JP2013147492A - Safe oral antipyretic pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antipyretic pharmaceutical composition that is effective and safe for fever onset or coughing in a common cold.SOLUTION: An antipyretic pharmaceutical composition is provided, including diisopropylamine dichloroacetate and a sympathetic stimulant.

Description

  The present invention relates to a pharmaceutical composition for oral antipyretic containing diisopropylamine dichloroacetate and a sympathomimetic drug. More specifically, the present invention relates to a safe pharmaceutical composition for antipyretic that can be used for cough and fever in 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 disease, and (a) promotes liver regeneration, and (b) antifat. Liver action has been reported (see, for example, Non-Patent Document 2). However, there is no report that DADA is effective as a cold use.

  Sympathomimetic drugs (sometimes referred to as sympathomimetics) have bronchodilation and decongestion, so they can relieve airway obstruction and nasal congestion during the cold, ease breathing, and cough It is blended because it has the effect of calming the skin and facilitating wrinkles. However, there are no reports that sympathomimetic drugs are effective (and have antipyretic action) against fever during the cold.

  To date, no antipyretic composition or anti-cold composition containing DADA and a sympathomimetic drug has been known, and there is no suggestion that the combination is effective against fever during colds.

Pediatrics, Vol.32 No.1 1991 p.11-21 2009 Edition Prescription Drug Collection JAPIC 2008 OTC Drug Manufacturing (Import) Approval Standard 2000

  An object of the present invention is to provide a pharmaceutical composition for antipyretic 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 isopropyl acetate diisopropylamine, which is a liver function improving agent, was used in combination with a sympathomimetic drug having no antipyretic action, an excellent antipyretic action was developed, and the present invention was completed. .

That is, the present invention relates to the following (1) to (4).
(1) An antipyretic pharmaceutical composition comprising diisopropylamine dichloroacetate and a sympathomimetic drug.
(2) The exchange nerve stimulant is epinephrine, l-isoprenarin, oxyprenalin, salbutamol, terbutaline, clenbuterol, tulobuterol, procaterol, mapterol, salmeterol, fenoterol, formoterol, trimethquinol, phenylpropanolamine, methoxyphenamine, ephedrine , Methylephedrine and pseudoephedrine, or a pharmaceutical composition for antipyretic according to (1), which is one or more selected from the group consisting of salts thereof.
(3) The antipyretic pharmaceutical composition according to (1), wherein the exchange nerve stimulant is methylephedrine hydrochloride.
(4) The antipyretic pharmaceutical composition according to any one of (1) to (3), which is used for the antipyretic of exothermic heat at the time of common cold.

  The composition containing diisopropylamine dichloroacetate and a sympathomimetic agent according to the present invention exhibits an excellent antipyretic action, and thus is useful not only for antitussive expectoration and nasal obstruction improvement in common colds but also for antipyretic purposes. Yes and high safety. 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.

  The sympathomimetic drug in the present specification is not particularly limited as long as it is a drug having a sympathomimetic (excitatory) action. , Mapterol, salmeterol, fenoterol, formoterol, trimethquinol, phenylpropanolamine, methoxyphenamine, ephedrine, methylephedrine and pseudoephedrine, or salts thereof. The sympathomimetic drug is preferably ephedrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, and methylephedrine hydrochloride, and more preferably methylephedrine hydrochloride. The ephedrines such as ephedrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, and methylephedrine hydrochloride may be herbal medicines containing ephedrines such as Mao. Here, epinephrine (adrenaline), l-isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate, tulobuterol hydrochloride, procaterol hydrochloride hydrate, formoterol fumarate hydrate, trimethquinol hydrochloride hydrate, ephedrine hydrochloride , And dl-methylephedrine hydrochloride are listed in the 16th revised Japanese Pharmacopoeia. Other sympathomimetic drugs are also commercially available and are readily available.

  Diisopropylamine dichloroacetate in the present invention is listed in the Japanese Pharmacopoeia Standards for Drugs 2002.

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. Further, the content of the sympathomimetic drug is preferably set such that 0.01 to 300 mg, more preferably 0.1 to 200 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 the sympathomimetic drug is preferably 0.01 to 300 mg / 100 mL, more preferably 0.1 to 200 mg / 100 mL.

  The composition of the present invention further comprises antipyretic analgesics, central nervous stimulants, antihistamines, anti-inflammatory drugs, expectorants, antitussives, antiacetylcholine drugs, vitamins, herbal medicines and herbal extracts. It can be added within a range that does not interfere. Here, as antipyretic analgesics, aspirin, acetaminophen, etenzamide, ibuprofen, loxoprofen, etc .; as central nervous stimulants, anhydrous caffeine; as antihistamines, chlorpheniramine, mequitazine, clemastine, carbinoxamine, ketotifen, azelastine, Anti-inflammatory drugs such as tranexamic acid, glycyrrhizic acid, etc .; expectorant drugs such as guaifenesin, bromhexine, ambroxol, etc .; antitussive drugs such as codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine hydrochloride , Cloperastine hydrochloride, Cloperastine phendizoate, Pentoxyberine citrate (Carbetapentan enoate), Tipepidine citrate, Tipepidine hibenzate, Dex Lomethorphan hydrobromide; belladonna alkaloids and isopropamide iodide as anti-acetylcholine drugs; vitamin B1, vitamin B2, vitamin C, vitamin P, etc. as vitamin drugs; herbal medicine and herbal extracts such as Keihi, Spruce, licorice, etc. Can be mentioned as preferred examples of the drug to be added.

  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, a sympathomimetic agent, and the above-mentioned additive component is a solid preparation such as a tablet, the solid preparation can be produced according to a conventional method. Alternatively, when a problem such as a contraindication with a sympathomimetic drug occurs 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 60
dl-Methylephedrine hydrochloride 60 − −
Pseudoephedrine hydrochloride-180-
Methoxyphenamine hydrochloride-150
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 60
dl-Methylephedrine hydrochloride 60 − −
Pseudoephedrine hydrochloride-180-
Methoxyphenamine hydrochloride-150
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) is manufactured by Daiichi Sankyo Co., Ltd., and methylephedrine hydrochloride (ME) is Alps Pharmaceutical Co., Ltd. The product made from was used.
60 mg of DADA was dissolved in 10 mL of 0.5% CMC (sodium carboxymethylcellulose) and used as a test substance for DADA alone. As for the combination of DADA and ME, 60 mg of DADA and 10 mg of ME 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 combined use group of DADA and ME (pseudovirus inoculation and DADA + ME administration; “DADA + ME” 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. Although antipyretic tendency was observed even when DADA single agent (30 mg / Kg / day) was administered, methylephedrine hydrochloride (ME, 5 mg / Kg / day), a sympathomimetic drug that does not have antipyretic effect, was used in combination It was found that a significant antipyretic effect was developed.

  Since the composition of the present invention exhibits an excellent antipyretic action, it can be used as a highly safe common cold medicine useful for antitussive and expectorant action, symptom improvement of nasal congestion, and antipyretic.

Claims (4)

  An antipyretic pharmaceutical composition comprising diisopropylamine dichloroacetate and a sympathomimetic drug.   Exchange neurostimulators are epinephrine, l-isoprenalin, oxyprenalin, salbutamol, terbutaline, clenbuterol, tulobuterol, procaterol, mapterol, salmeterol, fenoterol, formoterol, trimethquinol, phenylpropanolamine, methoxyphenamine, ephedrine, methylephedrine The pharmaceutical composition for antipyretic according to claim 1, which is one or more selected from the group consisting of and ephedrine and pseudoephedrine or a salt thereof.   The antipyretic pharmaceutical composition according to claim 1, wherein the exchange nerve stimulant is methylephedrine hydrochloride.   The antipyretic pharmaceutical composition according to any one of claims 1 to 3, wherein the antipyretic pharmaceutical composition is used for antipyretic of exothermic heat at the time of cold.