JPH10158193A - Composition for treating rhinitis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition high in totally demulcent effects on rhinitis symptoms such as sneeze, capable of alleviating adverse effects such as sleepiness, etc., by formulating an antiphlogistic enzyme agent with an antiinflammatory agent. SOLUTION: This composition comprises (A) a phenothiazine-based antihistamine agent (preferably mequitazine or promethazine methylenedisalicylate, (B) an antiphlogistic enzyme agent (preferably lysozyme, bromelain or their salt) and (C) an antiinflammatory agent. Preferably, the composition is formulated with (D) a central stimulant in a daily amount of 12-300mg and, for example, a daily dose of mequitazine is 0.3 6 mg and that of lysozyme is 3.6-90mg (titer).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a composition for treating rhinitis symptoms. Specifically, the present invention relates to a composition for treating rhinitis, comprising a phenothiazine antihistamine, an anti-inflammatory enzyme drug and an anti-inflammatory drug.

[0002]

2. Description of the Related Art In recent years, the topic of atopic diseases has been well reported in newspapers and televisions. Diseases based on atopy are caused by various factors such as pollen derived from plants such as cedar, dust, mites (hereinafter referred to as allergens), and specifically include, for example, allergic rhinitis and hay fever. . As specific symptoms of these atopic diseases, there are three main features of aqueous nasal discharge, nasal congestion, and sneezing. The manifestation of these three features usually involves nasal itching within minutes of inhalation of the allergen, followed by a sneezing attack, as well as massive nasal discharge and nasal congestion. In addition, the nasal congestion is persistent and lasts for several hours. In addition, the nasal congestion may make breathing of the nose difficult, and if it becomes severe, it may be accompanied by heavy head feeling. These rhinitis symptoms not only cause significant discomfort to the patient over a long period of time, but the symptoms cause a great disturbance to the patient's daily life. In addition, some patients often have symptoms such as inflammation of the nasal mucosa or nose bleeding due to cutoff of the nasal vessels due to frequent blowing of the nose. In Japan, not only allergic rhinitis symptoms but also influenza (epidemic cold) prevalent almost every year, and many patients complain of rhinitis symptoms as one of the various symptoms at that time. Under these circumstances, there are currently many commercially available combinations for alleviating rhinitis symptoms.

[0003] A commercially available general-use oral preparation (hereinafter referred to as "rhinitis internal use drug") for the purpose of improving the above-mentioned rhinitis condition.
) Has an antihistamine. Antihistamines are usually formulated for the purpose of alleviating itchy eyes, sneezing attacks, nasal discharge, nasal congestion, etc. due to their antihistamine action. Although there are many types of antihistamines, many of them have effects on the central nervous system, that is, sedative effects, drowsiness, malaise, etc., and occupations requiring continuous attention such as car drivers. It was necessary to select and administer a formulation with less hypnotic effect to the patients.

[0004] Recently, mequitazine is known as a non-sedating antihistamine having relatively few side effects such as drowsiness. However, although this mequitazine has weak side effects, it has a drawback that its antihistamine action is more moderate than the conventional one. Therefore, in order to compensate for such a drawback, a composition for treating rhinitis, which is combined with phenylpropanolamine hydrochloride (hereinafter referred to as PPA) having a vasoconstrictive action (see JP-A-7-188002 (Example 1 of the publication)). 3) description) and belladonna (total) alkaloids (hereinafter, referred to as anticholinergic agents having nasal secretion inhibitory action).
BA), tropane alkaloids such as datsura extract and rotochone or isopropamide iodide and mequitazine are combined with a composition for treating rhinitis (Japanese Patent Laid-Open No. 7-1).
JP-A-88040 (see Examples 1 and 2 of the publication) and JP-A-8-208483 (Examples 1 to 1 of the publication).
1)), and a preparation in which PPA and BA are combined (JP-A-7-53355 (see Reference Examples 3 and 4)). In these formulations, P
It is considered that the action of PA and / or BA or their interaction compensates for the weak antihistamine action.

However, in experiments conducted by the present inventors, when the above-mentioned conventional formulation was administered to a patient as a single preparation, a remarkable effect of improving rhinitis was not obtained as expected. For example, it is disclosed that a conventional combination of mequitazine and a vasoconstrictor enhances the vasoconstriction and improves nasal inflammation, particularly nasal congestion. However, the nasal congestion symptom is caused by inflammation in the local mucosa of the nasal mucosa, and is accompanied by a head weight. Such a vasoconstriction effect alone is not enough to improve the inflammation, and the head weight is not improved. An anticholinergic agent can be added in expectation of an effect of improving nasal inflammation by enhancing nasal secretion suppression. However, a clinical trial of mequitazine as a medicinal drug (Otolaryngology Outlook Vol.27 No. Suppl 5 PAGE.579-586 1984) shows that 60% of patients receive 3 mg of mequitazine twice daily. Is reported to complain of dry mouth, and it is considered that the combination of an anticholinergic agent having a secretory inhibitory action, combined with dry mouth caused by mequitazine itself, causes a very uncomfortable feeling for patients. A compounding ratio for reducing such side effects has been disclosed (Japanese Patent Application Laid-Open No. 8-208483). However, when a mequitazine preparation was prepared and administered to humans in the range of the compounding ratio, improvement of dry mouth side effects was not yet achieved. Not enough and there was room for further improvement.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to reduce side effects such as drowsiness, which have been a problem with conventional oral medicines for rhinitis containing an antihistamine having a strong antihistamine action, and to reduce sneezing, To provide a composition for the treatment of rhinitis, which has a high overall palliative effect on nasal inflammation such as nasal discharge, itching and nasal congestion, and also has a powerful rhinitis-reducing effect, which also improves head-heavy symptoms and relieves patients from discomfort. is there.

[0007]

Means for Solving the Problems In view of the above circumstances, the present inventors have intensively studied for a combination having a better overall palliative effect on rhinitis, and as a result, together with a phenothiazine antihistamine such as mequitazine, The present inventors have found that a total effect on rhinitis can be obtained by blending an anti-inflammatory enzyme drug and an anti-inflammatory drug, and have completed the present invention. The composition for the treatment of rhinitis of the present invention (hereinafter, also referred to as “the composition of the present invention”) has an antihistamine action of a phenothiazine antihistamine such as mequitazine, an antiinflammatory action and a mucolytic action of an anti-inflammatory enzyme drug, and an anti-inflammatory action. A composition for the treatment of rhinitis in which the anti-inflammatory action of the drug is remarkably enhanced. That is,
Anti-inflammatory drugs and anti-inflammatory drugs enhance the antihistamine action of mequitazine, and the combination of anti-inflammatory drugs and anti-inflammatory drugs themselves enhance each other's actions, resulting in the anti-inflammatory action of anti-inflammatory drugs. The mucosal repair effect based on the mucosa and the anti-inflammatory effect of the anti-inflammatory enzyme drug and the nasal discharge promoting effect based on the mucolytic action are respectively enhanced, whereby the nasal congestion and nasal secretion are strongly suppressed, so that the rhinitis symptoms are improved altogether. Also, as mentioned earlier, severe nasal congestion and nasal secretion is accompanied by head weight,
Even for such patients, taking the composition of the present invention suppresses nasal congestion or nasal secretion, improves nasal inflammation and removes the head weight, and discomforts patients in conjunction with improvement of rhinitis. Release from Furthermore, a central stimulant is more preferably incorporated in the composition of the present invention. Along with enhancing the effect of suppressing head weight, when using a phenothiazine antihistamine, for example, mequitazine, the side effects are relatively weak, and furthermore, the arousal effect of the central stimulant reduces side effects such as drowsiness, and extremely reduces side effects. Less rhinitis treatment composition.

That is, the present invention is as follows. (1) A composition for treating rhinitis, comprising a phenothiazine antihistamine, an anti-inflammatory enzyme drug and an anti-inflammatory drug. (2) The composition for treating rhinitis according to the above (1), wherein the phenothiazine antihistamine is selected from promethazine, alimemazine, isothipendyl or salts thereof, particularly, mequitazine or promethazine methylene disalicylate. (3) The anti-inflammatory enzyme drug is selected from lysozyme, bromelain, trypsin, α-chymotrypsin, semi-alkaline proteinase (seaprose S-AP), proteinase, serrapepteptidase (serrapeptase), streptokinase, streptodornase, bromhexine or salts thereof. The composition for treating rhinitis according to the above (1) or (2), wherein the composition is selected from lysozyme, bromelain and salts thereof. (4) The composition for treating rhinitis according to any one of the above (1) to (3), comprising a central stimulant. (5) The composition for treating rhinitis according to (4), wherein the compounding amount of the central stimulant is 12 mg to 300 mg per day.

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the contents of the present invention will be described in detail. The essential components of the composition of the present invention include a phenothiazine antihistamine, an anti-inflammatory enzyme, and an anti-inflammatory. The phenothiazine antihistamine to be incorporated in the composition of the present invention has a phenothiazine skeleton as the name implies. Specifically, there are, for example, promethazine, alimemazine, isotipendyl, mequitazine and the like, and usually a salt thereof is blended. For example, promethazine contains promethazine hydrochloride or promethazine methylene disalicylate, isotipendil contains isotipendyl hydrochloride, and alimemazine contains alimemazine tartrate. Therefore, the phenothiazine antihistamine used in the present invention includes not only promethazine, alimedazine, isotipendyl, mequitazine but also salts thereof. In addition, the hydrochloride, the tartrate, and the like shown above are only examples of what is blended in the composition of the present invention, and are not limited only to these examples. Among the phenothiazine antihistamines, the most preferred to be incorporated into the composition of the present invention are mequitazine and promethazine methylene disalicylate. Mequitazine is a typical phenothiazine antihistamine having a structure represented by the following formula (I), and has particularly low side effects of drowsiness. As the mequitazine to be incorporated into the composition of the present invention, in addition to those chemically synthesized and purified using a known method,
A commercially available product may be used.

[0010]

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[0011] Promethazine methylene disalicylate is advantageous in that it does not easily change its composition and exhibits high stability. In addition, it has almost no bitterness when administered orally to a patient, so that it has an advantage that discomfort during administration is extremely small. Further, promethazine methylene disalicylate is preferable from the viewpoint of stable supply since it is easily available in distribution.

The anti-inflammatory enzyme drug incorporated in the composition of the present invention has an anti-inflammatory action, an edema-suppressing action, and a mucous-decomposing action,
Decomposes and promotes excretion of inflammatory peptides, pus, and exudates in inflammatory areas. The anti-inflammatory enzyme drug is
It is not particularly limited as long as it has an effect of dissolving nasal mucus, but specific examples include lysozyme, bromelain, trypsin, α-chymotrypsin, semi-alkali proteinase (seaprose S-AP), proteinase, serratiopeptidase ( Serrapeptase), streptokinase, streptodornase, bromhexine and the like. Particularly preferred examples include lysozyme and bromelain, which have a remarkable overall therapeutic effect on rhinitis when combined with other compounding ingredients. Also,
The chemical form of these anti-inflammatory enzyme drugs may be any form as long as it is commonly used. For example, lysozyme is generally used in the form of chloride (lysozyme chloride), and bromhexine is used in the form of hydrochloride (bromhexine hydrochloride). Can be Further, among those listed in the Japanese Pharmacopoeia (hereinafter, referred to as "JP") such as the lysozyme chloride described above, when a commercially available lysozyme chloride is used, it conforms to the standards of JP (hereinafter, referred to as "JP"). It is needless to say that it is preferable to use a “product compatible with the Japanese Pharmacopoeia”), but the present invention is not limited to this. The anti-inflammatory enzyme drug is used in combination with a phenothiazine antihistamine, whereby the antihistamine action of the phenothiazine antihistamine (suppression of the vascular hyperpermeability of histamine) is caused by the interaction.
Is increased. Preferably, a combination of lysozyme chloride and mequitazine having a more remarkable mutual enhancing effect is selected. The anti-inflammatory enzyme drug also enhances the interaction by combination with the anti-inflammatory drug, which is another essential component in the composition of the present invention.

The anti-inflammatory drug of the present invention has an anti-inflammatory action and has an action of repairing the nasal mucosa. Examples of such anti-inflammatory drugs include glycyrrhizic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, diammonium glycyrrhizinate and salts thereof, and licorice and the like. In addition,
Licorice is the root of a plant and is a so-called crude drug, but its active ingredient is glycyrrhizic acid, so that the same pharmacological effects as glycyrrhizic acid and its salts can be obtained. In addition, the form when compounding is not particularly limited,
Licorice powder (powder) and Licorice extract are preferred. Among the anti-inflammatory drugs, those listed in the Japanese Pharmacopoeia are desirably compatible with the Japanese Pharmacopoeia when commercially available products are used, but needless to say, the present invention is not limited thereto. In addition, when these listed anti-inflammatory drugs are used in combination with a phenothiazine antihistamine or an anti-inflammatory enzyme drug, a mutual potentiating effect is observed. First, the combined use of an anti-inflammatory drug and a phenothiazine antihistamine enhances the antihistamine action of the phenothiazine antihistamine. In addition, any of the above-listed anti-inflammatory drugs is mainly composed of glycyrrhizic acid, and any of them may be selected. It is preferable to select mequitazine which is expected to have

As described above, in the composition of the present invention, a phenothiazine-based antihistamine (particularly mequitazine), an anti-inflammatory enzyme (particularly lysozyme chloride) and an anti-inflammatory agent are blended as essential components to form a phenothiazine-based compound. The antihistamine action of the antihistamine drug (suppression of histamine hyperpermeability action of histamine) and the anti-inflammatory action of the anti-inflammatory enzyme drug and the anti-inflammatory action of the anti-inflammatory drug are respectively enhanced. As a result, nasal discharge and nasal congestion symptoms are improved, and furthermore, the head is also removed, which is an effect that cannot be obtained with conventional oral medicines for rhinitis. Therefore, the effect on the rhinitis state is further enhanced, and the effect of comprehensively improving the rhinitis state can be obtained. Further, the composition of the present invention preferably contains a central stimulant in order to further enhance the ability to reduce side effects such as drowsiness and to enhance the effect of suppressing head heavyness associated with rhinitis symptoms. Examples of the central stimulant that can be used in the present invention include sodium benzoate caffeine, caffeine, and anhydrous caffeine.

The composition of the present invention may contain an anticholinergic or a sympathomimetic if necessary. For example, anticholinergic drugs are formulated in expectation of mucus secretion suppression (improvement of nasal discharge) based on the anticholinergic action. Examples of anticholinergic drugs that can be added include datsura extract, belladonna (total) alkaloid, belladonna extract, isopropamide iodide, and funnel extract. The sympathomimetics which can be added to the composition of the present invention are used for the purpose of alleviating the nasal congestion by the vasoconstriction and further enhancing the overall relieving effect of the composition of the present invention on rhinitis. . Sympathomimetics that can be specifically formulated include phenylpropanolamine, phenylephrine, d
Examples thereof include 1-methylephedrine, 1-methylephedrine, methoxyphenamine and the like. The chemical form of these sympathetic stimulants may be any form as long as it is commonly used, but usually contains a hydrochloride.
These sympathomimetics are usually used alone or in combination.
More than one component can be blended.

Next, the mixing ratio of each component that can be added to the composition of the present invention will be described. The mixing ratio of each component constituting the composition of the present invention is usually determined on the basis of a phenothiazine antihistamine. The mixing ratio of each drug with respect to the phenothiazine antihistamine differs depending on the type of the selected antihistamine. For example, when mequitazine is used, it is as follows. In addition, the compounding ratio of each component shall be described with respect to the compounding weight part of each component with respect to 1 part by weight of mequitazine, and the number of compounding units corresponding to 1 mg of mequitazine for bromelain, which is one of the anti-inflammatory enzyme drugs. Further, for lysozyme chloride, the compounding titer corresponds to 1 mg of mequitazine. First, when bromelain is used as an anti-inflammatory enzyme drug, for example, it is usually 0.8 to 400,000 units, preferably 4.0 to 400 units.
00 to 40,000 units, more preferably 6,000 to
When 40,000 units use lysozyme chloride, usually 0.6 to 300 mg (titer), preferably 3 to 30 m
g (titer), more preferably 4.5 to 30 mg (titer). The anti-inflammatory drug also varies depending on the drug used, but usually 0.6 to 667 parts by weight, preferably 3 to 67 parts by weight.
Parts by weight, more preferably 5 to 67 parts by weight; for example, in the case of glycyrrhizic acid such as glycyrrhizic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, diammonium glycyrrhizate and salts thereof, it is usually 0 in terms of glycyrrhizic acid. 0.6-667
Parts by weight, preferably 6.6 to 67 parts by weight, more preferably 10 to 67 parts by weight. When liquorice is selected as an anti-inflammatory drug, it is usually 17 to 17,000 parts by weight, preferably 170 to 1.7, in terms of liquorice extract.
00 parts by weight, more preferably 250 to 1,700 parts by weight. When including a central stimulant, for example, so-called caffeine, usually 2 to 2 as anhydrous caffeine
1,000 parts by weight, preferably 10 to 100 parts by weight, more preferably 15 to 100 parts by weight is blended.

When an anticholinergic agent is contained, for example, a funnel extract or a belladonna extract is usually used in an amount of 0.4%.
To 200 parts by weight, preferably 2 to 20 parts by weight, more preferably 3 to 20 parts by weight, if the belladonna alkaloid or Datsura extract is usually 0.004 to 2 parts by weight, preferably 0.02 to 0.2 parts by weight, More preferably, the amount is 0.03 to 0.2 parts by weight. In addition, although a sympathetic stimulant may be included depending on the drug used, for example, phenylpropanolamine hydrochloride usually has a concentration of 0.6 to 3.
34 parts by weight, preferably 3.3 to 33.4 parts by weight, more preferably 5 to 33.4 parts by weight, and in the case of phenylephrine hydrochloride 0.2 to 100 parts by weight, preferably 1 to 10 parts by weight, more preferably Is 1.5 to 10 parts by weight, and if dl-methylephedrine hydrochloride or 1-methylephedrine hydrochloride, it is usually 0.7 to 367 parts by weight, preferably 3.
6 to 36.7 parts by weight, more preferably 5.5 to 36.
7 parts by weight, 1 to 500 for methoxyphenamine hydrochloride
Parts by weight, preferably 5 to 50 parts by weight, more preferably 7.5 to 50 parts by weight.

Further, the composition of the present invention may contain antiallergic drugs such as tranilast, sodium cromoglycate or amlexanox, or mussels such as mussels, cycins, junipers, and ginger, depending on the factors such as the cause, symptoms and degree of rhinitis. Crude drugs can be blended. Further, when the composition of the present invention is applied to a preparation for alleviating various symptoms of cold syndrome (so-called cold medicine), components usually contained in cold medicine may be added. Therefore, the composition of the present invention includes, for example, various vitamins, codeine,
Antitussives such as dihydrocodeine and noscapine, antipyretic analgesics such as ethenzamide, acetaminophen, and acetylsalicylic acid, and antacid components such as magnesium oxide, silicates, and aluminum hydroxide gel may be added. The composition of the present invention containing these components is particularly excellent in treating rhinitis symptoms as compared with other common cold medicines. Thus, the composition of the present invention can be added to various preparations for the treatment of rhinitis or other purposes, as long as it does not have a relatively serious adverse effect on the other co-existing main drugs. In addition, the preparation has reduced side effects such as drowsiness.

The composition of the present invention can be formulated into tablets, coated tablets, granules, fine granules, powders, capsules, liquids, syrups and the like as oral dosage forms. In the composition of the present invention, in addition to the essential components of the present invention, which are the main drug, as required, excipients, binders, lubricants, disintegrants, coating agents, flavoring agents, flavoring agents, coloring agents, and preservatives Additives such as agents, dispersants, and solvents may be added. Specific examples of acceptable additives include excipients such as lactose, sucrose, sugars such as glucose and mannitol, potato starch, corn starch, starches such as wheat starch, calcium carbonate, Inorganic salts such as calcium sulfate, sodium bicarbonate, and sodium chloride; and crystalline cellulose. Suitable binders include starch paste, gum arabic, gelatin, sodium alginate, methylcellulose (MC), ethylcellulose (EC), polyvinylpyrrolidone (PV
P), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC) and the like. Suitable lubricants include magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil and the like. Suitable disintegrants include starch, agar, gelatin powder, crystalline cellulose, CMC.Na, CMC.C
a, calcium carbonate, sodium hydrogen carbonate, sodium alginate and the like. Suitable coating agents include sucrose, HPC, shellac and the like for sugar coating, gelatin, glycerin, sorbitol and the like for glue coating, and hydroxypropyl methylcellulose (HPM) for film coating.
C), EC, HPC, PVP and the like. Furthermore, examples of the enteric coating include hydroxypropyl methylcellulose terephthalate (HPMCP) and cellulose acetate phthalate (CAP). Suitable flavoring agents include lactose, sucrose, glucose, mannitol, D-sorbitol (liquid) and D-sorbitol (liquid), and suitable flavoring agents include aromatic essential oils. Further, as a preferable coloring agent, a water-soluble edible dye, a lake dye and the like, as a preferable preservative,
Benzoic acid, sodium benzoate, p-hydroxybenzoic acid,
Esters, inverted soaps, dehydroacetic acid, boric acid, chlorobutanol, benzyl alcohol and the like.
Suitable dispersants include, for example, polysorbate 8
0, glycerin fatty acid ester, and beeswax, and medium chain fatty acid triglyceride is preferably used as a solvent. Suitable stabilizers also include antioxidants such as ascorbic acid, tocopherol, sodium thiosulfate and chelating agents such as sodium edetate. The additives that can be added to the composition of the present invention are not limited to those listed above, and are not particularly limited as long as they are pharmaceutically usable.

The daily dose of the composition of the present invention can be appropriately increased or decreased depending on the age, body weight, medical condition, etc. of the patient to be administered. Specific ranges of the respective components in the composition are specifically exemplified. For example, the phenothiazine antihistamine as an essential component can be administered in an amount of 0.3 to 6 mg, preferably 3 to 6 mg, of mequitazine, which is a typical medicament. Next, another essential component of the anti-inflammatory enzyme drug is 3.6 to 90 mg (titer), preferably 18 to 90 mg (titer) for lysozyme (as lysozyme chloride), and 48,000 to 90% for bromelain. 120,000 units, preferably 24,000 to 120,000 units, may be administered. If the anti-inflammatory drug of another essential component is glycyrrhizic acid, it is 4 to 200 mg, preferably 40 to 200 mg.
mg, licorice extract 0.1 to 5 g, preferably 1 to 5 g, licorice powder 0.03 to 1.5
g, preferably 0.3 to 1.5 g. When including a central stimulant, caffeine (as caffeine) is 12 to 300 mg, preferably 60 to 300 mg,
More preferably 100-300 mg, even more preferably 150-300 mg can be administered.

Next, when a sympathetic stimulant is blended as a non-essential component that can be blended, methylephedrine (l,
4.4 as dl-methylephedrine hydrochloride)
Phenylpropanolamine (as phenylpropanolamine hydrochloride) 4 to 100 mg, preferably 20 to 1 mg.
In the case of 00 mg, phenylephrine (as phenylephrine hydrochloride), 1.2 to 30 mg, preferably 6 to 30 mg, and in the case of methoxyphenamine (as methoxyphenamine hydrochloride), 6 to 150 mg, preferably 30 to 150 mg can be compounded. When two or more sympathetic stimulants are blended, the blending amount is appropriately adjusted according to the blending ratio of each. In addition, when an anticholinergic agent is compounded as a non-essential component that can be similarly compounded, first, 2.4 to 60 mg, preferably 12 to 60 mg for a funnel extract, and 2.4 to 60 mg, preferably 1 for a belladonna extract.
2-60 mg, if belladonna alkaloid is 0.0
24-0.6 mg, preferably 0.12-0.6 mg,
In the case of datsura extract, 0.024 to 0.6 mg, preferably 0.12 to 0.6 mg, respectively, can be blended.

The composition of the present invention can be formulated into various dosage forms together with its essential constituents, non-essential components that can be blended, and various additives. The dosage form is not particularly limited, but includes, for example, so-called tablets including uncoated tablets, various coated tablets, chewable tablets, and effervescent tablets, as well as soft capsules, hard capsules, powders, granules, and fine granules. Solid dosage forms such as elixirs, limonades, drinks and syrups, and other dry syrups. In order to produce these various forms of drugs (compositions), it is necessary to add the above-mentioned commonly used general additives as necessary according to a general production method of these various preparations, that is, an ordinary method. Thereby, it can be manufactured relatively easily.

[0023]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples, but the present invention is not limited to these Examples. Example 1 Soft Capsules A soft capsule having the composition shown in Table 1 below was added to about 1
000 capsules were prototyped.

[0024]

[Table 1]

Medium chain fatty acid triglyceride (manufactured by NOF Corporation,
Product name: Panathate 810) 1,182.0 g, salami beeswax (Noda wax, trade name: bleached beeswax) 6
7.0 g, polysorbate 80 (manufactured by Nikko Chemicals, trade name: Nikkor TO-10M) 167.0 g, glycerin fatty acid ester (manufactured by RIKEN Vitamin, Poem S-10)
0) 67.0 g was stirred while being heated to 70 ° C. in a conventional manner, and mixed and dissolved. In addition, about 3 paddle mixers are used for stirring.
0 rpm (manufactured by Makino Sangyo) [Scraping mixer (about 3
0rpm) or Ultra Mixer (about 1,000r)
pm)]. Next, the obtained melt was cooled to 25 ° C. while stirring at about 30 rpm using a paddle mixer (scraping mixer: about 30 rpm). Next, 13.0 g of mequitazine, 290.0 g of lysozyme chloride (potency), 154.0 g of dipotassium glycyrrhizinate, 200.0 g of dl-methylephedrine hydrochloride, and 330.0 g of anhydrous caffeine were added to the cooled mixture after cooling. According to the method, the first stirring kneading was performed at about 30 rpm and at room temperature using a paddle mixer (or a scraping mixer) until the mixture was uniformly mixed for 20 to 40 minutes. Subsequently, 120.0 g of a funnel extract was added to the obtained kneaded mixture, and the mixture was added under the same conditions as in the first stirring kneading described above.
A second stirring kneading was performed. Next, the obtained kneaded mixture is placed in an airtight container, and air in the airtight container is suctioned according to a conventional method until the pressure in the container becomes approximately 720 mmHg to defoam the kneaded mixture. , After defoaming,
260 mg of gelatin capsules were filled by a usual method to obtain 9,900 capsules of 4 oval soft capsules.

Example 2 Soft Capsules Instead of 154.0 g of dipotassium glycyrrhizinate, 100.0 g of glycyrrhizic acid and 330.0 g of anhydrous caffeine were used.
Sodium benzoate caffeine 333.3 instead of g
g, dl-methylephedrine hydrochloride 200.0 g instead of 200.0 g, phenylpropanolamine hydrochloride 181.0 g, and the weight of medium-chain fatty acid triglyceride was replaced by 1,182.0 g and 1,239 g instead of the same as in Example 1. hand,
About 1 capsule was added to the soft capsule shown in Table 2 below.
As a result of trial production of 000 capsules, soft capsules 9,
800 capsules were obtained.

[0027]

[Table 2]

Example 3 Soft Capsules 176.0 g of diammonium glycyrrhizinate in place of 154.0 g of dipotassium glycyrrhizinate, 330.0 g of caffeine in place of 330.0 g of anhydrous caffeine, d
1-methylephedrine hydrochloride 200.0 g, and phenylephrine hydrochloride 145.3 g, and the weight of medium-chain fatty acid triglyceride was 1,182.0 g instead of 1,200.0 g
Approximately 10,000 soft capsules having the formulation shown in Table 3 below were experimentally produced in the same manner as in Example 1 except that the following conditions were used. As a result, 9,850 soft capsules were obtained.

[0029]

[Table 3]

Example 4 Soft capsules dl-200.0 g of methylephedrine hydrochloride was added to 100.
0 g, newly added 166.6 g of phenylpropanolamine hydrochloride, 176.0 g of diammonium glycyrrhizinate in place of 154.0 g of dipotassium glycyrrhizinate, 330.0 g of caffeine in place of 330.0 g of anhydrous caffeine, Approximately 10,000 soft capsules having the composition shown in Table 4 below were prepared in the same manner as in Example 1 except that the weight of the medium-chain triglyceride was changed to 1,080 g instead of 1,182.0 g. As a result, 9,750 capsules of soft capsules were obtained.

[0031]

[Table 4]

Example 5 Soft Capsules In place of 13.0 g of mequitazine, 133.0 g of promethazine methylene disalicylate, and 290 g of lysozyme chloride (potency), 330.0 g of bromelain (165 × 10 5
⁶ units), 2.0 g of belladonna (total) alkaloid instead of 120.0 g of funnel extract, 500.0 g of methoxyphenamine hydrochloride instead of 200.0 g of dl-methylephedrine hydrochloride, and the weight of medium-chain fatty acid triglyceride was 1,
About 10,000 capsules of soft capsules having the composition shown in Table 5 below were trial-produced in the same manner as in Example 1 except that the amount was changed to 836.0 g instead of 182.0 g. Capsules were obtained.

[0033]

[Table 5]

Example 6 Soft Capsules Arimemazine Tartrate 1 Instead of 13.0 g Mequitadine
Instead of 7.0 g, lysozyme chloride 290.0 g (titer)
495.0 g of bromelain (247.5 × 10 ⁶single
Dat extract instead of 120.0 g of funnel extract
40.0 g, dl-methylephedrine hydrochloride 200.0
g instead of methoxyphenamine hydrochloride, 500.0 g, medium chain
Changed the weight of fatty acid triglyceride to 1,182.0 g
Except that the amount was 753.3 g.
The soft capsules shown in Table 6 below were mixed with about 1
As a result of trial production of 000 capsules, soft capsules 9,
880 capsules were obtained.

[0035]

[Table 6]

Example 7 Soft Capsules 500 weight of anhydrous caffeine was replaced with 330.0 g.
0 g, 66.0 g instead of 167.0 g of polysorbate 80, and 6 g of glycerin fatty acid ester.
Example 1 was the same as Example 1 except that 23.1 g was used instead of 7.0 g, the weight of beeswax was changed to 23.1 g instead of 67.0 g, and the weight of medium-chain fatty acid triglyceride was changed to 990.0 g instead of 1,182 g. It was prepared in the same manner, filled in 240 mg portions, and about 10,000 capsules of soft capsules having the component composition shown in Table 7 below were prototyped. As a result, 9,900 soft capsules were obtained.

[0037]

[Table 7]

Example 8 Tablets Tablets having the composition shown in Table 8 below were mixed, kneaded, compressed and dried in accordance with a conventional method to obtain a tablet of about 190 mg.
A trial production of 000 tablets was performed to obtain 9,100 tablets (mequitadine: about 1.3 mg per tablet).

[0039]

[Table 8]

Example 9 Tablets Tablets having the composition shown in Table 9 below were mixed, kneaded, compressed and dried according to a conventional method to give a tablet of about 190 mg per tablet.
A trial production of 000 tablets was performed to obtain 9,100 tablets (promethazine hydrochloride: about 4.0 mg per tablet).

[0041]

[Table 9]

Example 10 Syrup About 400 L of purified water was charged into a stirring vessel, and 85 rpm at 50 rpm.
After heating to ~ 95 ° C, 300 g of preservative methyl parahydroxybenzoate (manufactured by Wako Pure Chemical) in the heated purified water.
And 150 g of propyl paraoxybenzoate (manufactured by Aioi Kako)
Was added and dissolved at 50 rpm under a condition of 85 to 95 ° C. while mixing. Next, 300 kg of white sugar (JP 13: manufactured by Mitsui Sugar Co., Ltd.) was added to the mixture in the stirring tank, and the mixture was stirred under the same conditions as above until the white sugar was dissolved. Next, 250 kg of a 70% D-sorbitol solution (manufactured by Towa Kasei Kogyo Co., Ltd.) as a flavoring agent was added to the mixture in the stirring vessel after the addition of sucrose, and the mixture was mixed well under the same conditions as described above to prepare mixture 1. Next, the mixture 1 was cooled to 40 ° C. or lower while stirring at 50 rpm. Separately, the composition 2k of the present invention shown in Table 10 below
g was put into a stirring tank together with about 10 L of purified water, and the mixture was dissolved with stirring to prepare a solution of the active ingredient composition.

[0043]

[Table 10]

Next, the mixture 1 cooled after the addition of the D-sorbitol solution was combined with the solution of the active ingredient composition, and the mixture was stirred at 50 rpm and 40 ° C. or lower for 30 minutes.
Mixture 2 was prepared. Separately, about 20 L of purified water, 10 kg of sodium citrate (manufactured by Kanto Kagaku) and 15 kg of citric acid (manufactured by Kanto Kagaku) are put into an enamel tank, and the mixture is dissolved and mixed while stirring manually at room temperature to dissolve the flavoring agent. A liquid was prepared. Next, the mixture 2 and the flavoring solution are combined,
This was stirred at 50 rpm for 20 minutes to obtain a mixture 3. Next, 2 kg of dl-camphor (manufactured by Takasago International Corporation) was added to the mixture 3 as a flavor, and the mixture was stirred at 50 rpm for 20 minutes to obtain a mixture 4. Next, a total amount of 1,000
Purified water was added until the volume became 0 L, and the volume was adjusted.
The mixture was stirred at 0 rpm for 30 minutes to prepare a mixture 5. Finally, the mixture 5 was filtered in a cartridge type with a filtration area of about 1,000.
a membrane filter of cm ^2, 2~3kg / cm ²
At a pressure of 500 to 1,000 L / hour at a pressure of
About 1,000 L of syrup was prepared.

Example 11 Syrup Promethazine hydrochloride in place of 23.8 g of mequitazine
The same ingredients as in Example 10 were used except that 4 g and 216.2 g of funnel extract were replaced with 26.6 g of isopropamide iodide. A syrup containing the indicated composition of the present invention was prepared.

[0046]

[Table 11]

Experimental Example 1 Evaluation Experiment on Combined Effect of Mequitazine (Phenothiazine Antihistamine), Glycyrrhizinate (Anti-Inflammatory Drug), and Lysozyme Chloride (Anti-Inflammatory Drug) Experimental Procedure and Test Drug Dose Approximately 200 to 250 g body weight 1 male SD rat
Each group consisted of 8 rats, and the test drug was orally administered to these groups of rats.
One hour after the administration, each group of rats was shaved and 0.05 ml of 0.2% histamine was placed in the back skin.
, And immediately thereafter, 1 ml of 0.5% Evans blue per animal was administered via the tail vein. Next, one hour after the injection of histamine, the rat group was killed by ether anesthesia, the skin tissue piece was peeled off from the back of the killed rat group, and the blue stained site of the peeled skin tissue piece was placed on graph paper. And the area of the blue dyed part was measured. Evans blue is a dye having a property of strongly binding to albumin, and as a result, a portion where vascular permeability is enhanced is dyed blue. The test drugs in this experiment were mequitazine (5 mg / kg), lysozyme chloride (100 mg (titer) / kg), and glycyrrhizic acid (100 mg / kg).
In the case of co-administration, the dose of each test drug alone was used. FIG. 1 is a graph showing the effects of mequitazine, lysozyme chloride, and glycyrrhizic acid on the vascular hyperpermeability effect of histamine in rat skin, and the effects of the combined use of each test drug, and the same table is shown in Table 12 below.

[0048]

[Table 12]

Experimental Results As is clear from the graph of FIG. 1 and Table 12, when each test drug was administered alone, only mequitazine showed an inhibitory effect on the vascular permeability-enhancing effect of histamine, and lysozyme chloride and glycyrrhizic acid showed Although both showed some suppression tendency, no suppression effect was seen that could be said to be significantly suppressed with respect to the control. On the other hand, in the combined use of mequitazine and either lysozyme chloride or glycyrrhizic acid, or in combination of all the three drugs, a significant difference was observed in the inhibitory effect on the vascular permeability enhancing effect as compared with the case of the administration of mequitazine alone. Was done.
In particular, the strongest inhibitory effect was seen with all three combinations of the above drugs, namely mequitazine, lysozyme chloride and glycyrrhizic acid. Therefore, this experiment confirmed that the antihistamine action of mequitazine, a phenothiazine antihistamine, was enhanced by using it in combination with lysozyme, an anti-inflammatory enzyme, and / or glycyrrhizinate, an anti-inflammatory drug. It has been found that the combination use of the above drugs is extremely useful for the treatment of rhinitis.

Experimental Example 2 Glycyrrhizic acid (anti-inflammatory drug)
Experiment on the combined effect of lysozyme and lysozyme chloride (an anti-inflammatory enzyme drug) From Experimental Example 1, it was found that a formulation having strong antihistamine action, which had not been seen before, can be obtained by combining lysozyme and glycyrrhizic acid with mequitazine. It became clear. Therefore, the combined effect of glycyrrhizic acid and lysozyme chloride, that is, the combined effect of an anti-inflammatory drug and an anti-inflammatory enzyme drug, was further investigated. 1) Combined effect of glycyrrhizic acid and lysozyme chloride on the proliferation reaction of granulation The effect of the combination of glycyrrhizic acid and lysozyme chloride on the basis of the inhibitory effect on the proliferation reaction of granulation, which is a form of inflammatory reaction, is used as an index. It was investigated whether the anti-inflammatory effect of the single use of each other was mutually enhanced. Experimental procedure and dose of test drug One male SD rat weighing approximately 150 to 180 g was used.
A group of 8 animals was prepared, and a small incision was made along the midline of the back under light ether anesthesia, and a weighed and sterilized paper disc (diameter 8 mm, thickness 1.5 mm, weight 2) was placed under the right shoulder blade.
7-33 mg) and the incision was sutured. Next, the test drug (glycyrrhizic acid, lysozyme chloride, a combination of both) was orally administered once a day for 7 days once immediately after the operation was completed. Twenty-four hours after the end of the oral administration, all rats were anesthetized with ether, and the granulation tissue grown together with the paper disk was excised, and the excised granulation tissue was dried at 50 ° C. for 24 hours and weighed. The weight of the granulation tissue was determined. The dose of each test drug was 100 mg (potency) / kg / lysozyme chloride for single administration.
Day and glycyrrhizic acid is 100 mg / kg / day,
In the combined administration, the same amount as in the case of the single administration was administered.
Table 13 shows the effects of the combined use of lysozyme chloride, glycyrrhizic acid and each drug on the granulation growth reaction of rats, and FIG. 2 shows a graph schematically showing the results.

[0051]

[Table 13]

Experimental Results As is evident from the graph of FIG. 2 and Table 13 shown above, the inhibition rate of the group administered lysozyme chloride and glycyrrhizic acid alone with respect to the control group was 21.7, respectively.
% And 14.1%, no significant difference was observed from the control, but the suppression rate of the combined administration group was 29.0%, which was significantly different from the control.

2) Combined effect of glycyrrhizic acid (anti-inflammatory drug) and lysozyme chloride (anti-inflammatory enzyme drug) on mucus dissolving action Combined effect of glycyrrhizic acid and lysozyme chloride on mucus dissolving action resulting in improvement of nasal discharge symptoms which is the action of lysozyme Was examined. Experimental Procedures and Concentration of Test Drug Nasal secretions were collected from five patients with acute rhinitis or allergic rhinitis, and the nasal secretions of each of the collected patients were dispensed at a rate of 0.3 ml into each of four test tubes. In addition, physiological saline (hereinafter, abbreviated as "raw food") of the test drug (each of lysozyme chloride and glycyrrhizic acid alone or in combination of both).
Three kinds of solutions and a control of only raw food were prepared. The concentration of the prepared saline solution of the test drug was 1 for each single substance.
%, And a solution of the concomitant drug was also prepared so that each of the test drugs in the saline was 1%. Next, into the dispensed test tubes, 3.0 ml each of three kinds of test drug solutions and one kind of control were added, and this was used as a reaction solution.
Incubated at 7 ° C. At 1, 3, 6, 12, and 24 hours after the start of the incubation, the test tube was shaken and the state of homogenization of the reaction solution was visually observed.
In addition, the determination regarding dissolution of nasal discharge was determined to be complete dissolution of nasal discharge when the reaction solution became substantially homogeneous. Table 14 shows the degree of dissolving effect of nasal secretion at each measurement time point when lysozyme chloride and glycyrrhizic acid alone or in combination were added.

[0054]

[Table 14]

Experimental Results As is clear from Table 14, in the control raw food treatment example (control) and the glycyrrhizic acid alone treatment example, all the examples (5 examples) showed that 24 hours after the start of the incubation. The reaction solution was hardly homogenized, confirming that glycyrrhizic acid alone had no mucolytic effect. On the other hand, in the case of lysozyme chloride treatment alone, the reaction solution was homogenized over time, and the homogenization was performed by 3 hours, 6 hours, and 12 hours after the start of incubation. One case was found to be uniform. In addition, in the remaining one case, although it was dissolved to some extent by 24 hours, it did not reach complete dissolution. In addition, in the example of the combined treatment of glycyrrhizic acid and lysozyme chloride, three out of five cases homogenized by 3 hours and 6 hours from the start of the incubation, and all the remaining cases homogenized by 12 hours, Completely dissolved.
These experimental results confirmed that the combination use of glycyrrhizic acid and lysozyme chloride, that is, the combination use of an anti-inflammatory drug and an anti-inflammatory enzyme enhances the mucolytic effect of lysozyme chloride, an anti-inflammatory enzyme.

Experimental Example 3 Evaluation Experiment on Head Weight Removal Effect From Experimental Examples 1 and 2, nasal inflammation was reduced by using lysozyme (an anti-inflammatory enzyme drug) and glycyrrhizic acid (an anti-inflammatory drug) together with mequitazine (a phenothiazine antihistamine). Significant improvement was found. Therefore, a sensory test was performed to examine the effect of the composition of the present invention on suppressing head weight and that the effect was further enhanced by adding caffeine (a central stimulant). Experimental procedure and dose of test drug As a daily dose, mequitazine 4 mg, lysozyme chloride 90
mg (titer), 46 mg of glycyrrhizic acid, and caffeine anhydride were added in the amounts shown in Table 15 to prepare Test Drug 1, 2, 3, 4, or 5, which is a composition of the present invention. In addition, as comparative examples, a combination example of mequitazine and lysozyme chloride alone and a combination example of mequitazine and glycyrrhizic acid alone were prepared, and were referred to as Comparative Examples 1 and 2, respectively. Next, these test drugs and Comparative Examples 1 and 2 were orally administered to five adult male and female rhinitis patients to conduct a sensory test. Experimental Results As is clear from the results shown in Table 15, Test Drug 1 in which mequitazine was mixed with lysozyme chloride and glycyrrhizic acid was used in Comparative Examples 1 and 2 in which only one of lysozyme chloride and glycyrrhizic acid was mixed with mequitazine. Compared with any of the above, it was confirmed that the head feeling was strongly improved. In addition, it was clarified that such a head weight removing effect was further enhanced by adding caffeine in an amount of 60 to 300 mg as compared with test drug 1. In addition, even when glycyrrhizates such as bromelain as an anti-inflammatory enzyme drug instead of lysozyme and glycyrrhizic acid as an anti-inflammatory drug were replaced with dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, and diammonium glycyrrhizinate, the above test was also conducted. As in the case of Drug 1, an excellent head weight removing effect was observed. Also, when caffeine or sodium benzoate is added as a central stimulant instead of anhydrous caffeine, the weight of the head is within the range of 60 to 300 mg as in the case of the aforementioned test drugs 3, 4 or 5. The enhancement of the removal effect was confirmed.

[0057]

[Table 15]

EXPERIMENTAL EXAMPLE 4 Evaluation Experiment on Drowsiness Reducing Effect From Experimental Examples 1, 2 and 3, rhinitis was obtained by using lysozyme (an anti-inflammatory enzyme drug) and glycyrrhizic acid (an anti-inflammatory drug) together with mequitazine (a phenothiazine antihistamine). It was found that the symptoms including head weight improved overall. Thus, in this experiment, when caffeine (a central stimulant) was added to the composition of the present invention as in Test Drugs 2, 3, 4, or 5 of Experimental Example 3, the effect of further reducing the side effects of drowsiness was examined. And a sensory test. Experimental procedure and dose of test drug As a daily dose, mequitazine 4 mg, lysozyme chloride 90
mg (titer), 46 mg of glycyrrhizic acid, and caffeine anhydride were added in the amounts shown in Table 16 to prepare Test Drugs 6, 7, 8, 9, or 10, which were compositions of the present invention.
As the test drug containing only mequitazine, lysozyme chloride and glycyrrhizic acid, test drug 1 of Experimental Example 3 was used. In addition, as a control, 12 mg of chlorpheniramine maleate was used instead of the phenothiazine-based mequitazine as an antihistamine, and 150 mg of anhydrous caffeine was added thereto.
Was prepared as Comparative Example 3. These test drugs and Comparative Example 3 were orally administered to five adult male and female rhinitis patients to conduct a sensory test. Experimental Results As is clear from the results shown in Table 16, Test Drug 1 and Test Drug 6, 7, 8, 9 or 10 containing mequitazine were mixed.
As compared with Comparative Example 3 in which the conventional antihistamine drug chlorpheniramine maleate was blended, the side effect of drowsiness was reduced, and the test drug 6 in which anhydrous caffeine was used in combination,
7, 8, 9 or 10 was found to further enhance its sleepiness reducing effect. Further, the effect of the reduction is remarkable in the case of Test Drugs 6, 7, 8, 9 or 10 in which the content of anhydrous caffeine is in the range of 12 to 300 mg, and in Test Drugs 8 and 9 in which the content of anhydrous caffeine is 100 to 300 mg. Or 10
It became clear that the case became more remarkable. Further, this effect is most remarkable in the case of Test Drug 9 or 10 in which the blending amount is 150 to 300 mg. Also, when caffeine or sodium benzoate caffeine is added instead of anhydrous caffeine as a central stimulant, 12 to 3 as in the case of the aforementioned test drugs 6, 7, 8, 9 or 10
The effect is remarkable in the range of 00 mg, more remarkable in the range of 100 to 300 mg as in the case of the test drug 8, 9 or 10, and is 150 to 300 m in the same manner as in the case of the test drug 9 or 10.
It was confirmed to be most remarkable in the range of g.

[0059]

[Table 16]

[0060]

EFFECT OF THE INVENTION In the composition for treating rhinitis of the present invention, a phenothiazine antihistamine, an anti-inflammatory enzyme and an anti-inflammatory drug are combined together to form an anti-histamine effect of the phenothiazine anti-histamine and an anti-inflammatory enzyme. The mucolytic action related to the anti-inflammatory action and the anti-inflammatory action of the anti-inflammatory drug are each enhanced. Therefore, when the composition of the present invention is administered to a rhinitis patient as a single preparation, the effect of the combination of the above components is enhanced, and the rhinitis state of the patient is totally and significantly improved without the side effect of drowsiness. In addition, the combination of mequitazine as a phenothiazine antihistamine, an anti-inflammatory enzyme drug (such as lysozyme chloride), and the anti-inflammatory drug (glycyrrhizic acid and salts thereof) used in the present invention has the strongest improvement effect on rhinitis. ,
Most preferably, this combination is selected. In the composition for treating rhinitis of the present invention, when a central stimulant such as caffeine is blended in addition to a phenothiazine antihistamine, an anti-inflammatory enzyme and an anti-inflammatory drug, the above-mentioned three kinds of components can be used. In addition to the enhancing effect, it further reduces side effects such as drowsiness and enhances the effect of suppressing the feeling of heavy head associated with rhinitis. Therefore, when the composition according to the present invention containing a central stimulant is administered to a rhinitis patient, side effects such as drowsiness for the rhinitis patient are strongly suppressed and the weight of the head is also suppressed, so that the discomfort of the rhinitis patient is greatly reduced. When the amount of the central stimulant is 12 mg to 300 mg per day, the effect of the central stimulant is remarkably exhibited. Therefore, it is preferable to add the central stimulant in such a range.

[Brief description of the drawings]

FIG. 1 is a bar graph showing the effects of mequitazine, lysozyme chloride, and glycyrrhizic acid on the vascular hyperpermeability effect of histamine in rat skin.

FIG. 2 is a bar graph showing the combined effect of glycyrrhizic acid, which is an anti-inflammatory drug, and lysozyme chloride, which is an anti-inflammatory enzyme drug, as an index of the inhibitory effect on the proliferation reaction of granulation, which is a form of inflammatory response.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 38/48 ABM A61K 37/547 ABM

Claims (7)

[Claims] 1. A composition for treating rhinitis, comprising a phenothiazine antihistamine, an anti-inflammatory enzyme drug and an anti-inflammatory drug. 2. The composition for treating rhinitis according to claim 1, wherein the phenothiazine antihistamine is selected from mequitazine, promethazine, alimemazine, isotipendil or a salt thereof. 3. The composition for treating rhinitis according to claim 2, wherein the phenothiazine antihistamine is mequitazine or promethazine methylene disalicylate. 4. The anti-inflammatory enzyme drug is lysozyme, bromelain, trypsin, α-chymotrypsin, semi-alkaline proteinase (seaprose S-AP), proteinase, serrapepteptidase (serrapeptase), streptokinase, streptodornase, bromhexine or salts thereof. The composition for treating rhinitis according to any one of claims 1 to 3, which is selected from the group consisting of: 5. The composition for treating rhinitis according to claim 4, wherein the anti-inflammatory enzyme drug is selected from lysozyme, bromelain and salts thereof. 6. The composition for treating rhinitis according to claim 1, which comprises a central stimulant. 7. The compounding amount of the central stimulant is 12 per day.
The composition for treating rhinitis according to claim 6, wherein the amount is from mg to 300 mg.