JP2007314517A - Antitussive or expectorant pharmaceutical composition comprising loxoprofen - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition useful for antitussive or expectorant by suppressing goblet cell hyperplasia of respiratory tract. <P>SOLUTION: The antitussive or expectorant pharmaceutical composition comprising loxoprofen which is a kind of non-steroid antipyretic analgesic antiphlogistic, and one or more members selected from caffeine, ephedrine and codeine. The composition has an efficacy of remarkably suppressing goblet cell hyperplasia of respiratory tract and useful for drug for common cold, treatment for acute respiratory disease symptom in chronic airways disease such as acute or chronic bronchitis, chronic obstructive pulmonary disease, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, pulmonary emphysema, diffuse panbronchitis, etc. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition for antitussive or expectorant containing loxoprofen and one or more selected from caffeine, ephedrine and codeine.

  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, sputum accumulates in the airway and the sputum serves as a hotbed for bacterial growth, thus causing repeated respiratory tract infections 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, etc., and if this persists, from acute respiratory disease to chronic intractable respiratory disease There is a risk of migration (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 take measures to suppress goblet cell hyperplasia.

  On the other hand, loxoprofen, which is a kind of nonsteroidal antipyretic analgesic / anti-inflammatory agent (hereinafter referred to as NSAID), is a prodrug-type drug that is converted into an active metabolite in the body and exhibits antipyretic analgesic / anti-inflammatory action. It is known that gastrointestinal disorders, which are the main side effects of the drug, are reduced and highly safe (see, for example, Non-Patent Document 2), and relatively quick-acting (see, for example, Non-Patent Document 3). In addition, efficacy and effect of antipyretic and analgesia in acute upper respiratory tract inflammation are recognized (for example, see Non-Patent Document 4).

  Since caffeine is known to enhance the antipyretic and analgesic effects of NSAIDs, caffeine may be included in antipyretic analgesics, and it also serves the purpose of suppressing drowsiness, which is a side effect of antihistamines. It is often blended with cold medicine (for example, see Non-Patent Document 5).

  Since ephedrines have the action of stimulating sympathetic nerves to widen the airways, they are often blended with cold medicines and antitussive expectorants (see, for example, Non-Patent Document 5).

  Codeines are often blended in cold medicines and antitussive expectorants as narcotic central antitussives (see, for example, Non-Patent Document 5).

  So far, there is no report on the action of loxoprofen or caffeine single agent on goblet cells. Among NSAIDs, ibuprofen and acetaminophen have been confirmed not to change the number of goblet cells in their single agent administration test (see Patent Document 1). In addition, it has been reported that dihydrocodeine phosphate slightly promotes the formation of goblet cells, and that goblet cell hyperplasia induced by dihydrocodeine phosphate is inhibited by trimethquinol, a bronchodilator (Patent Literature). 2).

As examples of the combined use of loxoprofen and caffeine, ephedrine or codeine, the following is disclosed.
1) The combined use of loxoprofen and caffeine produces a synergistic effect of anti-inflammatory and analgesic (see Patent Document 3).
2) The composition which mix | blended the antacid and the caffeine with the loxoprofen is described (refer patent document 4).
3) When methylephedrine is used in combination with loxoprofen, the anti-inflammatory action and antipyretic action of loxoprofen are enhanced (see Patent Document 7).
4) When dihydrocodeine phosphate is used in combination with loxoprofen, the anti-inflammatory action of loxoprofen is enhanced (see Patent Document 7).
5) When pseudoephedrine is used in combination with loxoprofen, the anti-sneezing action of loxoprofen is enhanced (see Patent Document 8).

However, the results of 1) to 5) above do not suggest an inhibitory effect on airway goblet cell hyperplasia, and so far one or two selected from loxoprofen and caffeine, ephedrine and codeine. There has been no report that the combined use of more than one species significantly suppresses the hyperplasia of airway goblet cells due to respiratory infection and the like, and further provides an excellent antitussive or expectorant effect.
WO2002 / 096406 JP 2003-95978 A Japanese Patent Laid-Open No. 11-139971 JP 2006-52210 A JP 2001-199882 A JP 2004-59579 A JP 2000-143505 A JP 2004-2362 A Pharmaceutical Journal, 2002, Vol. 38, No. 12, p121-126 Pharmacology and therapy, Vol. 16, no. 2, 1988, p. 611-619 CLINICA, Vol. 31, no. 1, 2004, p. 38-41 Japan Pharmaceutical Collection Medical Drug 2006 Edition, Jiho, 2005 Popular Medicine Dictionary 9th Edition, Jiho, 2004

  As a result of earnest research on a pharmaceutical composition having an inhibitory effect on goblet cell hyperplasia, the present inventor unexpectedly obtained one or more selected from loxoprofen and caffeine, ephedrine and codeine. The present inventors have found that the pharmaceutical composition contained significantly suppresses hyperplasia of airway goblet cells, and has completed the present invention.

The present invention is a pharmaceutical composition for antitussive or expectorant comprising (1) loxoprofen and one or more selected from caffeine, ephedrine and codeine,
(2) Loxoprofen and a pharmaceutical composition for suppressing goblet cell hyperplasia of the respiratory tract comprising one or more selected from caffeine, ephedrine and codeine,
(3) The pharmaceutical composition according to any one of (1) and (2), wherein loxoprofen is loxoprofen sodium;
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the ephedrine is ephedrine hydrochloride or methylephedrine hydrochloride,
(5) The pharmaceutical composition according to any one of (1) to (3), wherein the caffeine is caffeine or anhydrous caffeine,
(6) The pharmaceutical composition according to any one of (1) to (5), wherein the codeines are codeine phosphate or dihydrocodeine phosphate,
(7) The pharmaceutical composition according to any one of (1) to (6) for use as a cold remedy,
(8) The pharmaceutical composition according to any one of (1) to (6) for use in the treatment of acute or chronic bronchitis,
(9) For use in the treatment of symptoms during acute respiratory infections in chronic airway diseases such as chronic obstructive pulmonary disease, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis (1) Thru | or the pharmaceutical composition of any one of (6).
(10) Any one of (1) to (9), wherein loxoprofen and one or more selected from caffeine, ephedrine and codeine are contained in the same pharmaceutical composition (11) The pharmaceutical composition according to any one of (1) to (9), which is a kit comprising one or more selected from the pharmaceutical composition according to (11), loxoprofen, and caffeine, ephedrine, and codeine. It is a pharmaceutical composition.

The present invention also provides:
(12) The pharmaceutical according to any one of (1) to (9), wherein loxoprofen and one or more selected from caffeine, ephedrine and codeine are contained in the same pharmaceutical composition. Production method of the composition,
(13) Use of the pharmaceutical composition according to any one of (1) to (6) for producing a cold medicine,
(14) A method of administering loxoprofen and one or more selected from caffeine, ephedrine and codeine simultaneously, sequentially or separately, and (15) any of (1) to (6) to a mammal A method for preventing or treating common cold, which comprises administering an effective amount of the pharmaceutical composition described in any one of the above.

  In the present invention, “loxoprofen” is loxoprofen or a salt thereof (including a hydrated salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.

  The ephedrines are ephedrine, methylephedrine, pseudoephedrine or a salt thereof, preferably ephedrine, methylephedrine, or a salt thereof, and more preferably ephedrine hydrochloride or methylephedrine hydrochloride.

  Caffeine is caffeine or a salt thereof, preferably caffeine, anhydrous caffeine, sodium benzoate caffeine, caffeine hydrochloride or citrate caffeine, and more preferably caffeine or caffeine. Anhydrous caffeine.

  Codeine is codeine, dihydrocodeine or a salt thereof, preferably codeine phosphate or dihydrocodeine phosphate.

  The “salt” in the present invention, when the active ingredient of the present invention has an acidic group or basic group, can be converted into a basic salt or acidic salt by reacting with a base or acid. Indicates salt.

  The “basic salt” is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt; N-methylmorpholine salt, triethylamine salt, Organic base salts such as tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid Salts, amino acid salts such as aspartate, and more preferably alkali metal salts.

  As the “acid salt”, preferably, hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt and the like; and glycine salt, lysine salt , An amino acid salt such as arginine salt, ornithine salt, glutamate salt and aspartate salt, more preferably an inorganic acid salt or an organic acid salt.

  The active ingredient of the present invention may absorb moisture by adhering to the atmosphere or recrystallize, and may adsorb water or become hydrate. Are also used in the present invention.

  When administering the pharmaceutical composition of the present invention, each active ingredient can be administered simultaneously, sequentially or separately.

  In the present invention, “simultaneously” administration includes administration at exactly the same time as pharmacologically acceptable as well as administration at the same time. The dosage form is not particularly limited as long as it can be administered at approximately the same time, but it is preferably a single composition.

  “Sequential or separate” administration in the present invention is not particularly limited as long as it is a dosage form that can be administered separately at different times. For example, one component is administered, and then, after a predetermined time, There are ways to administer other ingredients.

  In the present invention, “treatment” means to cure or ameliorate a disease or symptom or suppress a symptom, and “prevention” means to prevent the onset of illness or symptom.

  In the present invention, the “compounding agent” refers to a single composition in which a plurality of components are mixed.

  In the present invention, a “kit” refers to a set of a plurality of separate compositions.

  The pharmaceutical composition for antitussive or expectorant containing loxoprofen of the present invention and one or more selected from caffeine, ephedrine and codeine is smoking, various air pollutants and inhalation of allergens, etc. It is useful because it has an action of significantly suppressing goblet cell hyperplasia caused by respiratory tract infection and the like, and also has an antitussive or expectorant action. It is also useful for treating coughing and expectoration associated with acute bronchitis including upper respiratory tract inflammation such as the common cold. Furthermore, for treatment of acute respiratory infection in chronic bronchitis including chronic obstructive pulmonary disease (COPD), bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis and other chronic airway diseases Useful.

  Loxoprofen sodium, ephedrine hydrochloride, methylephedrine hydrochloride, codeine phosphate, dihydrocodeine phosphate, caffeine, anhydrous caffeine and sodium caffeine benzoate are listed in the Japanese Pharmacopoeia XIV.

  Other components are also commercially available, and can be produced by known methods.

  The single dose of loxoprofen varies depending on the indication and age, but is usually 20 mg to 180 mg, which is administered 1 to 3 times a day.

  The single dose of codeines varies depending on the indication and age, but is usually 2 mg to 100 mg, which is administered 1 to 3 times a day.

  The single dose of caffeine varies depending on the indication and age, but is usually 20 mg to 400 mg, which is administered 1 to 3 times a day.

  The single dose of ephedrine varies depending on the indication and age, but is usually 10 mg to 190 mg, and this is administered 1 to 3 times a day.

  In the case of a solid preparation, the content of loxoprofen contained in a single dose is usually 10 mg to 400 mg, preferably 20 mg to 180 mg.

  The content of codeines is usually 2 mg to 100 mg, preferably 4 mg to 50 mg.

  The content of caffeine is usually 10 mg to 800 mg, preferably 20 mg to 400 mg.

  The content of ephedrines is usually 5 mg to 200 mg, preferably 10 mg to 90 mg.

  The content of loxoprofen contained in the case of a liquid preparation is usually 0.1 mg / mL to 200 mg / mL, and preferably 1 mg / mL to 100 mg / mL.

  The content of caffeine is usually 0.1 mg / mL to 400 mg / mL, and preferably 1 mg / mL to 200 mg / mL.

  The content of ephedrines is usually 0.05 mg / mL to 100 mg / mL, preferably 0.5 mg / mL to 50 mg / mL.

  In the present invention, in addition to the above active ingredients, bronchodilators, non-narcotic antitussives, expectorants, anticholinergic agents, anti-inflammatory enzymes, vitamins, herbal medicines, antacids, etc., as necessary. It can mix | blend in the range which is not impaired.

  Specific dosage forms of the present invention include, for example, tablets, fine granules (including powders), capsules, liquids (including syrups) and the like, and additives and groups suitable for each dosage form. It can be produced according to the usual method described in the Japanese Pharmacopoeia, using materials appropriately.

  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 metasilicate aluminate or magnesium oxide as a stabilizer, hydroxypropyl cellulose or the like as a coating agent, magnesium stearate or the like as a lubricant Can be used,
In the case of fine granules and capsules, lactose or purified sucrose is used as an excipient, magnesium aluminate or magnesium oxide as a stabilizer, corn starch or the like as an adsorbent, hydroxypropylcellulose or the like as a binder As can be used.

  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. Fragrance, etc. can also be added.

  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)
―――――――――――――――――――――――――――――――
Loxoprofen sodium 180 180 180
Anhydrous caffeine 90 − −
Methylephedrine hydrochloride-75-
Codeine phosphate--45
Crystalline cellulose 100 110 110
Hydroxypropyl cellulose 40 40 40
Magnesium stearate 10 10 10
Lactose appropriate amount appropriate amount appropriate amount ―――――――――――――――――――――――――――――――
(2) Manufacturing method Take the above ingredients and the amount, and manufacture tablets according to the section of “General Tablets” “Tablet”.

(Example 2) Fine granule (1) component (in 3 packages, mg)
(Table 2)
(2a) (2b) (2c)
――――――――――――――――――――――――――――――――
Loxoprofen sodium 180 180 180
Anhydrous caffeine 90 − −
Methylephedrine hydrochloride-75-
Dihydrocodeine phosphate --20
Crystalline cellulose 120 130 140
Hydroxypropyl cellulose 100 100 100
Magnesium stearate 10 10 10
D-mannitol 190 190 190
Lactose appropriate amount appropriate amount appropriate amount ――――――――――――――――――――――――――――――――
(2) Production method Take the above ingredients and quantities, and produce a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granule”.

(Example 3) Capsule (1) component (in 6 capsules, mg)
(Table 3)
(3a) (3b) (3c)
―――――――――――――――――――――――――――――――
Loxoprofen sodium 180 180 180
Anhydrous caffeine 90 − −
Methylephedrine hydrochloride-75-
Codeine phosphate--45
Magnesium stearate 10 10 10
Polysorbate 50 50 50
Corn starch 150 170 170
Lactose appropriate amount appropriate amount appropriate amount ―――――――――――――――――――――――――――――――
(2) Manufacturing method After taking the above components and quantities and preparing a fine granule according to the section of the General Rules for Pharmaceutical Preparations “Granule”, the capsule is filled into a hard capsule.

(Example 4) Syrup (1) component (mg in 30 mL)
(Table 4)
(4a) (4b) (4c)
―――――――――――――――――――――――――――――――
Loxoprofen sodium 180 180 180
Anhydrous caffeine 90 − −
Methylephedrine hydrochloride-75-
Dihydrocodeine phosphate --20
Sodium benzoate 200 200 200
Sucrose 2000 2000 2000
Concentrated glycerin 600 400 100
Ethanol (95%) 150 110 110
Purified water Remainder Remainder Remainder ―――――――――――――――――――――――――――――――
(2) Manufacturing method Take the above components and quantities, and manufacture a syrup according to the Japanese general formulation “Syrup” section, then fill it into a brown glass bottle to manufacture a syrup.

(Test example) Goblet cell formation inhibitory effect test (1) Test substance Loxoprofen sodium dihydrate and codeine phosphate were manufactured by Sankyo Co., Ltd., and anhydrous caffeine was manufactured by Shizuoka Caffeine Industries, Ltd. As the dl-methylephedrine hydrochloride, a product manufactured by Alps Pharmaceutical Co., Ltd. was used.

  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. 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 rat bracket taper cage, and the animals were preliminarily raised for about one week by freely ingesting feed (F-2 for breeding mice and rats, manufactured by Funabashi Farm) and tap water through a water filter. 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.

  After measuring the body weight on the 4th day, the carotid artery was amputated under pentobarbital anesthesia and euthanized by exsanguination, 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.

  Goblet cell formation inhibition rate (%) was calculated from the following formula.

(Formula 1)
Goblet cell formation inhibition rate (%) = [1-B / A] × 100
A: Average value of the number of goblet cells in the CMC administration group B: Average value of the number of goblet cells in the test substance administration group (4) Test results Table 5 shows the results of the obtained goblet cell formation inhibition rate. Each value is an average value of 6 to 7 animals per group.

(Table 5)
Test substance (dose: mg / Kg) Goblet cell formation inhibition rate (%)
----------------------------------
LxNa (15) 8.2
----------------------------------
Codeine phosphate (5) 2.9
LxNa (15) + codeine phosphate (5) 38.4
----------------------------------
dl-methylephedrine hydrochloride (10) 0.0
LxNa (15) + dl-methylephedrine hydrochloride (10) 35.0
----------------------------------
LxNa (15) + anhydrous caffeine (30) 33.7
----------------------------------
In Table 5, LxNa represents loxoprofen sodium dihydrate.

  From Table 5, it was found that when loxoprofen sodium dihydrate was used in combination with caffeine, methylephedrine hydrochloride or codeine phosphate, a significant goblet cell hyperplasia inhibitory effect was expressed.

  The pharmaceutical composition for antitussive or expectorant containing loxoprofen of the present invention and one or more selected from caffeine, ephedrine and codeine is smoking, various air pollutants and inhalation of allergens, etc. It is useful because it has an action of significantly suppressing goblet cell hyperplasia caused by respiratory tract infection and the like, and also has an antitussive or expectorant action. It is also useful for treating coughing and expectoration associated with acute bronchitis including upper respiratory tract inflammation such as the common cold. Furthermore, it is useful for treatment of acute respiratory infection in chronic bronchitis including chronic airway diseases such as COPD, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis and the like.

Claims (15)

A pharmaceutical composition for antitussive or expectorant comprising loxoprofen and one or more selected from caffeine, ephedrine and codeine. A pharmaceutical composition for suppressing goblet cell hyperplasia of the respiratory tract comprising loxoprofen and one or more selected from caffeine, ephedrine and codeine. The pharmaceutical composition according to any one of claims 1 and 2, wherein the loxoprofen is loxoprofen sodium. The pharmaceutical composition according to any one of claims 1 to 3, wherein the ephedrine is ephedrine hydrochloride or methylephedrine hydrochloride. The pharmaceutical composition according to any one of claims 1 to 4, wherein the caffeine is caffeine or anhydrous caffeine. The codeine according to any one of claims 1 to 5, wherein the codeines are codeine phosphate or dihydrocodeine phosphate. The pharmaceutical composition according to any one of claims 1 to 6, for use as a cold medicine. The pharmaceutical composition according to any one of claims 1 to 6, for use in the treatment of acute or chronic bronchitis. Claims 1 to for use in the treatment of symptoms of acute respiratory infection in chronic airway diseases such as chronic obstructive pulmonary disease, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis 7. The pharmaceutical composition according to any one of 6. The composition according to any one of claims 1 to 9, wherein loxoprofen and one or more selected from caffeine, ephedrine and codeine are a combination drug contained in the same pharmaceutical composition. Pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 9, which is a kit comprising one or more selected from loxoprofen and caffeine, ephedrine and codeine. The pharmaceutical composition according to any one of claims 1 to 9, comprising loxoprofen and one or more selected from caffeine, ephedrine and codeine in the same pharmaceutical composition. Production method. Use of the pharmaceutical composition according to any one of claims 1 to 6 for the manufacture of a cold medicine. A method of administering loxoprofen and one or more selected from caffeine, ephedrine and codeine simultaneously, sequentially or separately. A method for preventing or treating a common cold, wherein an effective amount of the pharmaceutical composition according to any one of claims 1 to 6 is administered to a mammal.