherol succinate, d-α-acetate acetate). Tocopherol, etc.), L-cysteine, vitamin B class ₁ (thiamine hydrochloride, thiamine nitrate, fursultiamine hydrochloride, discetiamine hydrochloride, octothiamine, chicotiamine, bisibutamine, bisbenchamine, benfotiamine, etc.), vitamin B ₂ types (riboflavin, riboflavin phosphate, etc. riboflavin butyrate), vitamin B ₆ compound (pyridoxine hydrochloride, etc. pyridoxal phosphate), vitamin B ₁₂ compound (cyanocobalamin, acetic hydroxocobalamin, etc. mecobalamin), calcium pantothenate Um, calcium pantothenate type S, nicotinic acid, nicotinic acid amide, gamma oryzanol, orotic acid, glucuronolactone, glucuronic acid amide, yocuinine, hesperidin, biotin and sodium chondroitin sulfate. You may mix | blend the above together.

  Examples of antacids include dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic hydrotalcite, magnesium oxide, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate. Precipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium hydroxide, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate, magnesium aluminate metasilicate, anhydrous Calcium hydrogen phosphate, calcium hydrogen phosphate, aminoacetic acid, dihydroxyaluminum aminoacetate, funnel extract and the like may be mentioned, and these may be used alone or in combination of two or more.

  Examples of the stomachic medicine include aloe, fennel, turmeric, duck, auren, processed potato, kojin, kokuboku, gyoza, assembly, keihi, daiou, chikutsuninjin, chimpi, spruce, nigaki, carrot, mint, hop, fennel Oil, cinnamon oil, pepper oil, spruce oil, peppermint oil, lemon oil, l-menthol, betaine hydrochloride, carnitine chloride and dry yeast, etc., and these may be used alone or in combination of two or more. Good.

  Examples of the digestive agent include starch digestive enzyme, protein digestive enzyme, fat digestive enzyme, fibrin digestive enzyme, ursodeoxycholic acid, and bile powder. These are used in combination of one or more. May be.

  Antidiarrheal agents include, for example, acrinol, berberine chloride, guaiacol, creosote, bismuth subsalicylate, bismuth hyponitrite, bismuth subcarbonate, bismuth subgallate, tannic acid, kaolin, pectin, medicinal charcoal, calcium lactate, precipitated Examples of analgesic and antispasmodic agents such as calcium carbonate and calcium hydrogen phosphate include papaverine hydrochloride and ethyl aminobenzoate, and these may be used alone or in combination of two or more.

  Examples of the mucosal repairing agent include aldioxa, L-glutamine, copper chlorophyllin potassium, copper chlorophyllin sodium, methylmethionine sulfonium chloride, and dimethylpolysiloxane. These may be used alone or in combination of two or more. Good.

  As a sour agent, you may mix | blend organic acids, such as a citric acid, sodium citrate, malic acid, tartaric acid, and lactic acid, for example.

  As the preservative or preservative, for example, benzoic acid, sodium benzoate, sodium sorbate or parabens (ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, etc.) are used alone or in combination. You may mix | blend.

  A surfactant, solubilizer, emulsifier or solvent may be added.

  Examples of the surfactant include sucrose fatty acid ester, polyoxyethylene (160) polyoxypropylene (30) glycol (poloxamer 188), polyoxyethylene hydrogenated castor oil 60, polysorbate 20, and polysorbate 80. You may mix | blend a seed | species or 2 or more types together.

  Examples of the solubilizer include purified soybean lecithin, soybean lecithin, soybean oil, medium chain fatty acid triglyceride, macrogol 4000, macrogol 6000, liquid paraffin, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil 60 and polysorbate 80. 1 type or 2 types or more may be blended together.

  Examples of the emulsifier include sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 80, purified soybean lecithin, soybean lecithin, medium chain fatty acid triglyceride, and liquid paraffin. May be blended together.

  Examples of the solvent include polyoxyethylene hydrogenated castor oil 60, polysorbate 80, soybean lecithin, medium chain fatty acid triglyceride, macrogol 4000, macrogol 6000, olive oil, sesame oil, castor oil, soybean oil, and liquid paraffin. You may mix | blend 1 type (s) or 2 or more types together.

  As a fragrance, for example, L-menthol or various flavors (such as strawberry flavor, cherry flavor, orange flavor, apple flavor, lemon flavor, grapefruit flavor, banana flavor, black tea flavor, herbal mint flavor and coffee flavor) are used as coloring agents. For example, you may mix | blend 1 type (s) or 2 or more types, such as caramel or a pigment | dye.

  The oral solution of the present invention is prepared by mixing and dissolving the formulation components and then filtering with a membrane filter (for example, 0.45 μm). If necessary, pasteurization (for example, 2 minutes at 60 ° C.) may be performed. The obtained liquid agent is filled in a glass bottle and the cap is tightened. An inner plug may be attached as necessary. In the case of a multi-dose solution, the oral solution of the present invention measures and takes a prescribed dose (for example, 10 mL) using a measuring container such as a measuring cup in the same manner as a known tranexamic acid-containing oral solution. . In the case of a liquid medicine in which a single dose is filled in a glass bottle and the cap is tightened, take the single dose after opening the cap.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Dihydrocodeine phosphate 20mg
dl-Methylephedrine hydrochloride 50mg
Guayfensin 200mg
Tranexamic acid 280mg
Senegal extract 0.4mL
Reduced maltose water candy 12g
Sucralose 10mg
Citric acid 40mg
Sodium citrate 100mg
L-menthol 4mg
Caramel KS-SB 120mg
Sodium benzoate 28mg
20 mg ethyl paraoxybenzoate
Herb mint flavor trace black tea flavor trace
Purified water
40 mL total
pH 5.5

  After mixing and dissolving the formulation components, the mixture was filtered through a membrane filter (0.45 μm) to prepare a solution.

Dihydrocodeine phosphate 20mg
dl-Methylephedrine hydrochloride 50mg
Guayfensin 200mg
Tranexamic acid 280mg
Senegal extract 0.4mL
Reduced maltose water candy 12g
Sucralose 20mg
Sodium benzoate 28mg
20 mg ethyl paraoxybenzoate
Strawberry flavor Trace 1mol / L Hydrochloric acid Suitable amount
Purified water
40 mL total
pH 5.5

A solution was prepared by the same method as in Example 1 above.
Comparative Example 1

Dihydrocodeine phosphate 20mg
dl-Methylephedrine hydrochloride 50mg
Guayfensin 200mg
Tranexamic acid 280mg
Senegal extract 0.4mL
1g of refined white sugar
Powdered maltose water candy 5g
Erythritol 5g
Trehalose 0.5g
Sodium benzoate 28mg
20 mg ethyl paraoxybenzoate
1mol / L hydrochloric acid
Purified water
40 mL total
pH 5.5

A solution was prepared by the same method as in Example 1 above.
Comparative Example 2

Dihydrocodeine phosphate 20mg
dl-Methylephedrine hydrochloride 50mg
Guayfensin 200mg
Tranexamic acid 280mg
Senegal extract 0.4mL
1g of refined white sugar
3g of powdered reduced maltose water candy
Erythritol 7g
Trehalose 0.5g
Sodium benzoate 28mg
20 mg ethyl paraoxybenzoate
1mol / L hydrochloric acid
Purified water
40 mL total
pH 5.5

A solution was prepared by the same method as in Example 1 above.
Comparative Example 3

Dihydrocodeine phosphate 20mg
dl-Methylephedrine hydrochloride 50mg
Guayfensin 200mg
Tranexamic acid 280mg
Senegal extract 0.4mL
Powdered maltose water candy 5g
Acesulfame K 30mg
Stevia extract purified product 15mg
Sodium benzoate 28mg
20 mg ethyl paraoxybenzoate
Strawberry flavor Trace 1mol / L Hydrochloric acid Suitable amount
Purified water
40 mL total
pH 5.5

A solution was prepared by the same method as in Example 1 above.
Comparative Example 4

Dihydrocodeine phosphate 20mg
dl-Methylephedrine hydrochloride 50mg
Guayfensin 200mg
Tranexamic acid 280mg
Senegal extract 0.4mL
Purified white sugar 8.67g
Citric acid 40mg
Sodium citrate 100mg
L-menthol 4mg
Caramel KS-SB 120mg
Sodium benzoate 28mg
20 mg ethyl paraoxybenzoate
Herb mint flavor trace black tea flavor trace
Purified water
40 mL total
pH 5.5

A solution was prepared by the same method as in Example 1 above.
Test example 1

The glass bottle bottle mouth is immersed in the liquid agent of Examples 1 and 2 and Comparative Examples 1 to 4, and then the glass bottle is pulled up from the liquid agent, and the glass bottle with the cap tightened on the bottle mouth is stored at 50 ° C. for 1 week, and sugar cement at the bottle mouth The presence or absence of precipitation was examined.

In Examples 1 and 2, there was no sugar cement precipitation at the bottle mouth after storage at 50 ° C. for 1 week. On the other hand, in all of Comparative Examples 1 to 4, sugar cement was deposited at the bottle mouth after storage at 50 ° C. for 1 week.
Test example 2

The solution of Example 1 and Comparative Example 4 was filled in a glass bottle and the cap was tightened, then stored at 60 ° C. for 1 to 3 weeks and at 50 ° C. for 2 to 8 weeks, and the content of tranexamic acid in the solution was measured. Calculated.

The tranexamic acid content in Example 1 was stable with no decrease in residual rate after storage at 60 ° C. for 3 weeks and after storage at 50 ° C. for 8 weeks. On the other hand, the tranexamic acid content in Comparative Example 4 was found to decrease in the residual rate after storage at 60 ° C. for 3 weeks and after storage at 50 ° C. for 8 weeks.
Test example 3

Three healthy adults (panels: A to C) included the solutions of Example 1 and Comparative Example 4 in their mouths, and sensory-evaluated their tastes (bitterness, sweetness, refreshing feeling). Evaluation was performed with a score of 3; strong, 2; moderate, 1;

  Both Example 1 and Comparative Example 4 were oral solutions with no bitter taste, moderate sweetness and refreshing feeling, and good dosing feeling.

  ADVANTAGE OF THE INVENTION According to this invention, the tranexamic acid containing oral solution which masked (1) stability of tranexamic acid, (2) sugar cement prevention, and (3) bitter taste of tranexamic acid can be provided.

Claims (6)

  An oral liquid preparation containing tranexamic acid and a sweetener, wherein the sweetener is reduced maltose water candy and sucralose.   The oral liquid preparation according to claim 1, comprising 10 to 50 w / v% of reduced maltose water candy.   The oral liquid preparation according to claim 1, comprising 0.005 to 0.100 w / v% sucralose.   A method for stabilizing a tranexamic acid-containing oral liquid, characterized by comprising tranexamic acid, and reduced maltose water candy and sucralose as sweetening agents.   A method for preventing sugar cement of a tranexamic acid-containing oral liquid, characterized by comprising tranexamic acid and reduced maltose water candy and sucralose as sweetening agents.   A method for masking bitterness of tranexamic acid-containing oral liquid, comprising combining tranexamic acid and reduced maltose water candy and sucralose as sweetening agents.