JP2013147493A - Safe pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that is effective and safe for fever onset or throat pain in a common cold.SOLUTION: An oral pharmaceutical composition is provided, including diisopropylamine dichloroacetate and tranexamic acid.

Description

  The present invention relates to a pharmaceutical composition containing diisopropylamine dichloroacetate and tranexamic acid. More specifically, the present invention relates to a safe oral pharmaceutical composition that can be used for fever and sore throat during the cold.

  Non-steroidal antipyretic analgesic / anti-inflammatory drugs (hereinafter sometimes referred to as NSAIDs) are often administered for the fever at the time of common cold, but side effects common to NSAIDs include (1) gastrointestinal disorders, (2) renal disorders , (3) aspirin hypersensitivity, and (4) blood disorders are known (for example, see Non-Patent Document 1). In addition, (5) Reyn's syndrome caused by aspirin in children and liver damage caused by a combination of acetaminophen and alcohol are well known.

  Diisopropylamine dichloroacetate (hereinafter sometimes abbreviated as DADA) has the effect of improving liver function in chronic liver diseases, and (a) promotes liver regeneration, (b) anti-fatty liver The action is reported (for example, refer nonpatent literature 2). However, there is no report that DADA is effective as a cold use.

  Tranexamic acid, which is an antiplasmin agent, is a pharmaceutical known to have 1) anti-bleeding action, 2) anti-allergic action, 3) anti-inflammatory action, and the like (for example, see Non-Patent Document 2). Furthermore, tranexamic acid is also incorporated into cosmetics as an anti-inflammatory agent (see, for example, Patent Document 1). As a pharmaceutical composition containing tranexamic acid for internal use, antipyretic analgesics, cold medicines, oral throat drugs, rhinitis drugs, liver It is also used for over-the-counter medicines as a spot (stain) improving drug (see Non-Patent Document 3, for example).

  In addition, there is no report that tranexamic acid is effective (has antipyretic effect) against the fever during the cold. In addition, no pharmaceutical composition containing DADA and tranexamic acid, which is used for antipyretic, cold, oropharyngeal throat, and rhinitis, is known. There is no suggestion of effectiveness.

JP 04-36215 A

Pediatrics, Vol.32 No.1 1991 p.11-21 2009 Edition Prescription Drug Collection JAPIC 2008 Japan Pharmaceutical Collection General Medicine 2010-11 Jiho 2009

  An object of the present invention is to provide an oral pharmaceutical composition that is effective and safe for fever and cough at the time of cold without containing NSAIDs.

  The present inventors have advanced earnestly research in view of such a situation. As a result, it was surprisingly found that when tranexamic acid having no antipyretic action was used in combination with diisopropylamine dichloroacetate, which is a liver function improving agent, an excellent antipyretic action was developed, and the present invention was completed.

That is, the present invention relates to the following (1) to (2).
(1) An oral pharmaceutical composition containing diisopropylamine dichloroacetate and tranexamic acid.
(2) The oral pharmaceutical composition according to (1), characterized in that it is used for antipyretic fever during colds.

  Since the composition containing diisopropylamine dichloroacetate and tranexamic acid according to the present invention exhibits an excellent antipyretic action, it is useful not only for the purpose of improving throat pain in the common cold but also for the purpose of antipyretic and is safe. High nature. Further, when antipyretic analgesic / anti-inflammatory drugs (NSAIDs) are added to the composition, the amount can be reduced.

It is the figure which showed the time fluctuation of rectal temperature in the mock infection model animal.

  Diisopropylamine dichloroacetate in the present invention is listed in the Japanese Pharmacopoeia Standards for Drugs 2002. Tranexamic acid is listed in the 16th revised Japanese Pharmacopoeia.

  The content of DADA in the composition of the present invention is preferably set so that 1 to 400 mg, more preferably 10 to 200 mg can be taken in 1 to 3 times a day.

  The content of tranexamic acid in the composition of the present invention is preferably set so that 0.1 to 3000 mg, more preferably 1 to 2000 mg can be taken in 1 to 3 times a day.

  For example, if the composition of the present invention is a liquid that is taken 100 mL once a day, the content of DADA in the liquid is preferably 1 to 400 mg / 100 mL, more preferably 10 to 200 mg / 100 mL. The content of tranexamic acid is preferably 0.1 to 3000 mg / 100 mL, more preferably 1 to 2000 mg / 100 mL.

  The composition of the present invention further comprises antipyretic analgesics, central nervous stimulants, antihistamines, anti-inflammatory drugs, expectorants, antitussives, sympathomimetics, antiacetylcholine drugs, vitamins, herbal medicines and herbal extracts. It can add within the range which does not prevent the effect of this invention. Here, as antipyretic analgesics, aspirin, acetaminophen, etenzamide, ibuprofen, loxoprofen, etc .; as central nervous stimulants, anhydrous caffeine; as antihistamines, chlorpheniramine, mequitazine, clemastine, carbinoxamine, ketotifen, azelastine, Fexofenadine, epinastine, etc .; glycyrrhizic acid, etc. as anti-inflammatory drugs; guaifenesin, bromhexine, ambroxol, etc. as expectorants; codeine phosphate, dihydrocodeine phosphate, noscapine, noscapine hydrochloride, cloperastine hydrochloride as antitussives Salt, cloperastine phendizoate, pentoxyberine citrate (carbetapentane enoate), tipepidine citrate, tipepidine hibenzate, dextromethorphan Hydride; ephedrine hydrochloride, methylephedrine hydrochloride, methoxyphenamine hydrochloride, pseudoephedrine hydrochloride or sulfate as sympathomimetic drugs; belladonna alkaloids as anti-acetylcholine drugs; isopropamide iodide; vitamins as vitamins B1, vitamin B2, vitamin C, vitamin P and the like; as herbal medicines and herbal extracts, mao, keihi, persimmon, licorice and the like can be mentioned as preferable ones.

  In the composition of the present invention, unless the effect of the present invention is inhibited, organic acids such as minerals, amino acids, gluconic acid or salts thereof, excipients, binders, lubricants, coating agents, preservatives , Colorants, stabilizers, pH adjusters, solubilizers, cooling agents, fragrances, pigments / colorants, and the like can be blended.

The composition of the present invention can be produced by a method known in the art. For example, in the case where the composition of the present invention is a tablet, it can be produced according to the section of the Japanese Pharmacopoeia General Rules “Tablets”. Moreover, when it is a liquid agent, it can be manufactured according to the section of the Japanese Pharmacopoeia General Rules “Liquid Agent”. In the present invention, when the composition containing DADA, tranexamic acid, and the above-described additive component is a solid preparation such as a tablet, the solid preparation can be produced according to a conventional method, but the above-described additive component is DADA and / or tranexam. When a problem such as incompatibility with an acid causes a problem in storage stability or the like, it may be formulated as appropriate so as not to contact each other by granulation or multilayering. Here, a known method may be used for formulation such as granulation and multilayering.
In addition, when the above preparation causes problems in storage stability or quality due to water absorption or the like, it can be appropriately handled by packaging with a desiccant and / or moisture-proof coating of the preparation or granules.

  Examples of the present invention are described below, but are not limited thereto.

(Example 1) Tablets The ingredients and amounts shown in Table 1 are taken, and tablets are produced according to the section of the Japanese Pharmacopoeia General Rules “Tablets”.

(Table 1)
3 tablets (mg) Tablet 1 Tablet 2 Tablet 3
――――――――――――――――――――――――――――――――――
Diisopropylamine dichloroacetate 60 60 90
Tranexamic acid 20 120 750
Lactose 90 90 90
Magnesium stearate 2 2 2
Hydroxypropyl cellulose Suitable amount Suitable amount Suitable amount

(Example 2) Solution The components and amounts shown in Table 2 are taken, and a solution is produced according to the section of “General Preparations” “Liquid”.

(Table 2)
In 50 mL (mg) Solution 1 Solution 2 Solution 3
――――――――――――――――――――――――――――――――――
Diisopropylamine dichloroacetate 60 60 90
Tranexamic acid 20 120 750
White sugar 4000 4000 4000
Sodium benzoate 5 5 5
pH adjuster Appropriate amount Appropriate amount Appropriate amount of purified water

(Test example) Mock infection model test (1) Test substance Diisopropylamine dichloroacetate (DADA) and tranexamic acid (hereinafter sometimes abbreviated as TRA) are both manufactured by Daiichi Sankyo Co., Ltd. did.
60 mg of DADA was dissolved in 10 mL of 0.5% CMC (sodium carboxymethylcellulose) and used as a test substance for DADA alone. For the combination of DADA and TRA, 60 mg of DADA and 60 mg of TRA were dissolved in 10 mL of 0.5% CMC and used as a test substance for the combination.

(2) Animals Seven-week-old Slc: SD male rats were purchased from Nippon Charles River Co., Ltd., preliminarily raised for one week, and then used in the experiments for good ones in which no abnormalities were observed in the general state.
After the acclimatization, the group was divided into 3 groups of 3 per group based on the closest body weight. Group 1 is a positive control group (mock virus inoculation and vehicle administration; “control” in FIG. 1), Group 2 is a DADA administration group (mock virus inoculation and DADA administration; “DADA single agent” in FIG. 1), The group was a combination group of DADA and TRA (pseudovirus inoculation and DADA + TRA administration; “DADA + TRA” in FIG. 1).

(3) Test method Using poly I: C (manufactured by Sigma) as a pseudovirus, this was diluted with physiological saline to a concentration of 5 mg / mL to prepare a virus inoculation administration solution. This was intraperitoneally administered at 1 mL / kg using the latest body weight of each administered rat to induce a pseudoviral infection state.

(4) Administration of test substance 0.05 mL of the above-mentioned test substance per 10 g of rat body weight (for the control group, only 0.5% CMC as a solvent is administered) once a day for 11 days from 4 days before pseudovirus inoculation. (Total 11 times), gastric sonde (manufactured by Fuchigami Instrument Co., Ltd.) and syringe (manufactured by Terumo Corporation) were forcibly orally administered.

(5) Measurement of deep body temperature (rectal temperature) Rectal temperature was measured once a day from the day after the end of grouping, that is, from 3 days before pseudovirus inoculation. On the day of simulated virus intake, after rectal temperature was measured, poly I: C was administered, and rectal temperature was measured every 2 hours after administration. Rectal temperature change [Δ (delta, ° C.)] after administration was determined by the following formula and evaluated.

(6) Test results The results obtained are shown in FIG. The horizontal axis in FIG. 1 is the elapsed time from mock infection, and the vertical axis is the change Δ (delta, ° C.) in rectal temperature.
In the vehicle-only administration group (control), it was confirmed that deep body temperature (as rectal temperature) increased with time by administration of poly I: C. A tendency to antipyretic effect was observed even when DADA single agent (30 mg / Kg) was administered, but when tranexamic acid (TRA, 10 mg / Kg), which does not have antipyretic effect, was used in combination, a significant antipyretic effect was revealed. did.

  Since the composition of the present invention exhibits an excellent antipyretic action, it is useful for antipyretic as well as ameliorating symptoms of sore throat, and therefore can be used as a highly safe common cold medicine.

Claims (2)

  An oral pharmaceutical composition comprising diisopropylamine dichloroacetate and tranexamic acid.   The oral pharmaceutical composition according to claim 1, which is used for antipyretic fever during cold.