JP5670006B2 - Pharmaceutical composition containing expectorant - Google Patents

Description

  The present invention relates to a pharmaceutical composition for suppressing goblet cell hyperplasia.

  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, when airway secretion increases, airway secretions or a mixture of airway secretions and foreign substances accumulate in the airways and become a hotbed for bacterial growth, which can cause repeated airway infections or airway obstruction. Are known. 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 prevent goblet cell hyperplasia. So far, fudostein is known as a drug having an inhibitory effect on goblet cell hyperplasia. Fudstein is a drug developed in Japan in 2001, and has an indication of expectoration in chronic airway diseases such as chronic bronchitis, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis (For example, see Non-Patent Document 2).

So far, the following have been reported as pharmaceutical compositions containing fudstein.
1) Formulation with a drug having antipyretic analgesic action (see Patent Document 1).
2) Formulation with a drug having an antitussive effect (see Patent Document 2).

  That is, at present, there is no literature that reports or suggests the combined use of fudostein and other expectorants, and of course, the effect of the combined use is unknown.

In addition, animal tests have shown that an expectorant other than fudostein, ie, ambroxol hydrochloride, bromhexine hydrochloride, L-cysteine, carbocysteine, etc., does not show an inhibitory effect on goblet cell hyperplasia (non-patent document) Reference 3).
International Publication No. 2002/096406 Pamphlet International Publication No. 2002/096405 Pamphlet Pharmaceutical Journal, Vol. 38, no. 12 (2002) p121-126 Breathing, Vol. 23, no. 2 (2004) p143-148 Jpn. J. Pharmacol., Vol. 77, no. 1 (1998) p71-77

  As a result of intensive studies on a pharmaceutical composition having an inhibitory effect on goblet cell hyperplasia for many years, the present inventor unexpectedly found that a single agent does not have an inhibitory effect on goblet cell hyperplasia alone, and an expectorant other than fudstein, In combination, the present inventors have found that the inhibitory effect of fudstein on the goblet cell hyperplasia increases synergistically, thereby completing the present invention.

The present invention is (1) a pharmaceutical composition containing fudstein and other expectorants,
(2) The pharmaceutical composition according to (1) for suppressing goblet cell hyperplasia,
(3) The pharmaceutical composition according to (1) or (2) for antitussive or expectorant,
(4) The pharmaceutical composition according to (1) for simultaneously suppressing goblet cell hyperplasia and coughing or expectoration,
(5) One or two of other expectorants selected from the group consisting of bromhexine, ambroxol, L-carbocysteine, L-methylcysteine, acetylcysteine, L-ethylcysteine and pharmacologically acceptable salts thereof The pharmaceutical composition according to any one of (1) to (4), which is a species or more,
(6) The pharmaceutical composition according to any one of (1) to (4), wherein the other expectorant is bromhexine hydrochloride or ambroxol hydrochloride,
(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 or prevention of acute or chronic bronchitis,
(9) The pharmaceutical composition according to any one of (1) to (8), wherein the fudostein and other expectorant are a combination agent, and (10) the pharmaceutical composition containing fudostein and another expectorant The pharmaceutical composition according to any one of (1) to (8), which is a kit comprising a pharmaceutical composition to be contained.

Furthermore, the present invention provides
(11) The method for producing a pharmaceutical composition according to any one of (1) to (8), wherein fudostein and another expectorant are contained in the same pharmaceutical composition,
(12) Use of the pharmaceutical composition according to any one of (1) to (6) for producing a cold medicine,
(13) A method of administering fusstein and other expectorant simultaneously, sequentially or separately, and (14) an effective amount of the pharmaceutical composition described in any one of (1) to (10) to a mammal A method for treating or preventing the common cold is provided.

  In the present invention, “Fudostein” is (−)-(R) -2-amino-3- (3-hydroxypropylthio) propionic acid, and includes pharmacologically acceptable salts thereof. Is (−)-(R) -2-amino-3- (3-hydroxypropylthio) propionic acid.

  In the present invention, the “other expectorant” is not particularly limited as long as it is an expectorant generally used in the pharmaceutical field other than fudostein. For example, bromhexine, ambroxol, L-carbocysteine, L-methylcysteine, acetylcysteine, L-ethylcysteine or a pharmacologically acceptable salt thereof, preferably bromhexine hydrochloride, ambroxol hydrochloride, L-carbocysteine, L-methylcysteine hydrochloride, acetylcysteine or L-ethylcysteine hydrochloride is more preferable, and bromhexine hydrochloride or ambroxol hydrochloride is more preferable.

  In the present invention, the “pharmacologically acceptable salt” means that when “Fudostein” or “other expectorant” of the present invention has an acidic group or a basic group, it is reacted with a base or an acid to form a base. A salt or acid salt, the salt is indicated.

  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 , An arginine salt, an ornithine salt, an amino acid salt such as glutamate and aspartate, and more preferably a hydrochloride, hydrobromide or sulfate.

  “Fudostain” and “other expectorants” which are the active ingredients of the present invention absorb moisture by adsorbing water or becoming hydrates by being left in the atmosphere or by recrystallization. Such hydrates are also used in the present invention.

  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.

  In the present invention, fudostein and other expectorants can be administered simultaneously, sequentially or separately, but generally it is convenient to administer at the same time clinically. Is preferably administered as a combination drug. In addition, when it is not preferable for the preparation technique to physically mix the two compounds, each single agent 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, “treat” means to cure or ameliorate a disease or symptom or to suppress a symptom.

  The pharmaceutical composition containing the fudostein and other expectorants of the present invention is useful because it significantly suppresses goblet cell hyperplasia and has an excellent antitussive and / or expectorant action.

  The pharmaceutical composition containing fudostein and other expectorants of the present invention is useful for the treatment or prevention of symptoms such as common cold, but preferably treatment or prevention of symptoms such as acute or chronic bronchitis. More preferably, symptoms such as acute bronchitis in patients with acute respiratory infection or chronic airway diseases such as COPD, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis It is also useful for the treatment or prevention of symptoms such as acute bronchitis in patients with the disease.

  The expectorant used in the present invention can be easily synthesized by a known method, and can also be obtained by purchasing a commercial product. Hereinafter, typical expectorants will be described.

  Bromhexine hydrochloride, L-carbocysteine, and L-ethylcysteine hydrochloride are listed in the Japanese Pharmacopoeia XIV.

  Acetylcysteine and L-methylcysteine hydrochloride are listed in the Japanese Pharmacopoeia Standards for Drugs 2002.

  Fudstein and ambroxol hydrochloride are already sold as pharmaceuticals, and can also be produced by known methods.

  The single dose of fudostein varies depending on the indication, age, weight, etc., but is usually 120 mg to 1200 mg, which is administered 1 to 3 times a day.

  In the case of a solid preparation, the content of fudstein in the daily dose is usually 60 mg to 2400 mg, preferably 120 mg to 1200 mg, and the content of ambroxol hydrochloride is usually 2 mg to 90 mg. Preferably, it is 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, and contains L-carbocysteine. The amount is usually 75 mg to 3000 mg, preferably 150 mg to 1500 mg, and the content of L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride or acetylcysteine is usually 15 mg to 600 mg, preferably Is 30 mg to 300 mg.

  The content of fudstein contained in the case of a liquid preparation is usually 1 mg / mL to 1200 mg / mL, preferably 5 mg / mL to 800 mg / mL, and the content of ambroxol hydrochloride is usually 0 mg / mL. 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. Is 0.05 mg / mL to 8 mg / mL, and the content of L-carbocysteine is usually 1.2 mg / mL to 1500 mg / mL, preferably 6 mg / mL to 100 mg / mL The content of L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride or acetylcysteine is usually 0.3 mg / mL to 300 A g / mL, preferably a 1mg to 200 mg.

  In the present invention, in addition to the above active ingredients, antipyretic analgesic / anti-inflammatory drugs, hypnotic sedatives, antitussives, antihistamines, antiallergic drugs, sympathomimetic drugs, parasympathomimetic drugs, anti-inflammatory enzymes, vitamins , Herbal medicines and the like 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 powders), capsules, liquids (including syrups) and the like, and additives and base materials suitable for each dosage form. Can be used 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)
1 to 2 tablets (mg) (1a) (1b) (1c) (1d)
------------------------------------
Hodstein 400 400 400 400
Ambroxol hydrochloride 15 − − −
Bromhexine hydrochloride -4--
L-carbocysteine − − 500 −
L-methylcysteine hydrochloride, − − − 100
Acetylcysteine, or
L-Ethylcysteine lactose hydrochloride 120 130 80 100
Magnesium stearate 8 8 10 9
Hydroxypropyl cellulose 25 25 30 27
Corn starch appropriate amount 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) Granules (1) Ingredients (Table 2)
In 1 package (mg) (2a) (2b) (2c) (2d)
-----------------------------------
Hodstein 400 400 400 400
Ambroxol hydrochloride 15 − − −
Bromhexine hydrochloride -4--
L-carbocysteine − − 500 −
L-methylcysteine hydrochloride, − − − 100
Acetylcysteine, or
L-ethylcysteine lactose hydrochloride 900 500 80 400
Polyvinylpyrrolidone 25 25 35 30
Corn starch appropriate amount 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 (Table 3)
1 to 2 capsules (mg) (3a) (3b) (3c) (3d)
-----------------------------------
Hodstein 400 400 400 400
Ambroxol hydrochloride 15 − − −
Bromhexine hydrochloride -4--
L-carbocysteine − − 500 −
L-methylcysteine hydrochloride, − − − 100
Acetylcysteine, or
L-ethylcysteine hydrochloride lactose 500 500 60 300
Polyvinylpyrrolidone 25 25 35 30
Corn starch appropriate amount 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) Ingredient (Table 4)
In 30 mL (mg) (4a) (4b) (4c) (4d)
-----------------------------------
Hodstein 400 400 400 400
Ambroxol hydrochloride 15 − − −
Bromhexine hydrochloride -4--
L-carbocysteine − − 500 −
L-methylcysteine hydrochloride, − − − 100
Acetylcysteine, or
Sodium L-ethylcysteine benzoate hydrochloride 70 70 80 80
Glycerin 100 100 150 20
Polyvinyl alcohol 80 80 100 10
White sugar 1200 1200 1200 1200
Purified water remainder remainder 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 Bromhexine hydrochloride manufactured by Sanyo Chemical Laboratory was used, and ambroxol hydrochloride manufactured by YIC Co., Ltd. was used. For Houdstein, Mitsubishi Pharma Co., Ltd.'s Clearnal tablet (trade name) was pulverized in a mortar.

  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. 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 visually observed for their health and confirmed to be good, and their body weight was measured. The animals were randomly divided into 5 groups per group.

(3) Preparation method of airway mucosal injury model Rats were anesthetized by intraperitoneal administration of pentobarbital 50 mg / Kg, fixed in the supine position, the skin on the cervical larynx was incised in the midline, and the muscles were 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-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 drug (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 a 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 7 animals per group.

(Table 5)
Test substance (dose: mg / Kg) Goblet cell formation inhibition rate (%)
------------------------------------
Hudstein (100) 9.4
Ambroxol hydrochloride (5) 13.2
Bromhexine hydrochloride (1) 9.0
Hudstein (100) + Ambroxol hydrochloride (5) 21.4
Fudstein (100) + bromhexine hydrochloride (1) 38.0
-----------------------------------.

  Table 5 shows that when ambroxol hydrochloride or bromhexine hydrochloride is added to fudostein, a further excellent goblet cell formation inhibitory effect is obtained.

  The pharmaceutical composition of the present invention containing fudstein and other expectorants is useful because it significantly suppresses goblet cell hyperplasia and has an excellent antitussive and / or expectorant action.

    The pharmaceutical composition containing fudostein and other expectorants of the present invention is useful for the treatment or prevention of symptoms such as common cold, but preferably treatment or prevention of symptoms such as acute or chronic bronchitis. More preferably, symptoms such as acute bronchitis in patients with acute respiratory infection or chronic airway diseases such as COPD, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, emphysema, diffuse panbronchitis It is also useful for the treatment or prevention of symptoms such as acute bronchitis in patients with the disease.

Claims (1)

A pharmaceutical composition for suppressing goblet cell hyperplasia containing only fudostein and bromhexine hydrochloride as active ingredients .