JP2008115167A - Suppressor for goblet cell hyperplasia of respiratory tract containing tranexamic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a suppressor for goblet cell hyperplasia of respiratory tract, and to provide a new antitussive and/or expectorant. <P>SOLUTION: The inventor found that tranexamic acid has a suppressing effect on goblet cell hyperplasia of respiratory tract and combination of the ibuprofen with the tranexamic acid remarkably enhances the suppressing effect. A composition comprising the tranexamic acid or tranexamic acid with the ibuprofen exhibits a significant suppressing effect to the goblet cell hyperplasia of respiratory tract caused by smoking, various air pollution substance and inhalation of allergen, etc., or infection of respiratory tract. The invention relates to the suppressor for goblet cell hyperplasia of respiratory tract, the antitussive and/or expectorant containing a pharmaceutical composition comprising the tranexamic acid or the tranexamic acid with ibuprofen. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an airway goblet cell hyperplasia inhibitor containing tranexamic acid or a salt thereof.

  Many of the normal airway surfaces are covered with ciliated epithelial cells, interspersed with goblet cells that produce airway mucus, and exclude foreign substances by the cooperative action of airway secretions and cilia. However, it is known that when airway secretion increases, they accumulate in the airway and become a hotbed for bacterial growth, causing repeated airway infection and airway obstruction. In addition, cigarette smoking, inhalation of various air pollutants or allergens, respiratory tract infections, etc. cause not only increased airway secretion but also hyperplasia of goblet cells. There is a fear of shifting (see, for example, Non-Patent Document 1).

  In order to prevent such a vicious cycle, it is necessary not only to treat with a normal expectorant in the acute phase but also to prevent hyperplasia of goblet cells. In addition, it is known that conventional cold medicines are not considered from such a viewpoint and do not show sufficient antitussive / descending action.

  Tranexamic acid is known to have an antiplasmin action, an antiallergic action, an antiinflammatory action, an antipigmentation action, an antiinfluenza virus action, and the like (see, for example, Patent Document 1). However, it has not been known so far that tranexamic acid has an action of suppressing the formation of airway goblet cells.

  It has been reported that ibuprofen, an antipyretic analgesic, has no effect of suppressing goblet cell hyperplasia or conversely promotes hyperplasia (see Patent Document 2).

So far, the following has been disclosed as a combination example of tranexamic acid and ibuprofen.
(1) When tranexamic acid, ibuprofen and caffeine are used in combination, gastric mucosal damage caused by ibuprofen is alleviated (see Patent Document 3), and antipyretic analgesics of the formulation are actually commercially available (Non-patent Documents) 2).
(2) Although anti-inflammatory action is enhanced by the combined use of tranexamic acid, bromhexine and clemastine (see Patent Document 4), further, an example of a formulation containing tranexamic acid, ibuprofen, bromhexine and clemastine is disclosed in the same document. .

However, in the above (1) to (2), there is no description or suggestion about the action of suppressing airway goblet cell hyperplasia.
International Publication No. 2004/032915 Pamphlet JP 2000-143505 A Japanese Patent No. 3667381 JP 2006-124380 A Pharmaceutical Journal, 2002, Vol. 38, No. 12, p.121-126 Japan Pharmaceutical Collection DB 2004 October Jiho

  In view of such circumstances, the present invention provides a novel airway goblet cell hyperplasia inhibitor, and further, an antitussive and / or expectorant.

  As a result of intensive studies, the present inventors have found that tranexamic acid has an excellent effect of suppressing hyperplasia of airway goblet cells, and completed the present invention. Furthermore, it has also been found that the combined use of tranexamic acid and ibuprofen significantly enhances the inhibitory effect of tranexamic acid on airway goblet cell hyperplasia.

That is, the present invention
(1) Airway goblet cell hyperplasia inhibitor containing tranexamic acid or a salt thereof,
(2) Antitussive and / or expectorant containing tranexamic acid or a salt thereof,
(3) The airway goblet cell hyperplasia inhibitor according to (1), further containing ibuprofen,
(4) The present invention relates to the antitussive and / or expectorant according to the above (2), which further contains ibuprofen.

  The tranexamic acid according to the present invention and the pharmaceutical composition containing tranexamic acid and ibuprofen significantly suppress goblet cell hyperplasia caused by smoking, inhalation of various air pollutants and allergens, respiratory tract infections, etc. showed that. Therefore, it is useful for showing antitussive and / or expectorant action. As a result, it is also useful for treatment of acute respiratory infection in chronic airway diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema.

  Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) or a salt thereof according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used, or it is produced based on a known method. It is also possible. Examples of salts of tranexamic acid include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrates, perchlorates, sulfates, phosphates, etc. Inorganic acid salts; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate, and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetate, malic acid Organic acid salts such as salt, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartic acid Acid salts such as amino acid salts such as salts, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; N-methylmol Organic base salts such as phosphorus salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt; glycine salt, lysine salt, arginine salt And basic salts such as amino acid salts such as ornithine, glutamate and aspartate. In the present invention, tranexamic acid or a salt thereof is preferably tranexamic acid.

  In addition, ibuprofen according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used, or it can be produced based on a known method.

  In the airway goblet cell hyperplasia inhibitor of the present invention, ibuprofen can be mentioned as the most preferred compounding component to be added to tranexamic acid or a salt thereof.

Furthermore, in addition to tranexamic acid or a salt thereof, tranexamic acid or a salt thereof and ibuprofen, the following pharmaceutical ingredients may be added to the airway goblet cell hyperplasia inhibitor of the present invention. Pharmaceutical ingredients that can be incorporated include antipyretic analgesics such as aspirin, aspirin aluminum, sazapiline, etenzamide, salicylamide, acetaminophen, isopropylantipyrine, caffeine, anhydrous caffeine, sodium benzoate caffeine, theophylline, aminophylline, diprofylline. Central nervous system stimulants, sedatives such as bromvalerylurea, allylisopropylacetylurea, clemastine fumarate, chlorpheniramine maleate, diphenhydramine, diphenhydramine salicylate, carbinoxane maleate, mequitazine, alimemazine tartrate, diphenylpyraline hydrochloride, triprolidine hydrochloride Antihistamines such as lysozyme chloride, bromelain, serrapeptase, semi-alkaline proteinase, glycyrrhizic acid, Anti-inflammatory drugs such as dipotassium tyrrhizate, ammonium glycyrrhizinate, glycyrrhetinic acid, sodium azulene sulfonate, dihydrocodeine phosphate, codeine phosphate, noscapine hydrochloride, noscapine, dextromethorphan hydrobromide, dextromethorphan phenolphthalein salt, Antitussives such as dimemorphan phosphate, tipepidine hibenzate, tipepidine citrate, eprazinone hydrochloride, L-ethylcysteine hydrochloride, potassium guaiacol sulfonate, potassium cresolate, guaifenesin, bromhexine hydrochloride, carbocysteine, ambroxol hydrochloride, etc. , Bronchodilators such as methylephedrine, methylephedrine hydrochloride, methoxyphenamine hydrochloride, trimethquinol hydrochloride, phenylpropanolamine hydrochloride, verado Na (total) alkaloids, belladonna extract, isopropamide iodide, scopolamine hydrobromide, funnel extract, butylscopolamine bromide, methylbenactidium bromide, thimepidium bromide, pirenzepine and other antiacetylcholine agents, cetylpyridinium, cetyl chloride Disinfectants such as pyridinium, popidone iodine, chlorhexidine gluconate, benzalkonium chloride, decalinium chloride, thymol, iodine / potassium iodide, phenol, chlorhexidine hydrochloride, creosote, benzethonium chloride, dibucaine hydrochloride, ethyl aminobenzoate, lidocaine, lidocaine hydrochloride, a local anesthetic agent such as oxethazaine, vitamin a, cod liver oil, vitamin _{B 1,} vitamin _{B 2,} vitamin _{B 6,} vitamin _{B 12,} vitamin C, calcium ascorbate, bi- Vitamin D such as Min D, vitamin E, tocopherol calcium succinate, pantothenic acid, panthenol, sodium pantothenate, calcium pantothenate, panthetin, nicotinic acid, nicotinamide, glucuronic acid, glucuronolactone, aminoethylsulfonic acid, Metabolic components such as biotin and γ-oryzanol, natural medicines such as earth dragons, keihi, gooh, shokyo, kyoukyo, maou, licorice, kyounin, hange, shazenso, senega, psycho, bukkyou, shinnyi and extracts of these herbal medicines ( Extract, tincture, and the like), but should not be limited to the above. These pharmaceutical ingredients may be blended in a single component or in combination of two or more. In the present invention, in addition to tranexamic acid or a salt thereof, or tranexamic acid or a salt thereof and ibuprofen, it is preferable to further contain bromhexine hydrochloride, clemastine fumarate, methylephedrine hydrochloride, dihydrocodeine phosphate, thiamine nitrate, riboflavin, and the like. .

  When tranexamic acid or a salt thereof according to the present invention or a pharmaceutical ingredient that can be blended in it absorbs moisture by attaching it to the atmosphere or by recrystallization, adsorbed water is added or becomes a hydrate. Such hydrates are also included in the present invention.

  The airway goblet cell hyperplasia inhibitor of the present invention can be administered orally, and specific dosage forms of the oral administration preparation include, for example, tablets, fine granules (including powders), capsules and the like. Solid preparations, liquid preparations (including syrup preparations), etc. can be mentioned, and additives and base materials suitable for each dosage form can be used as appropriate, and they can be produced according to the usual methods described in the Japanese Pharmacopoeia etc. it can.

  In the above dosage forms, various commonly used additives can be used depending on the dosage form.

  For example, in the case of tablets, lactose, crystalline cellulose or the like as an excipient, magnesium aluminate or magnesium oxide as a stabilizer, hydroxypropyl cellulose or the like as a coating agent, magnesium stearate or the like as a lubricant In the case of fine granules and capsules, lactose or purified sucrose can be used as an excipient, magnesium aluminate or magnesium oxide as a stabilizer, corn starch or the like as an adsorbent, Hydroxypropyl cellulose or the like can be used as a binder.

  In each of the above dosage forms, a disintegrant such as crospovidone; a surfactant such as polysorbate; an adsorbent such as calcium silicate; a colorant such as iron sesquioxide and caramel; and a pH adjuster such as sodium benzoate. A fragrance or the like can also be added.

  The single dose of tranexamic acid in the airway goblet cell hyperplasia inhibitor of the present invention varies depending on gender, indication, age, etc., and may be determined as appropriate, and an appropriate dose may be determined. It is 10 mg to 3000 mg, preferably 100 mg to 750 mg, and this may be administered 13 times a day.

In the case of an oral solid preparation, the content of tranexamic acid contained in a single dose is usually 10 mg to 3000 mg, preferably 100 mg to 750 mg.
In addition to tranexamic acid or a salt thereof, the content of ibuprofen, which is a preferable medicinal component, is usually 30 mg to 2000 mg, and preferably 100 mg to 600 mg. The content of bromhexine hydrochloride is usually 0.6 mg to 24 mg, and preferably 1.2 mg to 12 mg. The content of clemastine fumarate is usually 0.1 mg to 8 mg, preferably 0.4 mg to 4 mg. The content of methylephedrine hydrochloride is usually 1 mg to 80 mg, preferably 1 mg to 40 mg. The content of dihydrocodeine phosphate is usually 1.2 mg to 48 mg, preferably 2.4 mg to 24 mg. The content of thiamine nitrate is usually 1.2 mg to 48 mg, and preferably 2.4 mg to 24 mg. The content of riboflavin is usually from 0.6 mg to 24 mg, and preferably from 1.2 mg to 12 mg.

Hereinafter, the present invention will be described in more detail with reference to examples and the like, but the scope of the present invention is not limited thereto.
(Example 1) Tablet (1) component (in 6 tablets, mg)
(Table 1)
(1a) (1b) (1c) (1d)
――――――――――――――――――――――――――――――――――――――
Tranexamic acid 750 750 750 750
Ibuprofen 450 450-450
Bromhexine hydrochloride 12-12 12
Cremastine fumarate-1.34 1.34 1.34
Crystalline cellulose 100 100 90 100
Hydroxypropyl cellulose 80 70 40 90
Magnesium stearate 10 10 10 10
Lactose Appropriate amount Appropriate amount Appropriate amount Appropriate amount ――――――――――――――――――――――――――――――――――――――
(2) Manufacturing method The said component and quantity were taken, and tablet (1a)-(1d) was manufactured according to the 15th revision Japanese Pharmacopoeia preparation general rule "Tablet".
(Example 2) Fine granule (1) component (in 3 packages, mg)
(Table 2)
(2a) (2b) (2c) (2d)
――――――――――――――――――――――――――――――――――――――
Tranexamic acid 750 750 750 750
Ibuprofen 450 450-450
Bromhexine hydrochloride 12-12 12
Cremastine fumarate-1.34 1.34 1.34
Methylephedrine hydrochloride 60 60 60 60
Dihydrocodeine phosphate 24 24 24 24
Thiamine nitrate---25
Riboflavin − − − 12
Lactose Appropriate amount Appropriate amount Appropriate amount Appropriate amount ――――――――――――――――――――――――――――――――――――――
(2) Manufacturing method Taking the said component and quantity, according to the 15th revision Japanese Pharmacopoeia preparation general rule "granule", fine granules (2a)-(2d) were manufactured.

(Example 3) Capsule (in 6 capsules, mg)
(1) Ingredients (Table 3)
(3a) (3b) (3c) (3d)
――――――――――――――――――――――――――――――――――――――
Tranexamic acid 750 750 750 750
Ibuprofen 450 450-450
Bromhexine hydrochloride 12-12 12
Cremastine fumarate-1.34 1.34 1.34
Lactose Appropriate amount Appropriate amount Appropriate amount Appropriate amount ――――――――――――――――――――――――――――――――――――――
(2) Manufacturing method After taking the above ingredients and quantities, and producing fine granules according to the 15th revised Japanese Pharmacopoeia General Rules for “Granules”, they are filled into capsules and hard capsules (3a) to (3d) ) Was manufactured.

(Test example) Goblet cell hyperplasia inhibitory effect test (1) Test substance Tranexamic acid was manufactured by Daiichi Pharmaceutical Co., Ltd., and ibuprofen was manufactured by Yatsushiro Pharmaceutical Co., Ltd.

Each test substance was prepared by administering a 0.5% carboxymethylcellulose (CMC) solution on the day of the test and administered, and a 0.5% CMC solution was administered to the control group. The dose volume was adjusted to 5 mL / Kg in all cases.
(2) Animal F344 / DuCrj male rat 10-week-old was purchased from Charles River Japan Co., Ltd., and was controlled in a rat breeding room controlled at a temperature of 20 to 26 ° C., a humidity of 30 to 70%, and a lighting time of 7:00 to 19:00. Five rats were placed in a ratchet taper cage for rats, and feed (mouse / rat breeding F-2, manufactured by Funabashi Farm) and tap water passed through a water filter were freely ingested and pre-bred for about one week. On the day of the test, the animals were observed with the naked eye for health and confirmed to be good, and the body weight was measured. The animals were randomly divided into 6 groups per group.
(3) Method The rat is anesthetized by intraperitoneal administration of pentobarbital 50 mg / Kg, fixed in the supine position, the cervical laryngeal skin is incised in the midline, and inserted into the trachea while confirming from the exposed trachea, 100 μL of 1% lipopolysaccharide (LPS) solution was administered. Immediately, the peritracheal muscle and the skin of the incision were sutured to create an animal having an airway mucosa disorder.

  After the test substance (CMC solution for the subject group) was orally administered in the morning of the test start day, the LPS solution was intratracheally administered by the above-described method, and the test substance (subject group was not included in the subject group) after 16:00 on that day. CMC solution) was orally administered. On the second and third days, oral administration was performed twice a day in the morning (around 11:00) and in the afternoon (around 16:00).

  After measuring body weight on the 4th day, the carotid artery was amputated under pentobarbital anesthesia and exsanguinated, and the trachea from the epiglottis to the lungs was collected, washed with physiological saline, and 10% neutral buffered It was immersed in formalin solution and fixed sufficiently.

  After sufficiently fixing, the trachea was traversed about 10 mm above the left and right main bronchial bifurcations, and further traversed at a length of 6 mm or more, and the tubular trachea was cut out and used as an observation material.

  By a conventional method, a tubular trachea was longitudinally cut to prepare a strip-like thin cut trachea specimen, which was stained with Alcian blue / PAS stain, and then the number of goblet cells within a range of 6 mm length was measured under a microscope. In addition, the total number of goblet cells of two strip-shaped tracheal tissue specimens for one example was taken as the number of measurements.

  The inhibition rate of goblet cell hyperplasia (%) was obtained from the following formula.

Goblet cell hyperplasia inhibition rate (%) = [1-B / A] × 100
A: Average value of goblet cells in the CMC administration group B: Average value of goblet cells in the test substance administration group

(4) Test results The results of the goblet cell hyperplasia inhibition rate obtained are shown in Tables 4 and 5. Each value is an average value of 7 animals per group.

(Table 4)
Test substance (dose: mg / Kg) Goblet cell hyperplasia inhibition rate (%)
----------------------------------
Tranexamic acid (30) 16.0
Ibuprofen (50) -2.2
Tranexamic acid (30) + ibuprofen (50) 57.2 ^*
----------------------------------
*: P <0.05
From Table 4, it was found that tranexamic acid has an inhibitory effect on goblet cell hyperplasia. Surprisingly, it has also been found that when tranexamic acid is combined with ibuprofen having no effect on goblet cells, the inhibitory effect of tranexamic acid on goblet cell hyperplasia is significantly enhanced.

The tranexamic acid according to the present invention and the pharmaceutical composition containing tranexamic acid and ibuprofen significantly suppress goblet cell hyperplasia caused by smoking, inhalation of various air pollutants and allergens, respiratory tract infections, etc. Have Therefore, it is useful because it exhibits antitussive and / or expectorant action. As a result, it is also useful for treatment of acute respiratory infection in chronic airway diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema.

Claims (4)

An inhibitor of airway goblet cell hyperplasia containing tranexamic acid or a salt thereof. Antitussive and / or expectorant containing tranexamic acid or a salt thereof. The airway goblet cell hyperplasia inhibitor according to claim 1, further comprising ibuprofen. The antitussive and / or expectorant according to claim 2, further comprising ibuprofen.