JPH10298107A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine having extremely powerful suppressive action on airway hypersecretion by including an anticholinergic drug and a specific antiallergic drug. SOLUTION: This composition is an oral liquid or nasal drop as a suppressant of airway hypersecretion, remedy against cold syndromes, etc., and obtained by including (A) at least one kind of anticholinergic drug selected preferably from belladonna (total) alkaloids, isopropamide-iodide, ipratropium bromide, flutropium bromide and oxitropium bromide, and (B) 0.02-250 pts.wt., based on 1 pts.wt. of the component A, of at least one kind of drug selected from ketotifen, epinastin, and salts thereof. For example, for the oral liquid, 0.1-1.0 mg of belladonna (total) alkaloids as the component A and 0.2-5 mg of ketotifen fumarate as the component B are included as their respective effective dose for one day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel pharmaceutical composition. More specifically, the present invention is a pharmaceutical composition effective as an agent for suppressing airway secretion hypertension or the like which remarkably suppresses hyperactivity of airway secretory glands such as runny nose due to cold syndrome or the like.

[0002]

2. Description of the Related Art Hypersecretion of the respiratory tract (nasal sinuses, sinuses, pharynx, larynx, trachea and bronchi) is mainly caused by inflammation of the mucous membrane of the respiratory tract due to various causes. For example, runny nose, aqueous nasal discharge, aqueous rhinorrhea, etc. are directly due to hyperactivity of secretory glands mainly due to inflammation (rhinitis) of the nasal mucosa. These etiologies are diverse, including cold syndrome, allergic diseases such as allergic rhinitis, and infectious diseases such as bacteria.

[0003] In the treatment of such an increase in airway secretion, causal therapy is performed depending on the etiology. For example, in the case of the common syndrome, which is a common etiology, since the pathogenic virus is diversified, vaccines and antiviral drugs are used. At present there is no satisfactory treatment effect.

[0004] Therefore, in the treatment of hyperrespiratory secretion, the symptomatic treatment still plays a significant role, and is particularly important in the field of over-the-counter drugs. As such symptomatic treatment, antihistamines are used because histamine release is involved in the development of inflammation of the nasal mucosa and the like, and anticholinergic drugs are used because airway secretion is under the control of cholinergic nerves. Have been. However, the administration of these drugs alone is not necessarily enough to suppress the airway hypersecretion, and in order to achieve early treatment from the viewpoint of improving QOL and preventing secondary infection in cold syndrome and the like, There is a strong demand for the development of a drug having a further potent airway secretion inhibitory action.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned prior art, and has as its object to suppress an extremely potent suppression of airway hypersecretion which cannot be achieved by a conventional symptomatic agent. It is to provide a drug having an action.

Another object of the present invention is to provide a remedy for a cold syndrome and the like, which has an enhanced inhibitory action on airway hypersecretion.

[0007]

Means for Solving the Problems In order to achieve the above object, the present inventors have made intensive studies on the formulation of a pharmaceutical composition having an inhibitory effect on airway hypersecretion. The present inventors have found that the addition of an allergic drug has a dramatic effect on the suppression of airway hypersecretion, and completed the present invention.

That is, the present invention is a pharmaceutical composition comprising (a) an anticholinergic and (b) at least one drug selected from the group consisting of ketotifen and epinastine and salts thereof.

[0009] The present invention also relates to the medicament, wherein the anticholinergic is at least one selected from the group consisting of belladonna (total) alkaloids, isopropamide iodide, ipratropium bromide, flutropium bromide and oxitropium bromide. A composition.

In the present invention, the compound (b) may be added in an amount of 0.02 to 1 part by weight of the anticholinergic (a).
The pharmaceutical composition is 250 parts by weight.

[0011] The present invention also provides the above pharmaceutical composition which is an agent for suppressing airway hypersecretion.

The present invention is also the above pharmaceutical composition, which is a therapeutic agent for cold syndrome.

[0013] The present invention is also the above pharmaceutical composition which is an agent for oral administration.

[0014] The present invention is also the above pharmaceutical composition which is a nasal drop.

[0015]

DETAILED DESCRIPTION OF THE INVENTION The pharmaceutical composition of the present invention comprises an anticholinergic and a specific antiallergic.

The anticholinergic agents used in the pharmaceutical composition of the present invention include belladonna (total) alkaloids, isopropamide iodide, ipratropium bromide, flutropium bromide, oxitropium bromide and the like. Alternatively, two or more kinds can be used.

Here, the belladonna (total) alkaloid is a belladonna (Atropa belladonna).
a), Scopolia japoni
ca, funnel or hyoscyamus
nigre) or alkaloids extracted from their related plants, including those extracted from belladonna extract, funnel extract or datsura extract.

The antiallergic drugs used in the pharmaceutical composition of the present invention are ketotifen and epinastine and salts thereof. Specific examples include ketotifen, ketotifen fumarate, ketotifen maleate, epinastine, epinastine hydrochloride, epinastine nitrate and the like. And these may be used alone or in combination of two or more.

In the pharmaceutical composition of the present invention, the effective amount of the above-mentioned anticholinergic is 0.1 to 1.0 mg, preferably 0.3 to 0, per day for oral or belladonna (total) alkaloid. 0.8 mg, isopropamide iodide 1-9 mg, preferably 2-8 mg, and ipratropium bromide 0.3-1.5 mg, preferably 0.6-1.5 mg.
1.4 mg is good, and 0.5 to 2 for flutropium bromide.
0 mg, preferably 1.0 to 15 mg, and 1.5 to 7.5 mg, preferably 3.5 to 7.5 mg for oxitropium bromide.
6.5 mg is good. Daily dose for nasal drops, 10-200 μg, preferably 20 for belladonna (total) alkaloids
１６０160 μg is preferable, and 100 g for isopropamide iodide.
９００900 μg, preferably 200-800 μg, and 30-180 μg, preferably 6 for ipratropium bromide.
0 to 160 μg is preferable, and 45 to 45 μg for flutropium bromide.
2500 μg, preferably 90 to 1500 μg, and for oxitropium bromide, 150 to 750 μg, preferably 300 to 650 μg.

The effective amount of the anti-allergic agent is oral dose per day, and ketotifen fumarate is 0.2% per day.
-5 mg, preferably 0.5-4 mg, and for epinastine hydrochloride 2-25 mg, preferably 4-20 mg. In the case of nasal drops, the daily dose is 50-250 μg, preferably 100-200 μg, and the epinastine hydrochloride is 0.2-2.5 mg, preferably 0.4-2.0 mg, per day.

The compounding ratio of the active ingredient in the pharmaceutical composition of the present invention is preferably from 0.02 to 250 parts by weight of the antiallergic agent to 1 part by weight of the anticholinergic and 0.1 to 15 parts by weight.
0 is particularly preferred. If the compounding weight ratio is less than the lower limit, no more than the effect of the anticholinergic agent alone cannot be obtained, and if it exceeds the upper limit, side effects of the central nervous system such as drowsiness may occur, which is not preferable.

The pharmaceutical composition of the present invention comprises an agent for suppressing airway hypersecretion due to various etiologies, an agent for rhinitis, an agent for sinusitis, an agent for pharyngitis, an agent for laryngitis, an agent for bronchitis, an agent for treating cold syndrome, It can be used as an antiallergic agent and the like. In this case, in addition to the above-mentioned drug components, other drug components may be further compounded as necessary.

For example, when the pharmaceutical composition of the present invention is used as a remedy for cold syndrome, in addition to the above-mentioned components, antihistamines, other antiallergic drugs, adrenergic drugs, antitussive expectorants, anti-inflammatory enzyme drugs and anti-inflammatory drugs Drugs, caffeines, vitamins, crude drugs and the like can be appropriately compounded.

In this case, the antihistamines include:
Isotipendil, iproheptin, dipheterol, diphenylpyrazine, diphenhydramine, triprolidine, tripelenamine, promethazine, alimemazine, mequitazine, carbinoxamine, chlorpheniramine (d
Dl-form), astemizole, clemastine, tondylamine, dimethindene, homochlorcyclidine, phenetazine, meclizine, cyproheptadine and the like, and salts thereof, and these can be used alone or in combination of two or more.

The other antiallergic drugs include cromoglycic acid, tranilast, amlexanox, repirinast, ibudilast, tazanolast, pemirolast, ozagrel, tazanolast, suplatast, azelastine, oxatomide, terfenadine, astemizole,
Mequitadine, emedastine, and the like, and salts thereof, can be used alone or in combination of two or more.

Examples of the adrenergic drug include methylephedrine (1 form, dl form), phenylpropanolamine, phenylephrine, methoxyphenamine and the like, and salts thereof. These can be used alone or in combination of two or more. .

The antitussive expectorants include codeine, dihydrocodeine, dextromethorphan, noscapine,
Hominobene, Clofedanol, Benproperin, Dimemorphan, Cloperastine, Eprazinone, Clobutinol, Oxerazine, Isoaminyl, Pentoxiverine, Sodium dibunate, Hydrocotarnine, Bromhexine, Ambroxol, Potassium guaiacol sulfonate, L-methylcysteine, L -Ethylcysteine, carbocysteine, acetylcysteine and the like, and salts thereof, and these can be used alone or in combination of two or more.

Examples of the anti-inflammatory and anti-inflammatory drugs include lysozyme chloride, bromelain, serrapeptase, semi-alkaline proteinase, pronase, proctase, streptokinase, tranexamic acid, glycyrrhizic acid and related substances. 2
More than one species can be used.

The caffeine includes caffeine and anhydrous caffeine.

The vitamins include vitamin B ₁ ,
Vitamin B ₂ , vitamin C, and the like, and derivatives thereof, and salts thereof, may be used alone or in combination of two or more.

The crude drugs include midsummer, spicy, garlic,
Ginger, licorice, saiko, cinnamon bark (branch), (purple) soba, mako, shakuyaku, gomiko, yellow bon, river cucumber, ground yellow, yellow ren, bellflower, wheat gate winter, renchi, spicy, choji, uika , Eucalyptus, lavender, herbal powders such as light loads, extracts thereof, and the like, and these can be used alone or in combination of two or more.

These components can be used singly or as a mixture with each other, and are usually blended in accordance with the standards for over-the-counter drug manufacture (import) approval.

The pharmaceutical composition of the present invention can be administered orally systemically or topically by nasal spray, inhalation, spraying, etc., once or several times a day. In addition, the dose can be appropriately increased or decreased depending on the age, body weight, and medical condition.

When the pharmaceutical composition of the present invention is used as an agent for oral administration, solid preparations such as tablets, capsules, granules, fine granules, powders, chewables, foaming agents, drops, dissolving agents in the mouth, dry syrups, etc. It can be prepared into liquid preparations such as preparations and oral liquid preparations, and these can be prepared by conventional methods.

In this case, preparation of the solid preparation includes excipients such as lactose, starch, sugar, mannitol, crystalline cellulose, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, PVP, carboxymethylcellulose calcium, Disintegrators such as substituted hydroxypropyl cellulose, magnesium stearate, hydrogenated castor oil, lubricants such as talc are used, and if necessary, other solubilizers, buffers,
Preservatives, flavors, dyes, flavoring agents and the like can be used.

The preparation of the liquid preparation includes surfactants such as sucrose fatty acid esters, polyoxyl stearate, polyoxyethylene polyoxypropylene glycols, polyoxyethylene monofatty acid esters, synthetic aluminum silicate, Thickeners such as magnesium silicate, magnesium carbonate, magnesium oxide and magnesium aluminate metasilicate, and organic and inorganic acid pH adjusters such as citrate buffer and phosphate buffer are used. Solubilizers, buffers, preservatives, flavors, pigments, corrigents, sweeteners and the like can be used according to the requirements.

When the pharmaceutical composition of the present invention is used as an agent for topical administration such as nasal drops, it can be prepared into a solid spray or a liquid spray, all of which can be prepared by a conventional method. .

In this case, a solid propellant is prepared by adding excipients such as crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin,
Binders such as PVP, magnesium stearate, hydrogenated castor oil, lubricants such as talc, preservatives and the like can be used.

In preparing a liquid spray, in addition to a surfactant, a solubilizing agent, a buffer and the like, a preservative, if necessary,
Flavors such as menthol and camphor, pigments, preservatives and the like can be used.

[0040]

EXAMPLES Hereinafter, the pharmaceutical composition of the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Phenylpropanolamine hydrochloride 80 g Ketotifen fumarate 2 g Belladonna (total) alkaloid 0.4 g Phenylpropanolamine hydrochloride 80 g Lactose 100 g Microcrystalline cellulose 60 g Magnesium stearate 48 g Hardened castor oil 9.6 g After weighing the components and mixing them uniformly, the resulting mixed powder was weighed 100 m / tablet by a direct compression method.
to obtain a tablet.

(Example 2) Phenylpropanolamine hydrochloride 100 g Epinastine hydrochloride 20 g Belladonna (total) alkaloid 0.4 g Lysozyme chloride 90 g (titer) Anhydrous caffeine 300 g Lactose 100 g Microcrystalline cellulose 80 g Magnesium stearate 52 g Hardened castor oil 7. 6 g After weighing and uniformly mixing each component in the above-mentioned formulation, 100 mg tablets were obtained according to Example 1.

Example 3 Phenylephrine hydrochloride 30 g Epinastine hydrochloride 20 g Isopropamide iodide 7.5 g Dipotassium glycyrrhizinate 200 g Lidocaine hydrochloride 500 g Lactose 200 g Lactose 200 g Microcrystalline cellulose 130 g Magnesium stearate 90 g Hardened castor oil 22.5 g The above formula After each component was weighed and mixed uniformly, 200 mg tablets were obtained according to Example 1.

Example 4 1-Methylephedrine hydrochloride 110 g Ketotifen fumarate 2 g Isopropamide iodide 7.5 g Lysozyme chloride 90 g (titer) Anhydrous caffeine 300 g Fine spicy 3 g (equivalent to crude drug) Amount) Lactose 100 g Microcrystalline cellulose 70 g Magnesium stearate 60 g Hardened castor oil 8.5 g After weighing and uniformly mixing the components in the above formulation and uniformly mixing, 100 mg tablets were obtained according to Example 1.

Example 5 Naphazoline hydrochloride 50 mg Ketotifen fumarate 25 mg Ipratropium bromide 100 mg Lidocaine hydrochloride 250 mg After weighing and uniformly mixing the components in the above formulation, and dissolving in 100 ml of purified water, a liquid preparation was obtained. .

(Example 6) Tetrahydrozoline hydrochloride 100 mg Ketotifen fumarate 50 mg Flutropium bromide 150 mg Lysozyme chloride 250 mg Lidocaine hydrochloride 300 mg After weighing each component in the above formulation, mixing uniformly, and dissolving in 100 ml of purified water, I got

(Example 7) Tetrahydrozoline hydrochloride 100 mg Ketotifen fumarate 35 mg Oxytropium bromide 450 mg Lysozyme chloride 250 mg Lidocaine hydrochloride 250 mg Benzethonium chloride 20 mg Each component was weighed in the above formulation, mixed uniformly, and purified water 100 ml To give a solution.

(Example 8) Oxymetazoline hydrochloride 25 mg Ketotifen fumarate 50 mg Belladonna total alkaloid 50 mg Fluticasone propionate 50 mg Lysozyme chloride 250 mg Lidocaine hydrochloride 250 mg 1-Menthol 10 mg Benzethonium chloride 20 mg Then, the mixture was dissolved in 100 ml of purified water to obtain a liquid preparation.

(Test for inhibiting airway hypersecretion by systemic administration)
The inhibitory effect of systemic administration (oral) of the pharmaceutical composition of the present invention on the function of airway secretory glands was examined using normal rats.

The pharmaceutical composition of the present invention prepared according to the formulation shown in Table 1 was diluted in 100 ml of purified water for each group and orally administered to 5 ddY male rats in each group by 2 ml. Two hours after the administration, the chest was incised to remove the airway, the amount of airway fluid was measured, the average value was calculated, and compared with the average value of the non-administration group (control group) to which 2 ml of purified water was orally administered. Table 2 shows the results.

[0051]

[Table 1]

[0052]

[Table 2]

The degree of suppression of airway fluid secretion was significantly enhanced in groups A to D compared to the other groups, and the pharmaceutical composition of the present invention
It was found that the oral systemic administration exhibited a potent airway secretion hyperactivity inhibitory effect that could not be obtained by single administration of each active ingredient.

(Test for suppression of airway hypersecretion by local administration)
The inhibitory effect of topical administration (nasal drop) of the pharmaceutical composition of the present invention on the function of nasal endocrine glands was examined using normal rats.

The pharmaceutical composition of the present invention prepared according to the formulation shown in Table 3 was diluted in 100 ml of purified water for each group, and 0.2 ml of each ddY male rat was intranasally administered to 5 male ddY rats in each group. Two hours after administration, the nasal cavity was incised, the amount of secretion fluid on the nasal membrane was measured, the average value was calculated, and compared with the average value of the non-administration group (control group) to which 0.2 ml of purified water was intranasally administered. . Table 4 shows the results.

[0056]

[Table 3]

[0057]

[Table 4]

The degree of suppression of the amount of nasal endocrine secretion was markedly enhanced in groups I to L as compared with the other groups.
It was found that even by topical administration by nasal drop, a potent nasal endocrine hyperactivity suppression effect, which cannot be obtained by single administration of each active ingredient, was exhibited.

[0059]

As described above, the pharmaceutical composition of the present invention comprises:
Since (a) an anticholinergic drug and (b) at least one drug selected from the group consisting of ketotifen and epinastine and salts thereof are mixed, the respiratory tract gland is exposed to both systemic and local administration. It shows an extremely excellent inhibitory effect on hyperactivity. Therefore, the pharmaceutical composition of the present invention can be used as a topical agent such as an agent for oral administration and nasal drops, for cold syndrome, allergic diseases such as allergic rhinitis, infectious diseases such as bacteria, runny nose, aqueous nasal discharge, aqueous nasal solution. It is extremely useful when used to enhance the function of airway secretory glands such as leaks.

The pharmaceutical composition of the present invention may contain, if necessary, an antihistamine, another antiallergic drug, an adrenergic drug, another anticholinergic drug, an antitussive expectorant, an anti-inflammatory enzyme / anti-inflammatory drug, By combining caffeine, vitamins, crude drugs, etc., it is excellent in suppressing the increase in respiratory tract secretion such as runny nose, among other symptoms of cold, and formulating and cold medicine in accordance with other symptoms of cold And is useful as an agent for treating various cold syndromes and the like.

Claims (7)

[Claims] 1. A pharmaceutical composition comprising (a) an anticholinergic and (b) at least one drug selected from the group consisting of ketotifen, epinastine and salts thereof. 2. The anticholinergic agent is belladonna (total)
The pharmaceutical composition according to claim 1, which is at least one member selected from the group consisting of alkaloids, isopropamide iodide, ipratropium bromide, flutropium bromide and oxitropium bromide. 3. The compounding ratio of the anticholinergic (a) 1
The pharmaceutical composition according to claim 1 or 2, wherein the amount of the drug (b) is 0.02 to 250 parts by weight based on part by weight. 4. The method according to claim 1, which is an agent for suppressing airway hypersecretion.
The pharmaceutical composition according to any one of the preceding claims. 5. The pharmaceutical composition according to claim 1, which is an agent for treating a cold syndrome. 6. The pharmaceutical composition according to claim 1, which is an agent for oral administration. 7. The pharmaceutical composition according to claim 1, which is a nasal drop.