JP2008013542A - Pharmaceutical composition for expectoration or inhibiting airway caliciform cell hyperplasia - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition having expectorative activity or airway goblet cell hyperplasia-inhibitory activity. <P>SOLUTION: The pharmaceutical composition for expectoration or inhibiting airway goblet cell hyperplasia contains loxoprofen and one or more substances selected from ambroxol and bromhexine. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition for inhibiting goblet cell formation in expectoration or airways.

  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, thus causing repeated airway infection and airway obstruction. In addition, cigarette smoking, inhalation of various air pollutants or allergens, respiratory tract infection, etc. cause not only increased airway secretion but also hyperplasia of goblet cells, etc. If prolonged, this changes 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).

  Although the action of loxoprofen on goblet cells is not known, ibuprofen and acetaminophen of the same NSAID have no effect of suppressing goblet cell hyperplasia, or conversely, results of promoting hyperplasia have been reported (patents) Reference 2) suggests that loxoprofen sodium alone increases goblet cells slightly.

  Ambroxol hydrochloride is known as an airway lubrication type expectorant and is a medicinal agent and has effects and effects such as acute and chronic bronchitis and bronchial asthma (for example, see Non-patent Document 4). In addition, for airway goblet cell hyperplasia caused by exposure of lipopolysaccharide (hereinafter referred to as LPS) to rats, an extremely high dose of 100 mg / kg of ambroxol hydrochloride was administered 30 minutes before exposure, 1 day and 2 days after exposure. The results were not suppressed even after oral administration for 3 days (see Fig. 6 of Non-Patent Document 5), and were significantly suppressed by oral administration of 100 mg / Kg from the 4th day to the 10th day after exposure. The results (see Fig. 2 of Non-Patent Document 6) have been reported so far.

  On the other hand, bromhexine hydrochloride is known as an airway mucus-dissolving expectorant, and a medicinal product has efficacy and effects of expectoration such as acute and chronic bronchitis (for example, see Non-patent Document 4). In addition, extremely high doses of 100 mg / day bromhexine hydrochloride were orally administered to rats for 30 days before exposure, 1 day after exposure, and 3 days after exposure for 2 days. Results (see Fig. 6 of Non-Patent Document 5) have been reported.

So far, the following has been disclosed as examples of the combination of loxoprofen and ambroxol or bromohexine.
(1) When loxoprofen sodium and bromhexine hydrochloride were used in combination, carrageenin-induced foot edema was remarkably suppressed (see Patent Document 2).
(2) When combined with loxoprofen sodium bromhexine hydrochloride or ambroxol hydrochloride, capsaicin-induced cough was remarkably suppressed (see Patent Document 3).

However, it is clear that the above results (1) and (2) do not suggest an effect of suppressing airway goblet cell hyperplasia, nor directly suggest an expectorant action.

International Publication No. 2002/096406 Pamphlet JP 2000-143505 A JP 2001-172175 A Pharmaceutical Journal, Vol.38, No.12, 2002, p.121-126 Pharmacology and treatment, Vol.16, No.2, 1988, p.611-619 CLINICA, Vol.31, No.1, 2004, p.38-41 Japan Pharmaceutical Collection, Medical Drugs 2006 Edition, Jiho, 2005 Environmental Toxicology and Pharmacology, Vol.5, 1998, p.173-178 Applied Pharmacology, Vol.67, No.1 / 2, 2004, p.299-306

  As a result of intensive studies on a pharmaceutical composition having an inhibitory effect on goblet cell hyperplasia, the present inventors have surprisingly found that a pharmaceutical composition containing loxoprofen and ambroxol or bromhexine has an excellent goblet cell hyperactivity. The present inventors have found that a formation-inhibiting action is exhibited, and have completed the present invention.

The present invention is (1) a pharmaceutical composition for suppressing gonorrhea or airway goblet cell hyperplasia containing loxoprofen and one or more selected from ambroxol or bromhexine, ,
(2) The pharmaceutical composition according to (1), wherein the loxoprofen is loxoprofen sodium,
(3) The pharmaceutical composition according to (1) or (2), wherein the ambroxol is ambroxol hydrochloride,
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the bromhexine is bromhexine hydrochloride,
(5) Any one selected from (1) to (4), wherein loxoprofen and one or more selected from ambroxol or bromohexine are contained in the same pharmaceutical composition A pharmaceutical composition according to
(6) The pharmaceutical composition according to any one of (1) to (4), which is a kit comprising loxoprofen and one or more selected from ambroxol or bromhexine,
(7) The pharmaceutical according to any one of (1) to (4), which contains loxoprofen and one or more selected from ambroxol or bromohexine in the same pharmaceutical composition Method for producing composition and (8) Loxoprofen and one or more selected from ambroxol or bromhexine are administered simultaneously, sequentially or separately to mammals, and expectoration or airway goblet cell hyperplasia A method of suppressing is provided.

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

  In the present invention, “ambroxol” is ambroxol or a salt thereof (including a hydrated salt), preferably ambroxol hydrochloride.

  In the present invention, “bromhexine” is bromhexine or a salt thereof (including a water-containing salt), and preferably bromhexine hydrochloride.

  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 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 Amino acid salts such as arginine salt, ornithine salt, glutamate and aspartate, and more preferably hydrochloride, hydrobromide and sulfate.

  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 expectoration or goblet cell hyperplasia containing loxoprofen and ambroxol or bromhexine according to the present invention is caused by smoking, inhalation of various air pollutants and allergens, respiratory tract infections, etc. It is useful because it has an effect of significantly suppressing goblet cell hyperplasia and, consequently, an expectorant effect. In addition, the pharmaceutical composition of the present invention is useful for the treatment of coughing and expectoration associated with acute bronchitis including upper respiratory tract inflammation such as the common cold, and further, chronic obstructive pulmonary disease (COPD), bronchiectasis, bronchial It is also useful for the treatment of acute respiratory infections in chronic bronchitis, including chronic airway diseases such as asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, and diffuse panbronchitis.

  Loxoprofen sodium and bromhexine hydrochloride are listed in the Japanese Pharmacopeia XIV.

  Ambroxol hydrochloride has already been widely sold as a pharmaceutical and can be produced by a known method.

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

In the case of a solid preparation, the content of loxoprofen sodium contained in a single dose is usually 10 mg to 400 mg, preferably 20 mg to 180 mg.
The content of ambroxol hydrochloride is usually 2 mg to 90 mg, preferably 4.5 mg to 45 mg, and the content of bromhexine hydrochloride is usually 0.6 mg to 24 mg, preferably 1.2 mg to 12 mg.

The content of loxoprofen sodium 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 ambroxol hydrochloride is usually 0.03 mg / mL to 45 mg / mL, preferably 0.2 mg. mL to 30 mg / mL, and the content of bromhexine hydrochloride is usually 0.001 mg / mL to 12 mg / mL, and preferably 0.05 mg / mL to 8 mg / mL.

  In the present invention, in addition to the above active ingredients, bronchodilators, antitussives, antihistamines or antiallergic agents, anticholinergic agents, anti-inflammatory enzymes, caffeine, vitamins, herbal medicines, antacids and the like as necessary. It can mix | blend in the range which does not impair the effect of this invention.

  Specific dosage forms of the analgesic of the present invention include, for example, tablets, fine granules (including powders), capsules, liquids (including syrups) and the like, and additions suitable for each dosage form It can be produced according to the usual methods described in the Japanese Pharmacopoeia, using agents and base materials as appropriate.

  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 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
Ambroxol hydrochloride 45-15
Bromhexine hydrochloride -12 8
Belladonna (total) alkaloids-0.2
Crystalline cellulose 100 100 100
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
Ambroxol hydrochloride 45-15
Bromhexine hydrochloride -12 8
Belladonna (total) alkaloids-0.2
Crystalline cellulose 130 130 130
Hydroxypropyl cellulose 100 100 100
Magnesium stearate 10 10 10
D-mannitol 290 290 290
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 (in 6 capsules, mg)
(1) Ingredients (Table 3)
(3a) (3b) (3c)
――――――――――――――――――――――――――――――――
Loxoprofen sodium 180 180 180
Ambroxol hydrochloride 45-15
Bromhexine hydrochloride -12 8
Belladonna (total) alkaloids-0.2
Magnesium stearate 10 10 10
Polysorbate 50 50 50
Corn starch 180 200 190
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 Japanese Pharmacopoeia General Rules “Granules”, it is filled into capsules to produce hard capsules.

(Example 4) Syrup (1) component (mg in 30 mL)
(Table 4)
(4a) (4b) (4c)
――――――――――――――――――――――――――――――――
Loxoprofen sodium 180 180 180
Ambroxol hydrochloride 45-15
Bromhexine hydrochloride -12 8
Belladonna (total) alkaloids-0.2
Sodium benzoate 200 200 200
Sucrose 2000 2000 2000
Concentrated glycerin 350 350 350 350
Ethanol (95%) 50 50 50
Purified water Remaining Remaining Remaining Remaining ――――――――――――――――――――――――――――――――
(2) Manufacturing method Take the above ingredients 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 is from Sankyo Co., Ltd. Ambroxol hydrochloride is from YIC Co., Ltd. Bromohexine hydrochloride manufactured by Sanyo Chemical Laboratory 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., 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.

  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 goblet cell formation inhibition rate obtained. 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
Ambroxol hydrochloride (5) 13.2
LxNa (15) + ambroxol hydrochloride (5) 36.2
----------------------------------
Bromhexine hydrochloride (1) 9.0
LxNa (15) + bromhexine hydrochloride (1) 16.6
----------------------------------.

  In Table 5, LxNa represents loxoprofen sodium dihydrate.

  From Table 5, it was surprisingly found that loxoprofen sodium dihydrate exhibits an inhibitory effect on goblet cell hyperplasia.

  In addition, loxoprofen sodium dihydrate is combined with ambroxol hydrochloride to produce a significant goblet cell hyperplasia-inhibiting effect, and is also superior to goblet cell hyperplasia when combined with bromhexine hydrochloride. It has been found that an inhibitory effect is brought about.

  The pharmaceutical composition for expectoration or goblet cell hyperplasia containing loxoprofen and ambroxol or bromhexine according to the present invention is caused by smoking, inhalation of various air pollutants and allergens, respiratory tract infections, etc. It is useful because it has an effect of significantly suppressing goblet cell hyperplasia and, consequently, an expectorant effect. In addition, the pharmaceutical composition of the present invention is useful for the treatment of coughing and expectoration associated with acute bronchitis including upper respiratory tract inflammation such as the common cold, and further, chronic obstructive pulmonary disease (COPD), bronchiectasis, bronchial It is also useful for the treatment of acute respiratory infections in chronic bronchitis, including chronic airway diseases such as asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, and diffuse panbronchitis.

Claims (8)

A pharmaceutical composition for suppressing expectoration or airway goblet cell hyperplasia containing loxoprofen and one or more selected from ambroxol or bromhexine. The pharmaceutical composition according to claim 1, wherein the loxoprofen is loxoprofen sodium. The pharmaceutical composition according to claim 1 or 2, wherein the ambroxol is ambroxol hydrochloride. The pharmaceutical composition according to any one of claims 1 to 3, wherein the bromhexine is bromhexine hydrochloride. The loxoprofen and one or more selected from ambroxol or bromhexine are compounding agents contained in the same pharmaceutical composition, according to any one of claims 1 to 4. Pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 4, which is a kit comprising loxoprofen and one or more selected from ambroxol or bromhexine. The pharmaceutical composition according to any one of claims 1 to 4, which contains loxoprofen and one or more selected from ambroxol or bromhexine in the same pharmaceutical composition. Production method. A method for inhibiting gonorrhea or airway goblet cell hyperplasia by simultaneously or sequentially administering loxoprofen and one or more selected from ambroxol or bromhexine to a mammal.