JP2010111667A - Medicinal composition for antitussive action and/or expectoration containing fexofenadine or ebastine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new medicinal composition having an excellent action to suppress the hyperplasia of airway goblet cells, particularly useful for the prophylaxis or treatment of respiratory diseases, further for the prophylaxis or treatment of cold or the like. <P>SOLUTION: The problem has been solved by finding that fexofenadine or salts thereof or ebastine, which are anti-allergic agents, has an excellent action to suppress the hyperplasia of airway goblet cells. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition for airway goblet cell hyperplasia containing fexofenadine or ebastine, and thus antitussive and / or expectorant.

  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 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, not only treatment with a normal expectorant in the acute phase but also a countermeasure for suppressing goblet cell hyperplasia is necessary.

  Fexofenadine hydrochloride (fexofenadine hydrochloride), one of the antiallergic agents, is (a) histamine H1 receptor antagonistic action, (I) I (immediate) type allergic reaction inhibitory action, (U) eosinophil In Japan, pruritus associated with allergic rhinitis, hives, skin diseases (eczema / dermatitis, cutaneous pruritus, atopic dermatitis) , Etc. are recognized (for example, refer nonpatent literature 2).

  Moreover, ebastine, a kind of antiallergic agent, has actions such as (a) histamine H1 receptor antagonism, (b) histamine release inhibitory action, and (c) antiallergic action. Efficacy and effects of rhinitis, urticaria, eczema / dermatitis, urticaria and pruritus are recognized (for example, see Non-Patent Document 2).

  However, both fexofenadine and ebastine are presumed to be prescribed or used as cold medicines from the viewpoint of their approved efficacy, and there are things that are difficult to think at present.

On the other hand, the followings have been disclosed as cold-related pharmaceutical compositions containing fexofenadine or ebastine, but these are only disclosed for the technique of suppressing nasal inflammation such as runny nose and nasal congestion at the time of cold. It can be said that this is not too much
(1) It is disclosed that the antinasal cholinergic nasal discharge suppression effect by belladonna total alkaloids is enhanced by the combined use of fexofenadine (see Patent Document 1).
(2) It has been disclosed that when fexofenadine and ferrinephrin are used in combination, the nasal inflammation is remarkably improved (see Patent Document 2).
(3) It has been disclosed and suggested that the combined use of ebastine and an anticholinergic agent is effective in removing and reducing nasal discharge (nasal mucus) excessive symptoms associated with increased abnormal secretion of nasal mucosa (see Patent Document 3).
(4) Antipyretic analgesic selected from ibuprofen or acetaminophen as an active ingredient, antiallergic agent selected from cetirizine, ebastine, fexofenadine and loratadine, antitussive, expectorant, sputum solubilizer, sympathomimetic and central A cold medicine capsule containing a drug selected from nerve stimulants has been disclosed (see Patent Document 4).

  Further, it has been disclosed by the present inventors that azelastine, mequitazine, ketotifen and clemastine have an airway goblet cell hyperplasia inhibitory effect (see Patent Document 5), but other antihistamines and antiallergic agents are unknown. It is.

JP 2002-255816 A Japanese Patent Laid-Open No. 2002-212067 JP 2002-338486 A JP 2008-143807 A JP 2008-169193 A

Pharmaceutical Journal, 2002, Vol. 38, No. 12, p121-126 Collection of ethical drugs 2009 edition JAPIC 2008

  It is an object of the present invention to find a novel pharmaceutical composition having an excellent inhibitory effect on airway goblet cell hyperplasia. Until now, it cannot be said that the research in the said field | area was fully done, and it is thought that the pharmaceutical composition which has a novel preventive or therapeutic effect can be provided by the result of this invention. In particular, the present invention is considered to be useful for the prevention or treatment of respiratory diseases and the like, and further the prevention or treatment of common colds.

  The present inventor has conducted intensive research for many years on a pharmaceutical composition having an inhibitory effect on airway goblet cell hyperplasia. In this study, antihistamines and antiallergies other than azelastine, mequitazine, ketotifen and clemastine disclosed above were studied. The effect of the agent on airway goblet cells was also examined. As a result, the present inventors completed the present invention by newly finding the surprising fact that only certain anti-allergic agents exhibit an inhibitory effect on airway goblet cell hyperplasia and some anti-allergic agents exacerbate them. It was.

That is, the present invention
1. Airway goblet cell hyperplasia inhibitor containing fexofenadine or a salt thereof or ebastine,
A pharmaceutical composition for antitussive and / or expectorant, comprising the airway goblet cell hyperplasia inhibitor according to 2.1,
3. 2. A pharmaceutical composition according to 2, for use in the treatment of colds,
4). 2. A pharmaceutical composition according to 2, for use in the treatment of acute or chronic bronchitis,
5). 2. The pharmaceutical composition according to 2, for use in the treatment of symptoms during acute respiratory infection in chronic airway diseases.

  In the present invention, fexofenadine has a chemical name of 2-methyl-2- [4- [1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidyl] butyl] phenyl] propionic acid. , A known compound also called terfenadine carboxylate or carboxyterphenazine. The salt of fexofenadine is not particularly limited as long as it is a pharmaceutically acceptable salt, but fexofenadine hydrochloride (hereinafter also referred to as fexofenadine hydrochloride) is preferable.

  Ebastine in the present invention has a chemical name of 4 ′-(1,1-dimethylethyl) -γ- [4- (diphenylmethoxy) piperidin-1-yl] butyrophenone 4′-tert-butyl-γ- [4. -(Diphenylmethoxy) piperidino] butyrophenone, which is a known compound.

  Examples of the “chronic airway disease” of the present invention include chronic obstructive pulmonary disease (COPD), bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis and the like.

  In the present invention, “treat” means to cure or ameliorate a disease or symptom or to suppress a symptom.

  The pharmaceutical composition containing fexofenadine or a salt thereof or ebastine of the present invention is useful because it significantly suppresses hyperplasia of airway goblet cells and thus has excellent antitussive and / or expectorant action.

  The pharmaceutical composition containing fexofenadine or a salt thereof or ebastine of the present invention is useful for treatment or prevention of symptoms such as common cold, but preferably treatment of symptoms such as acute or chronic bronchitis. Or, more preferably, symptoms such as acute bronchitis in patients with acute respiratory infection or chronic such as COPD, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis, etc. It is also useful for the treatment or prevention of symptoms such as acute bronchitis in patients with airway diseases.

    Fexofenadine hydrochloride (fexofenadine hydrochloride) and ebastine used in the present invention are commercially available as pharmaceuticals and can be easily obtained.

  The single dose of fexofenadine hydrochloride varies depending on the indication and age, but is usually 10 mg to 100 mg, and this is administered 1 to 3 times a day. Moreover, although the single dose of ebastine varies depending on the indication and age, it is usually 1 mg to 50 mg, and this is administered once or twice a day.

  When the dosage form of the pharmaceutical composition of the present invention is a solid preparation, the content of fexofenadine hydrochloride is usually 10 mg to 100 mg, preferably 20 mg to 80 mg. The content of ebastine is usually 1 mg to 50 mg, preferably 2 mg to 20 mg.

  When the dosage form of the pharmaceutical composition of the present invention is a liquid, the content of fexofenadine hydrochloride is usually 0.5 mg / mL to 100 mg / mL, preferably 1 mg / mL to 80 mg / mL. is there. Further, the content of ebastine is usually 0.05 mg / mL to 50 mg / mL, and preferably 0.1 mg / mL to 20 mg / mL.

  In the present invention, in addition to the above active ingredients, antipyretic analgesic / anti-inflammatory drugs, other antitussives, other expectorants, sympathomimetic drugs, central nervous stimulants, anti-inflammatory enzymes, vitamins, herbal medicines, etc. Can be contained within a range not impairing the effects of the present invention.

  Specific examples of these dosage forms include tablets, fine granules (including granules and powders), capsules, liquids (including syrups) and the like, and additives suitable for each dosage form. Can be produced according to the usual methods described in the Japanese Pharmacopoeia.

  In the above dosage forms, various commonly used additives can be used depending on the dosage form. For example, an excipient, a stabilizer, a coating agent, a lubricant, an adsorbent, a binder, a disintegrant, a surfactant, a colorant, a pH adjuster, and a fragrance can be added.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

(Example 1) Tablet (1) Component (Table 1)
In 1 tablet (mg) (1a) (1b)
--------------------------
Fexofenadine hydrochloride 60 −
Ebastine-10
Lactose 70 60
Magnesium stearate 8 5
Hydroxypropylcellulose 25 25
Corn starch 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) Granules (1) Ingredients (Table 2)
In 1 package (mg) (2a) (2b)
--------------------------
Fexofenadine hydrochloride 60 −
Ebastine-10
Lactose 300 250
Polyvinylpyrrolidone 25 25
Corn starch 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 (Table 3)
In 1 capsule (mg) (3a) (3b)
--------------------------
Fexofenadine hydrochloride 60 −
Ebastine-10
Lactose 150 100
Polyvinylpyrrolidone 25 25
Corn starch 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) Ingredient (Table 4)
In 10 mL (mg) (3a) (3b)
--------------------------
Fexofenadine hydrochloride 60 −
Ebastine-10
Sodium benzoate 70 70
Glycerin 100 50
Polyvinyl alcohol 80 80
Sucrose 1200 1200
Purified water remainder remainder --------------------------.

(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 The anti-allergic agent, pemirolast potassium is a brand name of Allegisal (registered trademark) 10 mg tablet manufactured by Mitsubishi Pharma, and amlexanox is a brand name of Takeda Pharmaceutical Co., Ltd. Solfa (registered trademark) 50 mg tablets and fexofenadine hydrochloride, trade name Allegra (registered trademark) 60 mg tablets manufactured by sanofi-aventis, were refined in a mortar, respectively. Ebastine was manufactured by Estech Pharma.

  Each test substance was prepared by adding a 0.5% carboxymethylcellulose (CMC) solution on the test day so that the dose amount was 5 mL / Kg.

(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 health condition of the animal was observed with the naked eye to confirm that it was good, the body weight was measured, and the animals were randomly divided into 7 groups per group.

(3) Preparation method of airway mucosal injury model Rats are anesthetized by intraperitoneal administration of pentobarbital 50mg / Kg, fixed in the supine position, the skin of the cervical larynx is incised in the midline, and the muscles are bluntly separated. The trachea was exposed. Using the liquid endotracheal administration device for rats from the oral cavity, it was inserted into the trachea while confirming from the exposed part of the trachea, and 0.1 mL of 1% lipopolysaccharide (LPS) solution was administered. Immediately, the peritracheal muscle was sutured, and the skin of the incision was adhered with Aron Alpha (registered trademark) to create an airway mucosal disorder animal.

(4) Test 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-mentioned method, and again in the evening of the day, the test substance (to the subject group). Was administered orally. On the second and third days, the test substance (CMC solution in the subject group) was orally administered twice a day (morning and evening).

  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 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 goblet cells in the CMC administration group B: Average value of goblet cells in the test substance administration group

(5) Test results Table 5 shows the results of the goblet cell formation inhibition rate obtained. Each value is an average value of 7 animals per group.

(Table 5)
Test substance (dose: mg / Kg / time) Goblet cell formation inhibition rate (%)
--------------------------------
Pemirolast potassium (1) -27.1
Anlexanox (10) 0.9
Fexofenadine hydrochloride (10) 32.3
Ebastine (0.5) 21.5
--------------------------------.

  Table 5 shows that even with the same antiallergic agents, there are those that exacerbate goblet cell hyperplasia, those that do not exhibit an effect, those that have an inhibitory effect, and fexofenadine and ebastine have an inhibitory effect on airway goblet cell formation. found.

  The pharmaceutical composition containing fexofenadine or a salt thereof or ebastine of the present invention is useful because it suppresses hyperplasia of airway goblet cells and thus has an excellent antitussive and / or expectorant action.

  The pharmaceutical composition containing fexofenadine or a salt thereof or ebastine of the present invention is useful for treatment or prevention of symptoms such as common cold, but preferably treatment of symptoms such as acute or chronic bronchitis. Or, more preferably, symptoms such as acute bronchitis in patients with acute respiratory infection or chronic such as COPD, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis, etc. It is also useful for the treatment or prevention of symptoms such as acute bronchitis in patients with airway diseases.

Claims (5)

  An airway goblet cell hyperplasia inhibitor containing fexofenadine or a salt thereof or ebastine.   A pharmaceutical composition for antitussive and / or expectorant, comprising the airway goblet cell hyperplasia inhibitor according to claim 1.   A pharmaceutical composition according to claim 2 for use in the treatment of the common cold.   A pharmaceutical composition according to claim 2 for use in the treatment of acute or chronic bronchitis. The pharmaceutical composition according to claim 2, for use in the treatment of symptoms during acute respiratory infection in chronic airway diseases.