JP5615821B2 - Indigo carmine preparation - Google Patents

Description

  The present invention relates to a storage stabilized indigo carmine preparation.

Indigo carmine [chemical name: 3,3′-dioxo-2,2′-biindolinidene-5,5′-disulfonic acid disodium (Disodium 3, 3′-dioxo [−Δ ^{2, 2 ′} -biindoline] -5, 5'-disulfonate)] is represented by the following formula [I]
It is a compound useful as a drug for endoscopy such as cancer or tumor or a drug for renal function test (Patent Documents 1 and 2 and Non-Patent Document 1).

  However, since indigo carmine has problems with stability such as heat and light weakness and is easily oxidized, when it is used for endoscopy as a solution, the injection described in Non-Patent Document 1 is diluted. It is used and needs to be prepared at the time of use (Patent Document 1). Even if an indigo carmine solution can be prepared, indigo carmine may be precipitated if left for a while. On the other hand, it is conceivable to suppress oxidation by filling with nitrogen, but there is a problem that indigo carmine deteriorates due to the remaining trace amount of oxygen.

  Therefore, to improve the convenience of handling indigo carmine-containing preparations, to provide ready-to-use preparations that do not require pre-preparation without indigo carmine precipitating even after storage for a long time. Was desired.

JP 2008-273900 A JP 2003-171318 A

Japanese Pharmacopoeia Indigo Carmine Injection Solution Renal Function Test Agent “Indigo Carmine Injection 1”, Manufacturer / Daiichi Sankyo's package insert; Revised June 2008 (5th edition)

  An object of the present invention is to provide an indigo carmine preparation with improved storage stability.

  As a result of intensive studies to solve the above problems, the present inventors have found that the stability of indigo carmine can be significantly improved by including a specific reducing agent in the indigo carmine preparation. The present invention has been completed through repeated studies.

That is, the present invention
[1] A storage-stabilized indigo carmine preparation characterized by containing at least one reducing agent selected from the group consisting of ascorbic acid, isoascorbic acid, L-cysteine, and tannic acid, and indigo carmine. ,
[2] The indigo carmine preparation according to the above [1], wherein the reducing agent is ascorbic acid,
[3] The indigo carmine formulation according to [1] or [2], which is an aqueous formulation,
[4] The indigo carmine preparation according to any one of [1] to [3], which is a diagnostic agent for cancer,
[5] A method for diagnosing cancer using the indigo carmine preparation according to any one of [1] to [4], and [6] [1] for producing a diagnostic agent for cancer Use of the indigo carmine preparation according to any one of to [3],
About.

  The indigo carmine preparation of the present invention has the characteristics that storage stability is remarkably improved, discoloration of the preparation is suppressed, and it can be stably stored over time even at room temperature. Moreover, the indigo carmine formulation of this invention does not need to prepare at the time of use, and can prevent the preparation mistake at the time of preparation at the time of use.

FIG. 1 is a diagram showing the results of Test Example 1. The vertical axis represents the content (%) of indigo carmine. FIG. 2 is a photograph showing the results of Test Example 1. A shows Comparative Example 1, B shows Example 1, and C shows Comparative Example 3.

  Indigo carmine (hereinafter sometimes abbreviated as IDG) used in the present invention can be produced by a known method. A method for producing such indigo carmine is not particularly limited. For example, it is concentrated against Indigo [chemical name: 2,2′-bis (2,3-dihydro-3-oxoindolilidene)]. It can be produced by sulfonation using sulfuric acid or fuming sulfuric acid. Indigo carmine may be a commercially available product. The content of indigo carmine in the indigo carmine preparation of the present invention is not particularly limited, but is preferably about 0.001 to 1% by weight, more preferably about 0.01 to 0.4% by weight, based on the whole indigo carmine preparation. Preferably, about 0.05 to 0.3% by weight is particularly preferable.

  Preferred examples of the reducing agent used in the present invention include ascorbic acid, isoascorbic acid, L-cysteine, tannic acid, and pharmacologically acceptable salts thereof, and ascorbic acid is particularly preferable. This is because when the sulfurizing agent or pyrosulfite is used as the reducing agent, there is a problem that indigo carmine is discolored to light yellow. The pharmacologically acceptable salt is not particularly limited, and examples thereof include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. The pharmacologically acceptable acid addition salt is not particularly limited, and is an inorganic acid salt such as hydrochloride, sulfate, phosphate, acetate, maleate, fumarate, tartrate, citrate. Examples of organic acid salts such as sodium salts and potassium salts, alkaline earth metals such as sodium salts and potassium salts, calcium salts and magnesium salts are not particularly limited. Examples include salts, aluminum salts, zinc salts, etc., and pharmacologically acceptable organic amine addition salts are not particularly limited, and examples include addition salts such as morpholine and piperidine. Acceptable amino acid addition salts are not particularly limited, and examples include addition salts of lysine, glycine, phenylalanine, and the like. These reducing agents can be used alone or in combination of two or more. The content of the reducing agent in the indigo carmine preparation of the present invention is not particularly limited, but is preferably about 0.001 to 3% by weight, more preferably about 0.005 to 1% by weight, based on the entire indigo carmine preparation. About 0.01 to 0.1% by weight is particularly preferable. If the content of the reducing agent is too low, the stability of indigo carmine is poor, and if the content is too high, the dark blue color of indigo carmine may fade.

  When formulating the indigo carmine preparation of the present invention, the dosage form is not particularly limited, and various dosage forms widely used as pharmaceuticals can be selected. Examples of the dosage form include powders and granules. Agents, fine granules, capsules, tablets, troches, chewable tablets, ointments, aqueous preparations (including lotions, emulsions, aerosols, drinks, syrups, etc.), gels (liquid crystals, Microemulsions, liposomes, etc.), creams, etc., aqueous preparations (including lotions, emulsions, aerosols, drinks, syrups, etc.), gels (liquid crystals, microemulsions, liposomes) Etc.), and aqueous preparations are particularly preferred. In formulating the above-mentioned preparation, any conventionally known method can be used in this field.

  In the production of the indigo carmine preparation of the present invention, one or two or more additives conventionally used in pharmaceuticals may be used in appropriate combination with the reducing agent. The additive is not particularly limited as long as it is acceptable for pharmaceuticals, and examples thereof include binders, disintegrants, thickeners, excipients, lubricants, preservatives, chelating agents, and pH adjusters. As mentioned.

  The binder used in the present invention is not particularly limited, and hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, pregelatinized starch (rice, corn, potato, wheat), gum arabic, gum tragacanth, gelatin and the like are examples. Can be mentioned.

  The disintegrant used in the present invention is not particularly limited, and carmellose calcium, partially pregelatinized starch, starch, low-substituted hydroxypropylcellulose, croscarmellose sodium, anhydrous calcium hydrogen phosphate, calcium carbonate, and crosslinked polyvinylpyrrolidone. Etc. are mentioned as examples.

  The thickener used in the present invention is not particularly limited, and is not particularly limited. Glycol ester, gelatin, guar gum, locust bean gum, pectin, tragacanth gum, tara gum, gum arabic, karaya gum, starch, starch derivative, deacylated gellan gum, native gellan gum, curdlan, azotobacter vinegar gum, pullulan, arabi Nogalactan, dextran, hydroxyethylmethylcellulose, hydroxyethylcellulose Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium chondroitin sulfate, magnesium aluminum silicate, and the like as examples.

  The excipient used in the present invention is not particularly limited, and is a solid excipient such as lactose, mannitol, corn starch, crystalline cellulose, dextrin, and cyclodextrins, and a liquid excipient such as water, distilled water, methanol, and ethanol. Is given as an example.

  The lubricant used in the present invention is not particularly limited, but stearic acid, calcium stearate, magnesium stearate, talc, polyoxyethylene lauryl alcohol ether, sucrose fatty acid ester, glycerin fatty acid ester, light anhydrous silicic acid, hydrogenated vegetable oil Etc. are mentioned as examples.

  The preservative used in the present invention is not particularly limited, but sodium benzoate, sodium hydrogen sulfite, paraben, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyrichloride Examples include, for example, sodium, chlorobutanol, benzyl alcohol, phenethyl alcohol, sodium dehydroacetate, sorbic acid, sodium sorbate, parachloromethoxyphenol, or parachlorometacresol.

  The chelating agent used in the present invention is not particularly limited. For example, ethylenediaminetetraacetic acid (edetic acid), ethylenediaminetetraacetic acid salt (sodium salt (sodium edetate: Japanese Pharmacopoeia, EDTA-2Na, etc.), potassium salt, etc.) , Phytic acid, citric acid, malic acid, tartaric acid, gluconic acid, polyphosphoric acid, metaphosphoric acid and the like, edetic acid, sodium edetate or potassium edetate are preferred, and sodium edetate is particularly preferred. These chelating agents can be used singly or in combination of two or more, and the proportion to be blended in the aqueous preparation of the present invention is not particularly limited as the total amount of the chelating agent, but is 0.0005 to the entire aqueous preparation. About 0.5% by weight is preferable, about 0.001 to 0.3% by weight is more preferable, and about 0.01 to 0.1% by weight is particularly preferable.

The pH adjuster used in the present invention is not particularly limited, and hydrochloric acid, gluconic acid, acetic acid, lactic acid, boric acid, phosphoric acid, sulfuric acid, tartaric acid, citric acid, trisodium citrate, potassium hydroxide, calcium hydroxide, Examples include sodium hydroxide, magnesium hydroxide, sodium hydrogen phosphate, sodium dihydrogen phosphate, monoethanolamine, diethanolamine, triethanolamine, glycine, histidine, and ε-aminocaproic acid. These may all have a hydrate form, for example, citric acid monohydrate, trisodium citrate dihydrate, sodium hydrogenphosphate hydrate (Na ₂ HPO ₄ · 12H ₂ O), sodium hydrogen phosphate dihydrate (Na ₂ HPO ₄ .2H ₂ O), sodium dihydrogen phosphate monohydrate (NaH ₂ PO ₄ .H ₂ O), sodium dihydrogen phosphate diwater Japanese (NaH ₂ PO ₄ .2H ₂ O) and the like can be mentioned. Of these, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate dihydrate, citric acid monohydrate, and trisodium citrate are preferably used. When the indigo carmine preparation of the present invention is a liquid, the pH is preferably about 4 to 9, and more preferably about pH 6 to 8 from the viewpoint of enhancing the storage stability. The content of the pH adjuster is not particularly limited, but is usually about 0.01 to 1% by weight, preferably about 0.1 to 0.7% by weight, more preferably 0.3 to It is about 0.6% by weight.

  The indigo carmine preparation of the present invention is not particularly limited as long as the effects of the present invention are not hindered, but an osmotic pressure ratio of about 0.05 to 1 is preferable, and about 0.1 to 0.8 is more preferable.

  The production method of the indigo carmine preparation of the present invention is not particularly limited, and indigo carmine, the reducing agent, and if necessary, an additive is added, and a solvent is added according to a conventional method of wet granulation, followed by kneading, A process for granulating; a process for dissolving or suspending indigo carmine in the solvent, the reducing agent, and if necessary, other additives; a process for freeze-drying the solution; a process for spray drying, etc. General pharmaceutical manufacturing methods apply. For example, in the case of producing as a granule, a liquid solvent is added to the above components, and a homomixer, a colloid mill, a three roll mill, a turbine type internal toothed stirrer, a high discharge type propeller, Satake P36 type (manufactured by Satake Chemical Machinery Co., Ltd.) ), An indigo carmine preparation can be produced by uniformly mixing and kneading using a mixer such as a universal mixer and extrusion granulator. In the case of manufacturing as an aqueous preparation, it can be manufactured using a conventional method, and the method is not particularly limited, but each component and a part of purified water are mixed and dissolved in advance, and the rest The method of adding the water of and preparing a liquid quantity is mentioned preferably. In addition, purified water may be heated in accordance with a general aqueous liquid preparation method at the time of dissolution, headspace nitrogen replacement may be performed during filling into the container, or filtration and sterilization may be performed. Although it does not specifically limit as said liquid solvent, A polar solvent is preferable, Specifically, polar proticity, such as water or alcohols (for example, 1-butanol, 2-propanol, 1-propanol, ethanol, methanol, etc.). Examples of preferred solvents include polar aprotic solvents such as tetrahydrofuran, methylene chloride, acetone, acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and the like, about 20 to 90% (w / w). Ethanol is particularly preferred. Further, the indigo carmine preparation of the present invention is not particularly required, but may be subjected to nitrogen bubbling or nitrogen encapsulation during production, if desired.

  The indigo carmine preparation of the present invention is not particularly limited, but when performing nitrogen bubbling or nitrogen encapsulation, the indigo carmine formulation may be enclosed and sealed with an oxygen scavenger in an oxygen barrier container. The oxygen barrier container may be a sealed container having low oxygen permeability, such as an aluminum foil bag, an aluminum vapor-deposited polyester film bag, or a bag made of an aluminum vapor-deposited polyester film / polyethylene film laminate. And so-called aluminum bags, silica-deposited polyester bags, ethylene vinyl alcohol bags, barrier nylon bags, polyvinylidene chloride bags, and the like.

  The indigo carmine preparation of the present invention is not particularly limited, but is preferably used as a diagnostic agent for cancer or a diagnostic agent for a lesion site such as a tumor. Although it does not specifically limit as said cancer or tumor, For example, esophageal cancer, stomach cancer, colon cancer (for example, colorectal cancer etc.) etc. are mentioned suitably. Further, the indigo carmine preparation of the present invention may be used not only for neoplastic polyps but also for non-neoplastic polyps. Examples of the large intestine include the cecum, colon, and rectum, and examples of the colon include the ascending colon, the transverse colon, the descending colon, and the sigmoid colon. The indigo carmine preparation of the present invention is not particularly limited, but is preferably used for endoscopy and particularly preferably for cancer or tumor endoscopy.

  The indigo carmine preparation of the present invention does not particularly require an aqueous acetic acid solution when used as a diagnostic agent for cancer or a diagnostic agent for a lesion site such as a tumor, but may be used in combination with an aqueous acetic acid solution. When used in combination with an acetic acid aqueous solution, for example, the indigo carmine preparation may be mixed with an acetic acid aqueous solution, and the mixed solution may be applied to the application site. It may be sprayed. The concentration of the aqueous acetic acid solution is preferably 3.0 to 5.0 w / v%.

  The administration method of the indigo carmine preparation of the present invention in the above application is not particularly limited as long as it is oral administration or parenteral administration. For example, the indigo carmine preparation of the present invention is filled in a syringe, and the syringe is used as an endoscope apparatus. The indigo carmine preparation of the present invention is directly inserted into the diagnostic site from a tube inserted through the forceps port of the electronic scope of the endoscope apparatus. Can be sprayed. When the endoscope device is inserted into the body, a local anesthetic (for example, Xylocaine Jelly (registered trademark) (product name, manufactured by AstraZeneca)) or the like is applied to the endoscope device as necessary. Also good.

  The dosage of the indigo carmine preparation of the present invention in the above use varies depending on the sex, age, health condition, administration site, etc. of the person to be administered, so it cannot be said unconditionally. The indigo carmine preparation of the present invention has sufficient effects. Although it will not specifically limit if it is the range which exhibits, For example, 20 ml of preparations which prepared content of indigo carmine to about 0.15-0.25 weight% are mentioned. This is to avoid that indigo carmine diminishes in the intestinal fluid over time, making observation difficult.

  In addition, the present invention can provide a method for diagnosing cancer using an indigo carmine preparation, and is useful. Examples of the diagnostic method include a pretreatment step of removing air bubbles, stool juice, mucus and the like from the surface of the lesion site by washing, a step of spraying the indigo carmine preparation of the present invention to the diagnostic site, and a diagnostic method. A pretreatment step of removing bubbles, stool, mucus, etc. from the surface of the lesion site by washing, a step of spraying the indigo carmine preparation of the present invention on the diagnostic site after spraying an aqueous acetic acid solution on the diagnostic site, and a step of observing Including diagnostic methods.

  If the indigo carmine preparation is sprayed with bubbles, stool, mucus, etc. attached to the lesion site without washing bubbles, stool, mucus, etc., the structure of the lesion site surface is unclear. This may be a hindrance to diagnosis. If water pressure is too strong at the time of washing, the lesion may bleed, so the endoscope device is inserted into the body (for example, stomach or large intestine) orally, and the washing solution is usually placed in a 20 ml syringe. Wash directly from the forceps opening of the endoscope. Moreover, you may wash | clean under water immersion according to a condition. When washing a lesion site, it is preferable to use slightly warm water (37 ° C. to 40 ° C.) in order to prevent peristalsis induction. Moreover, it is preferable to mix a small amount of a gastrointestinal gas exclusion agent in mild hot water in order to prevent the generation of bubbles during lesion site washing. Examples of the gastrointestinal gas exclusion agent include Gascon (registered trademark) (product name, general name: dimethicone, main component: dimethylpolysiloxane, manufactured by Kissei Pharmaceutical Co., Ltd.). Furthermore, it is preferable to use a proteolytic preparation for the sticky mucus that is difficult to remove. Examples of the proteolytic preparation include Pronase MS (registered trademark) (product name, manufactured by Kaken Pharmaceutical Co., Ltd.), Gas Team (registered trademark) (product name, manufactured by Nichi-Iko Pharma) and the like. In the spraying step, a mode in which 20 ml of the diagnostic agent prepared at a high concentration of about 0.15 to 0.25% by weight is directly sprayed from the forceps port of the electronic scope of the endoscope apparatus is preferable. In order to avoid that indigo carmine dilutes in the intestinal fluid with time and observation becomes difficult, it is preferable to observe immediately after spraying. In the observation step, enlargement observation may be performed as necessary, such as when the lesion site is about 50 to 80 μm and enlargement is necessary. Although the magnification at the time of magnified observation is not particularly limited, it is usually preferably about 20 to 200 times and about 30 to 100 times.

  Furthermore, in the diagnostic method, a staining method using crystal violet may be added as necessary, such as when indigo carmine is stored in the surface layer of the lesion site. Crystal violet (trade name, Pyoktanin Blue, manufactured by Yoneyama Yakuhin Kogyo Co., Ltd.) becomes difficult to diagnose if it is dyed too deeply, and is usually about 0.01 to 0.08%, preferably 0.02 Use 0.05% concentration. When staining, apply the necessary minimum amount to each lesion using a spray tube. As with the indigo carmine preparation, when sprayed directly from the forceps opening, the mucous membrane is stained in a wide range, and the amount of light becomes insufficient during observation, resulting in a dark field of view.

The indigo carmine preparation of the present invention is preferably provided in the form of a sterilized solution. Examples of sterilization methods include filtration sterilization and autoclave sterilization. Autoclave sterilization is also called high-pressure steam sterilization, and is a sterilization method in which saturated steam at a predetermined temperature and pressure is made and heated. The temperature at the time of autoclave treatment is not particularly limited, but is preferably about 90 to 135 ° C., 110 About ~ 130 ° C is more preferable. The autoclave treatment time is not particularly limited, but is preferably about 1 minute to 1 hour. For example, in the Japanese Pharmacopoeia, sterilization conditions of 115 ° C. for 30 minutes, 121 ° C. for 20 minutes, and 126 ° C. for 15 minutes can be mentioned. Filtration sterilization is a method of removing microorganisms by filtration using a filtration device. Examples of the filtration device include a filtration device using a cellulose derivative such as polyvinylidene fluoride, polyether sulfone, nylon, nitrocellulose, and acetocellulose, a plastic such as polycarbonate, or a membrane filter made of Teflon (registered trademark). Examples of commercially available products include Durapore (trade name, Millipore). A filter having a pore diameter of 0.22 μm (or smaller, and in some cases 0.45 μm) can be used according to the purpose. The filter for sterilization is challenged with more than ^10-7 indicator bacteria Brerevundimonas diminuta or smaller appropriate bacteria cultured under appropriate conditions per effective filtration area (cm ² ) of the membrane, and the secondary side (membrane or As long as a sterile filtrate can be obtained on the liquid side after filtration of the filter, it can be used without any particular limitation.

  The indigo carmine preparation of the present invention can be stably stored at room temperature for 3 years or more without indigo carmine being decomposed.

  Hereinafter, the present invention will be described using examples and comparative examples, but the present invention is not limited thereto.

[Examples 1 to 4 and Comparative Examples 1 to 4]
After adding sodium hydrogenphosphate hydrate to 2.5 kg of purified water and dissolving, it was stirred while gradually adding indigo carmine to obtain a dissolved solution. Next, 250 g of the above solution was dispensed into a beaker, each additive was added and dissolved so as to have the prescribed amount shown in Table 1 below, and then a 0.1 mol / L citric acid solution was added, pH 6.4 to It was set to 7.4. The obtained solution was filled in 20 mL brown vial (manufactured by Fuji Glass Co., Ltd.), and rubber stoppers were plugged and tightened to produce each sample of Example products 1 to 4 and Comparative products 2 to 4. Moreover, the comparative example product 1 was manufactured without adding the said additive. In this example and comparative example, each sample was manufactured without performing nitrogen bubbling or nitrogen filling.

[Test Example 1]
The above-mentioned Example products 1 to 4 and Comparative Example products 1 to 4 were prepared three by three, stored at 80 ° C. for 3 days after sample preparation, the content of indigo carmine was measured by the following method, Stability was evaluated from the presence of foreign matter and the content of indigo carmine. The change in appearance was determined by visually observing fading or discoloration of each sample after storage under the above conditions. The presence or absence of foreign matter was judged by whether or not there was a foreign matter that could be visually confirmed when each sample was filtered with an 11 μm filter after storing under the above conditions. For the evaluation of the change in appearance, one of each sample was filled in a colorless transparent vial and stored in a cool dark place as a control. The measurement result of the content of indigo carmine (average value of 3 samples) is shown in FIG. Moreover, the external appearance of the sample of Comparative Examples 1 and 3 and Example 1 is shown in FIG.

[Method for measuring content of indigo carmine]
About each sample of the said Example goods 1-4 and the comparative example goods 1-4, content (mg) of the indigo carmine after preparation at the following conditions and 80 degreeC three days storage is calculated, and content at the time of adjustment is calculated. The content (%) of indigo carmine after storage at 80 ° C. for 3 days was calculated as 100%.
For each sample, a volume corresponding to about 20 mg of indigo carmine was accurately weighed and diluted dilute hydrochloric acid (1 → 100) was added to give exactly 200 mL of solution. 2.5 mL of this solution was accurately weighed and diluted diluted hydrochloric acid (1 → 100) was added to obtain exactly 25 mL of solution, which was used as a sample solution. Separately, about 20 mg of indigo carmine for quantification (separately measure the loss on drying at 1 g, 105 ° C. for 2 hours), add diluted dilute hydrochloric acid (1 → 100) to make exactly 25 mL solution, It was set as the solution.
For the sample solution and the standard solution, the absorbance at a wavelength of 610 nm was measured according to the method described in “Fifteenth revision Japanese Pharmacopoeia, General Test Method, UV-Visible Absorbance Measurement Method”. Product name: UV-2550, manufactured by Shimadzu Corporation ).
From the measured absorbance value, the content (mg) of indigo carmine was calculated using Equation (1).
(Wherein, W _S represents the balance up amount for quantification indigo carmine in terms of dry matter, A _T represents the absorbance of the sample solution, A _S is the absorbance of the standard solution.)

  About Example goods 1-4 and comparative example goods 1, 2, and 4, when filtering with a filter, the foreign material (precipitate) which can be confirmed visually was not seen, but remarkable fading or discoloration was not seen. In Comparative product 3, a brown precipitate was visually confirmed. Moreover, in Comparative Example goods 1-4, content of indigo carmine decreased and it did not have stability. From these results, it was confirmed that in Comparative Example 3, even if a reducing agent was contained, indigo carmine deteriorated and discolored, and not all reducing agents could improve the stability of indigo carmine. Furthermore, when propyl gallate or disodium edetate was added as an additive (Comparative Examples 2 and 4), the solubility of the indigo carmine (solvent: water, 25 ° C.) was improved, but the stability was not improved. . This means that even if the solubility of indigo carmine is improved, the stability of indigo carmine is not necessarily improved. On the other hand, the indigo carmine preparation of the present invention did not produce a precipitate, did not cause discoloration, and the content of indigo carmine was sufficient, so it was confirmed that the indigo carmine preparation has significantly superior storage stability over time. .

  According to the present invention, indigo having improved storage stability by containing at least one reducing agent selected from the group consisting of ascorbic acid, isoascorbic acid, L-cysteine, and tannic acid, and indigo carmine. Carmine formulations can be provided.

Claims (5)

It contains at least one reducing agent selected from the group consisting of ascorbic acid, isoascorbic acid, L-cysteine, and pharmacologically acceptable salts thereof , and indigo carmine, and the content of the reducing agent is indigo carmine. A storage-stabilized indigo carmine preparation, characterized by being 0.001 to 3% by weight based on the whole preparation.   The indigo carmine preparation according to claim 1, wherein the reducing agent is ascorbic acid.   The indigo carmine preparation according to claim 1 or 2, which is an aqueous preparation.   The indigo carmine preparation according to any one of claims 1 to 3, which is a diagnostic agent for cancer.   Use of the indigo carmine preparation according to any one of claims 1 to 3 for the production of a diagnostic agent for cancer.