JP2009108044A - Pharmaceutical composition comprising azelastines and antiphlogistic enzyme agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a goblet cell hyperplasia inhibitor. <P>SOLUTION: It has been found that use of azelastine together with an antiphlogistic enzyme agent develops an excellent inhibitory action on airway goblet cell hyperplasia. The airway goblet cell hyperplasia inhibitor comprising an azelastine and an antiphlogistic enzyme agent remarkably inhibits goblet cell hyperplasia and in its turn, is useful for having an excellent antiussive action. The pharmaceutical composition is useful for treating or preventing symptoms of generally considered common colds, etc., preferably useful for treating or preventing symptoms of acute or chronic bronchitis, more preferably useful for treating or preventing symptoms of acute bronchitis etc., in acute respiratory tract infection patients or symptoms of acute bronchitis in patients having chronic respiratory tract diseases such as COPD, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, pulmonary emphysema, diffuse bronchitis etc. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition for inhibiting goblet cell hyperplasia of the 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 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 measures for suppressing goblet cell hyperplasia are necessary.

  Azelastine hydrochloride, one of the antihistamines, is known to have efficacy and effects as medical drugs such as bronchial asthma, allergic rhinitis, hives, eczema / dermatitis, atopic dermatitis, skin pruritus, etc. (For example, refer nonpatent literature 2). In addition, azelastine hydrochloride is approved as a so-called switch OTC drug and is marketed as an over-the-counter drug because it is an allergic drug for internal use, alleviating symptoms of nasal allergies and symptom due to urticaria, eczema and rash. It has become. However, it is difficult to think about the prescription or use of both medical drugs and general drugs as a cold medicine from the viewpoint of the approved efficacy.

  Anti-inflammatory enzyme agents are generally known to have an expectorant action, an action of increasing ciliary movement, an anti-inflammatory action, etc. that lowers the viscosity of a viscous wrinkle and facilitates discharge (for example, see Non-patent Document 2). In addition, over-the-counter drugs may be incorporated into general cold medicines, antitussive expectorants, and oral rhinitis drugs (see Non-patent Document 3, for example).

In connection with the present invention,
A) One or more selected from the group consisting of codeines, bromhexine, ambroxol, dextromethorphan, and noscapine,
B) One or more selected from the group consisting of lysozyme, bromelain, serratiopeptidase, semi-alkaline proteinase,
C) one or more selected from the group consisting of mequitazine, astemizole, carbinoxamine, chlorpheniramine, clemastine, and
D) One or more selected from the group consisting of amlexanox, ibudilast, azelastine, epinastine, terfenadine, ketotifen, pemirolast, and repirinast,
Ingredients consisting of
E) It is disclosed that a cold remedy composition that masks unpleasant taste and is easy to take when compounded with stevia (see Patent Document 1).

However, there is no description that specifies the combination of azelastine and an anti-inflammatory enzyme. Furthermore, there is no description of airway goblet cell hyperplasia inhibitory action in each single agent of azelastine or anti-inflammatory enzyme, and of course, the airway goblet cell hyperplasia inhibitory action by the combined use of azelastine and anti-inflammatory enzyme is not known.
Pharmaceutical Journal, 2002, Vol. 38, No. 12, p121-126 Japan Pharmaceutical Collection Medical Drugs 2008 Edition, Jiho, 2007 Japan Pharmaceutical Collection General Medicine 2008-9 edition, Jiho, 2007 JP-A-9-52849

  It is an object of the present invention to find an excellent airway goblet cell hyperplasia inhibitor. Until now, research in this field has not been sufficiently conducted, and it is considered that a pharmaceutical composition having a novel preventive or therapeutic effect can be provided by the results of the present 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 colds and the like.

  The present inventor has conducted extensive research on airway goblet cell hyperplasia inhibitors for many years. In this study, azelastine and an anti-inflammatory enzyme agent, both of which have no known effect on airway goblet cells, were investigated. As a result, it has been found that the combined use of azelastine and an anti-inflammatory enzyme exhibits an excellent airway goblet cell hyperplasia inhibitory effect, thereby completing the present invention.

That is, the present invention is (1) an airway goblet cell hyperplasia inhibitor comprising azelastine and an anti-inflammatory enzyme,
(2) A pharmaceutical composition comprising the airway goblet cell hyperplasia inhibitor according to (1),
(3) The pharmaceutical composition according to (2) for antitussive,
(4) The pharmaceutical composition according to any one of (2) to (3), wherein the azelastine is azelastine hydrochloride,
(5) The medicament according to any one of (2) to (4), wherein the anti-inflammatory enzyme is one or more selected from the group consisting of semi-alkaline proteinase, serrapeptase, pronase, bromelain, and lysozyme hydrochloride. Composition,
(6) The pharmaceutical composition according to any one of (2) to (4), wherein the anti-inflammatory enzyme is serrapeptase or lysozyme hydrochloride,
(7) The pharmaceutical composition according to any one of (2) to (6), which is used as a cold medicine,
(8) The pharmaceutical composition according to any one of (2) to (6) for use in the treatment of acute or chronic bronchitis and (9) the symptoms of acute respiratory infection in chronic airway disease The pharmaceutical composition according to any one of (2) to (6), which is used for treatment.

  The “azelastine” of the present invention is azelastine or a pharmacologically acceptable salt thereof, and preferably azelastine hydrochloride.

  The “anti-inflammatory enzyme” of the present invention is semi-alkaline proteinase, serrapeptase, pronase, bromelain, lysozyme and pharmacologically acceptable salts thereof, preferably serrapeptase or lysozyme hydrochloride.

  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 airway goblet cell hyperplasia inhibitor comprising azelastine and an anti-inflammatory enzyme of the present invention is useful because it significantly suppresses goblet cell hyperplasia, and thus has an excellent antitussive effect.

  The pharmaceutical composition of the present invention is useful for the treatment or prevention of symptoms such as common cold, but is preferably useful for the treatment or prevention of symptoms such as acute or chronic bronchitis. Include acute bronchitis in patients with acute respiratory infections or chronic bronchitis such as COPD, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis, etc. It is also useful for the treatment or prevention of such symptoms.

  The azelastine and anti-inflammatory enzyme agent used in the present invention can be easily synthesized by a known method, and can also be obtained by purchasing a commercial product.

  Azelastine hydrochloride is commercially available as a pharmaceutical and can be easily obtained (for example, it can be purchased from Sanyo Chemical Laboratories).

  Serrapeptase and lysozyme hydrochloride are listed in the 15th revision Japanese Pharmacopoeia. Semi-alkaline proteinase and bromelain are listed in Japanese Pharmacopoeia Standard 2002. Pronase is also available because it is commercially available as a pharmaceutical product.

  The single dose of azelastine varies depending on the indication and age, but is usually 0.2 mg to 10 mg, and this is administered 1 to 3 times a day.

  In the case of a solid preparation, the content of azelastine is usually 0.1 mg to 20 mg, and preferably 0.5 mg to 4 mg.

  The content of the anti-inflammatory enzyme is usually 1 mg to 600 mg, preferably 5 mg to 400 mg.

  In the case of a liquid preparation, the content of azelastine is usually 0.05 mg / mL to 4 mg / mL, and preferably 0.1 mg / mL to 2 mg / mL.

  The content of the anti-inflammatory enzyme is usually 0.1 mg / mL to 600 mg / mL, and preferably 1 mg / mL to 400 mg / mL.

  In the present invention, antipyretic analgesic / antitussive, antitussive, expectorant, sympathomimetic, central nervous stimulant, vitamins, herbal medicines and the like are not impaired as necessary in addition to the above active ingredients. It can be contained in a range.

  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 and the like.

  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) (mg)
--------------------------
Azelastine hydrochloride 2 2
Semi-alkaline proteinase 15 −
Or serrapeptase lysozyme hydrochloride-60
Lactose 70 70
Magnesium stearate 8 8
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) (mg)
--------------------------
Azelastine hydrochloride 2 2
Semi-alkaline proteinase 15 −
Or serrapeptase lysozyme hydrochloride-60
Lactose 300 300
Polyvinylpyrrolidone 25 25
Corn starch Suitable amount Suitable 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 1-2 capsules (mg) (mg)
--------------------------
Azelastine hydrochloride 2 2
Semi-alkaline proteinase 15 −
Or serrapeptase lysozyme hydrochloride-60
Lactose 150 150
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) (mg)
--------------------------
Azelastine hydrochloride 2 2
Semi-alkaline proteinase 15 −
Or serrapeptase lysozyme hydrochloride-60
Sodium benzoate 70 70
Glycerin 100 100
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 Azelastine hydrochloride is manufactured by Sanyo Chemical Laboratories, and serrapeptase is a commercially available product (product name: Dazan granule, manufactured by Takeda Pharmaceutical Co., Ltd.) The lysozyme hydrochloride manufactured by Sigma was used.

  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., 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 to confirm their health and the body weight was measured. 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 50 mg / 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 a 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 100 μL of 1% lipopolysaccharide (LPS) solution was administered. Immediately, the muscles around the trachea were sutured, and the skin of the incision was adhered with Aron alpha to produce an animal having an airway mucosa disorder.

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

  After measuring the 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 a formalin solution and fixed sufficiently.

  After being sufficiently fixed, the trachea was traversed at 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 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 (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 (%)
----------------------------------
Azelastine hydrochloride (0.2) 8.7
Serrapeptase (2) 8.4
Azelastine hydrochloride (0.2) + serrapeptase (2) 38.4
----------------------------------
Lysozyme hydrochloride (10) -39.4
Azelastine hydrochloride (0.2) + lysozyme hydrochloride (10) 19.4
----------------------------------
From Table 5, it was found that when azelastine and an anti-inflammatory enzyme were used in combination, an excellent airway goblet cell formation inhibitory effect was expressed.

  The airway goblet cell hyperplasia inhibitor comprising azelastine and an anti-inflammatory enzyme of the present invention is useful because it significantly suppresses goblet cell hyperplasia, and thus has an excellent antitussive effect.

  The pharmaceutical composition of the present invention is useful for the treatment or prevention of symptoms such as common cold, but is preferably useful for the treatment or prevention of symptoms such as acute or chronic bronchitis. Include acute bronchitis in patients with acute respiratory infections or chronic bronchitis such as COPD, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis, etc. It is also useful for the treatment or prevention of such symptoms.

Claims (9)

  An airway goblet cell hyperplasia inhibitor comprising azelastine and an anti-inflammatory enzyme.   A pharmaceutical composition comprising the airway goblet cell hyperplasia inhibitor according to claim 1.   The pharmaceutical composition according to claim 2 for antitussive.   The pharmaceutical composition according to any one of claims 2 to 3, wherein the azelastine is azelastine hydrochloride.   The pharmaceutical composition according to any one of claims 2 to 4, wherein the anti-inflammatory enzyme is one or more selected from the group consisting of semi-alkaline proteinase, serrapeptase, pronase, bromelain, and lysozyme hydrochloride.   The pharmaceutical composition according to any one of claims 2 to 4, wherein the anti-inflammatory enzyme is serrapeptase or lysozyme hydrochloride.   The pharmaceutical composition according to any one of claims 2 to 6, which is used as a cold medicine.   The pharmaceutical composition according to any one of claims 2 to 6, for use in the treatment of acute or chronic bronchitis.   The pharmaceutical composition according to any one of claims 2 to 6, for use in the treatment of symptoms during acute respiratory infection in chronic airway diseases.