JP6087988B2 - Composition for inhibiting nasal secretion - Google Patents

Description

  The present invention relates to a composition for suppressing nasal secretion, and particularly to a composition for suppressing nasal secretion containing an antihistamine.

Rhinitis is an inflammation of the nasal mucosa and shows various related symptoms depending on the etiology. Such associated symptoms include nasal discharge (nasal discharge, runny nose), nasal congestion, sneezing, itching, nasal congestion, nasal bleeding, and nasal mucosal atrophy or sclerosis.
In particular, nasal discharge, nasal congestion, and sneezing are typical symptoms in allergic rhinitis, and allergic rhinitis is roughly classified into the following two types according to these typical symptoms. That is, a sneezing / nasal nose type in which sneezing and nasal discharge are core symptoms, and a nasal congestion type in which nasal congestion is a core symptom. Antihistamines are commonly used for the former (sneezing, nasal congestion), and sympathomimetic drugs such as pseudoephedrine are commonly used for the latter (nasal congestion) (see, for example, Non-Patent Document 1).
For example, Patent Document 1 includes a phenothiazine antihistamine, an anti-inflammatory enzyme, and an anti-inflammatory agent as a composition for treating rhinitis that relieves nasal inflammation such as nasal discharge, containing an antihistamine. A composition for treating rhinitis is disclosed.
On the other hand, pseudoephedrine, a sympathomimetic agent, is not known to have a nasal secretion inhibitory effect, and it is not known what effect pseudoephedrine has on the nasal secretion inhibitory effect of mequitazine.

JP 10-158193 A

“OTC drugs and self-medication—finding the right drug from symptoms”, Kanbara Publishing, 2009, p. 79

  In general, antihistamines are known to have side effects such as drowsiness, and therefore, there is a demand for the development of a medicine that can exert an excellent effect on suppressing nasal secretion without increasing the dose of antihistamines. .

As a result of intensive studies to solve the above problems, the present invention selects mequitazine, which is an antihistamine, as a nasal secretion inhibitor, and uses it in combination with pseudoephedrine, which is a sympathomimetic drug, or a salt thereof. The present inventors have found that the suppression of nasal secretion of mequitazine can be remarkably enhanced, and the present invention has been completed.
That is, the present invention
[1]
A composition for inhibiting nasal secretion containing mequitazine and pseudoephedrine or a salt thereof;
[2]
The composition for inhibiting nasal secretion according to the above [1], wherein the pseudoephedrine or a salt thereof enhances the nasal secretion inhibiting action of mequitazine;
[3]
The composition for suppressing nasal secretion according to the above [1] or [2], wherein the pseudoephedrine or a salt thereof is pseudoephedrine hydrochloride;
[4]
The composition for suppressing nasal secretion according to any one of [1] to [3] above, wherein mequitazine is contained in an amount of 3 to 7 mg as an adult daily dose;
[5]
The composition for suppressing nasal secretion according to any one of [1] to [4] above, containing pseudoephedrine or a salt thereof as an adult daily dose of 35 to 180 mg;
[6]
The composition for inhibiting nasal secretion according to any one of [1] to [5] above, containing 5 to 45 parts by weight of pseudoephedrine or a salt thereof with respect to 1 part by weight of mequitazine;
[7]
The composition for suppressing nasal discharge according to any one of [1] to [6], which is an orally administered composition;
[8]
The composition for suppressing nasal secretion according to any one of [1] to [7], which is a liquid preparation;
[9]
A soft capsule obtained by filling the composition for suppressing nasal secretion according to [8] in a soft capsule; and [10]
The present invention provides a composition for enhancing nasal secretion inhibition action of mequitazine, which contains pseudoephedrine or a salt thereof in combination with mequitazine.

  The composition with enhanced nasal secretion suppression effect of the present invention can exhibit an effect excellent in suppressing nasal secretion while maintaining the dose of the antihistamine within a highly safe range. Therefore, it is possible to effectively suppress the secretion of nasal discharge without increasing drowsiness etc., which is a side effect of antihistamines.

FIG. 1 is a graph showing the nasal secretion inhibiting action of the composition for inhibiting nasal secretion of the present invention.

The composition for suppressing nasal secretion of the present invention contains mequitazine and pseudoephedrine or a salt thereof.
Mequitazine is an antiallergic agent known as a nasal secretion inhibitor and also has an antihistamine action. On the other hand, pseudoephedrine is a known sympathomimetic drug. Each of them can be obtained as a commercial product or can be produced by a known production method.

  In the composition for inhibiting nasal secretion of the present invention, pseudoephedrine or a salt thereof enhances the nasal secretion inhibiting action of mequitazine (in other words, acts as an enhancer of the nasal secretion inhibiting action of mequitazine). Furthermore, known effects inherent to pseudoephedrine or salts thereof, such as nasal congestion, can also be exhibited.

  The salt of pseudoephedrine is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, oxalate, maleate, fumaric acid A salt etc. can be mentioned, Especially, hydrochloride is especially preferable.

The dose (dosage) of mequitazine by the composition for inhibiting nasal secretion of the present invention may vary depending on the patient's condition (body weight, age, symptoms, physical condition, etc.) and the dosage form of the composition for inhibiting nasal secretion of the present invention. However, from the viewpoint of exerting a sufficient nasal secretion suppression effect, a larger amount tends to be preferable, while from the viewpoint of suppressing the occurrence of side effects, a smaller amount tends to be preferable. Usually, when orally administered to an adult weighing about 60 kg, preferably 3 to 7 mg / day, more preferably 3.5 to 6 mg / day, still more preferably 3.5 to 5 mg / day, and particularly preferably about 4 mg / day. Day.
Therefore, the composition for suppressing nasal secretion of the present invention is preferably 3-7 mg, more preferably 3.5-6 mg, still more preferably 3.5-5 mg, particularly preferably mequitazine as a daily dose. Contains 4 mg.

The dose (dosage) of pseudoephedrine or a salt thereof by the composition for inhibiting nasal secretion of the present invention is the patient's condition (weight, age, symptom, physical condition, etc.), the dosage form of the composition for inhibiting nasal secretion of the present invention, etc. However, from the viewpoint of sufficiently enhancing the nasal secretion suppression effect of mequitazine, a larger amount tends to be preferable, while from the viewpoint of suppressing the occurrence of side effects, a smaller amount tends to be preferable. It is in. Usually, when orally administered to an adult weighing approximately 60 kg, preferably 35 to 180 mg / day, more preferably 35 to 130 mg / day, still more preferably 50 to 100 mg / day, particularly preferably 65 to 85 mg / day. It is.
Therefore, the composition for suppressing nasal secretion of the present invention preferably has pseudoephedrine or a salt thereof as a daily dose, preferably 35 to 180 mg, more preferably 35 to 130 mg, still more preferably 50 to 100 mg, Particularly preferably, it contains 65 to 85 mg.

  The composition for inhibiting nasal secretion of the present invention can be administered usually 1 to 6 times a day, preferably 1 to 3 times a day. Therefore, the composition for inhibiting nasal secretion of the present invention for a single administration preferably contains the above-mentioned daily dose divided by the number of administrations per day. In addition, since the composition for nasal secretion secretion of this invention also has the sustainability of an effect, even if it is once or twice daily administration, a high effect continues.

  The composition for suppressing nasal secretion of the present invention comprises pseudoephedrine or a salt thereof with respect to 1 part by weight of mequitazine from the viewpoint of sufficiently enhancing the nasal secretion suppression action of mequitazine, from the viewpoint of cost effectiveness and side effects. Preferably, it contains 5 to 45 parts by weight, more preferably 5 to 35 parts by weight, still more preferably 8 to 35 parts by weight, particularly preferably 10 to 30 parts by weight, and still more preferably 15 to 25 parts by weight.

The composition for inhibiting nasal secretion of the present invention has a high nasal secretion inhibiting action and a low side effect (eg, drowsiness etc.) as a daily dose,
It is preferable to contain 3 to 7 mg of mequitazine and 35 to 180 mg of pseudoephedrine or a salt thereof,
More preferably, it contains 3.5 to 6 mg of mequitazine and 35 to 130 mg of pseudoephedrine or a salt thereof,
More preferably, it contains 3.5 to 5 mg of mequitazine and 50 to 100 mg of pseudoephedrine or a salt thereof,
It is particularly preferable that 4 mg of mequitazine and 65 to 85 mg of pseudoephedrine or a salt thereof are contained.

The composition for inhibiting nasal secretion of the present invention may contain other physiologically active ingredients in addition to mequitazine and pseudoephedrine or a salt thereof, if desired.
Examples of such physiologically active ingredients include:
(1) Parasympathetic nerve blocking components (for example, atropine, scopolamine, belladonna total alkaloids, iodopropamide, datsura extract, funnel extract, etc.),
(2) Other sympathomimetic components other than pseudoephedrine (eg phenylephrine, phenylpropanolamine, ephedrine, ethylephrine, methoxamine, middolin, methoxyphenamine),
(3) Anti-inflammatory enzymes (eg lysozyme, serrapeptase, bromelain, pronase)
(4) herbal medicines and herbal medicine-derived components (eg, salamander, licorice, carrot, mah, keihi, kei-gai, saishin, shin-i, nantenjitsu, ohhi, juniper, zenko, kyoto, shazenshi, gooh, gadju, juniper, gentian, gentian , Fennel, Onji, Awaku, Auren, Chiksetsuninjin, Chimpi, Clove, Senega, Shazenso, Shajin, Glycyrrhizic acid, etc.),
(5) xanthine derivatives (for example, caffeine, theophylline, aminophylline, theobromine, diprofeline, proxyphylline, pentoxyphylline),
(6) antipyretic analgesic ingredients (eg, aspirin, aspirin aluminum, acetaminophen, etenzamide, sazapyrine, salicylamide, sodium salicylate, lactylphenetidine, ibuprofen, ketoprofen, etc.)
(7) Antitussive ingredients (eg, achloramide, cloperastine, pentoxyberine (Carbetapentane), tipepidine, dibutate, dextromethorphan, codeine, dihydrocodeine, noscapine, etc.)
(8) expectorants (eg, potassium guaiacol sulfonate, guaifenesin, etc.),
(9) vitamins (for example, vitamins A [for example, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, etc.), vitamin B [for example, thiamine, thiamine disulfide, discetiamine, octothiamine, chicotiamine, bisive Thiamine, bisbenchamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folate, tetrahydrofolate, dihydrofolate, nicotine Acid, nicotinamide, nicotinyl alcohol, pantothenic acid, panthenol, biotin, choline, inositol, etc.], vitamin C [eg ascorbine , Erythorbic acid, or derivatives thereof], vitamin Ds [eg, ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotachysterol, etc.], vitamins [eg, tocopherol and its derivatives , Ubiquinone derivatives, etc.], other vitamins [eg hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, etc.], and
(10) Mucosal protective components (for example, aminoacetic acid, dry aluminum hydroxide gel, aluminum hydroxy-mucosal protective agent such as dihydroxyaluminum / aminoacetate; magnesium aluminate metasilicate, aluminum silicate, hydrotalcite, magnesium aluminate hydroxide) , Aluminum hydroxide gel, Aluminum hydroxide / sodium bicarbonate coprecipitation product, Aluminum hydroxide / magnesium carbonate mixed dry gel, Aluminum hydroxide / Calcium carbonate / magnesium carbonate coprecipitation product, Magnesium carbonate, Magnesium oxide, Magnesium-based mucosal protective agents such as coprecipitation products of magnesium hydroxide, magnesium silicate, magnesium hydroxide and potassium aluminum sulfate)
Etc.
These physiologically active ingredients may be free forms or salts.

  The composition for suppressing nasal secretion of the present invention is preferably an orally administered composition. The dosage form is not particularly limited. For example, tablets (including intraoral quick disintegrating tablets, chewable tablets, effervescent tablets, jelly-like drops, etc.), lozenges, granules, pills, powders (fine Granules), capsules (including hard capsules and soft capsules), solutions, suspensions, emulsions, syrups (including dry syrups), elixirs, limonades, tinctures, extracts, jelly Examples include agents, gels, liposomes and the like. Among these, a liquid preparation containing mequitazine and pseudoephedrine or a salt thereof is preferable from the viewpoints of further exerting the effects of the present invention and rapid efficacy. A liquid preparation is a preparation in which a drug or additive is dissolved, suspended, or dispersed in a liquid solvent or base (whether aqueous or oily), and the drug or additive is completely Even if it melt | dissolves, it does not need to melt | dissolve and a uniformity is not ask | required. That is, the liquid preparation may be, for example, a slurry. Liquid preparations may be used as they are as syrups, solutions, suspensions, etc., and as capsules and the like, for example, they are encapsulated with a capsule base and used as soft capsules and hard capsules. Good. In particular, soft capsules are more preferable because the effects of the present invention are high, the taste of the preparation can be masked, and the dosage is easy.

When the composition for inhibiting nasal secretion of the present invention is a liquid preparation, the content of pseudoephedrine or a salt thereof in the preparation is usually 0.1 to 30 w / w%, preferably 0.5 to 25 w / w. %, And more preferably 0.5 to 20 w / w%. The content of mequitazine is usually 0.01 to 3 w / w%, preferably 0.02 to 2 w / w%, more preferably 0.03 to 1 w / w%.
When the composition for inhibiting nasal secretion of the present invention is a liquid preparation, from the viewpoint of high nasal secretion inhibiting action and low side effects (eg, sleepiness etc.),
It is preferable that the content of mequitazine in the preparation is 0.01 to 3 w / w%, and the content of pseudoephedrine or a salt thereof is 0.1 to 30 w / w%,
More preferably, the content of mequitazine is 0.02 to 2 w / w%, and the content of pseudoephedrine or a salt thereof is 0.5 to 25 w / w%,
More preferably, the content of mequitazine is 0.03 to 1 w / w%, and the content of pseudoephedrine or a salt thereof is 0.5 to 20 w / w%.
As described above, it is preferable to fill such a liquid preparation into a soft capsule or the like and use it as a soft capsule or the like.
When the composition for suppressing nasal secretion of the present invention is a tablet, the content of pseudoephedrine or a salt thereof in the tablet is usually 0.1 to 30 w / w%, preferably 0.5 to 25 w / w%. More preferably, it is 0.5-20 w / w%. The content of mequitazine is usually 0.01 to 3 w / w%, preferably 0.02 to 2 w / w%, more preferably 0.03 to 1 w / w%.
When the composition for inhibiting nasal secretion of the present invention is a tablet, from the viewpoint of high nasal secretion inhibiting action and low side effects (eg, sleepiness etc.),
It is preferable that the content of mequitazine in the tablet is 0.01 to 3 w / w%, and the content of pseudoephedrine or a salt thereof is 0.1 to 30 w / w%,
More preferably, the content of mequitazine is 0.02 to 2 w / w%, and the content of pseudoephedrine or a salt thereof is 0.5 to 25 w / w%,
More preferably, the content of mequitazine is 0.03 to 1 w / w%, and the content of pseudoephedrine or a salt thereof is 0.5 to 20 w / w%.
When the composition for inhibiting nasal secretion of the present invention is a hard capsule, the content of pseudoephedrine or a salt thereof in the content for the hard capsule not containing the capsule skin is usually 0.1 to 30 w / w. %, Preferably 0.5 to 25 w / w%, more preferably 0.5 to 20 w / w%. The content of mequitazine is usually 0.01 to 3 w / w%, preferably 0.02 to 2 w / w%, more preferably 0.03 to 1 w / w%.
When the composition for inhibiting nasal secretion of the present invention is a hard capsule, from the viewpoint of high nasal secretion inhibiting action and low side effects (eg, sleepiness etc.),
The content of mequitazine in the content for the hard capsule not containing a capsule skin is 0.01 to 3 w / w%, and the content of pseudoephedrine or a salt thereof is 0.1 to 30 w / w%. Preferably,
More preferably, the content of mequitazine is 0.02 to 2 w / w%, and the content of pseudoephedrine or a salt thereof is 0.5 to 25 w / w%,
More preferably, the content of mequitazine is 0.03 to 1 w / w%, and the content of pseudoephedrine or a salt thereof is 0.5 to 20 w / w%.

  Moreover, the composition for nasal secretion secretion of this invention may contain a suitable additive according to the dosage form. As such additives, in the case of solid compositions (for example, tablets, hard capsules, powders, etc.), binders (for example, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, Polyvinyl alcohol, etc.), excipients (eg, sucrose, lactose, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (eg, sucrose fatty acid ester, magnesium stearate, talc, etc.), disintegration Agents (eg, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, etc.), foaming agents (eg, sodium bicarbonate), fluidizing agents (eg, sodium aluminate metasilicate, light anhydrous silica And the like) and the like. Additives in the case of liquid preparations (eg, syrups, solutions, suspensions, soft capsule contents, hard capsule contents, etc.) include oily bases (eg, olive oil, corn oil) Vegetable oils such as soybean oil, sesame oil, cottonseed oil; medium chain fatty acid triglycerides, etc., aqueous bases (eg, Macrogol 400, water), gel bases (eg, carboxyvinyl polymer, gums, etc.), surfactants (eg For example, polysorbate 80, hydrogenated castor oil, glycerin fatty acid ester, sorbitan sesquioleate, etc.), suspending agent (eg, white beeswax and various surfactants, gum arabic, gum arabic powder, xanthan gum, soybean lecithin, etc.), dispersion Agents, emulsifiers, stabilizers, buffers, solubilizers, pH adjusters, preservatives (preservatives) and the like.In any case, an antioxidant, a sweetener, a sour agent, a colorant, a fragrance, a flavoring agent, and the like may be appropriately added to these compositions.

  The composition for inhibiting nasal secretion of the present invention is obtained by formulating mequitazine, pseudoephedrine or a salt thereof, and other physiologically active ingredients and additives used as necessary according to the dosage form by conventional methods. be able to.

  The composition for suppressing nasal secretion of the present invention is considered to be applicable to all pathological conditions involving nasal discharge as a symptom. In particular, acute rhinitis and sinusitis caused by viruses and bacterial infections, mites and houses are considered. Highly effective against allergic rhinitis (including perennial allergic rhinitis and seasonal allergic rhinitis (such as nasal inflammation symptoms of hay fever)) caused by allergens such as dust and pollen. The composition for inhibiting nasal secretion of the present invention is particularly useful for inhibiting nasal secretion in patients with allergic rhinitis or for inhibiting nasal secretion associated with allergic rhinitis. The composition for enhancing the nasal secretion inhibiting action of mequitazine according to the present invention is particularly for enhancing the nasal secretion inhibiting action by mequitazine for allergic rhinitis patients, or for enhancing the nasal secretion inhibiting action by mequitazine of nasal discharge associated with allergic rhinitis. Useful as.

  The composition for inhibiting nasal secretion of the present invention may be a single formulation obtained by simultaneously formulating mequitazine and pseudoephedrine or a salt thereof, or a combination of two types of formulations obtained separately. May be. In either case, the effects of the present invention can be achieved.

The composition for enhancing the nasal secretion inhibitory action of mequitazine of the present invention contains pseudoephedrine or a salt thereof in combination with mequitazine.
The composition for enhancement is a composition used for enhancing the nasal secretion suppression action of mequitazine. The enhancing composition may be a formulation that does not contain mequitazine and is administered in combination with a formulation that contains mequitazine, or
Along with pseudoephedrine or a salt thereof, it may contain mequitazine which is a target for enhancing its action.
The enhancing composition may be a composition used for producing the composition for suppressing nasal secretion of the present invention, and may be a composition not containing mequitazine.
In either case, the effects of the present invention can be achieved.
The composition and dosage form (for example, pseudoephedrine or its salt content) of the composition for enhancing the nasal secretion inhibiting action of mequitazine of the present invention are set according to the nasal secretion inhibiting composition of the present invention described above. do it.
The composition for enhancing the nasal secretion inhibitory action of mequitazine according to the present invention comprises, according to the dosage form, pseudoephedrine or a salt thereof, and mequitazine, other physiologically active ingredients, and additives, which are optionally used, as usual. It can be obtained by formulation by a method.

  The composition for inhibiting nasal secretion and the composition for enhancing nasal secretion inhibiting action of mequitazine according to the present invention can be administered to a patient by a conventional administration method depending on the dosage form. The composition for enhancing the nasal secretion suppression effect of mequitazine is also used for the production of a composition for suppressing nasal secretion containing mequitazine and enhancing the action of this mequitazine according to a conventional formulation method. be able to.

  Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

Example 1 (nasal mucosa pigment leakage test)
(1) Preparation of rat experimental allergic rhinitis model EA (Egg albumin, egg albumin) / inactivated pertussis suspension was subcutaneously administered to the back of the rat and sensitized for the first time. On the 5th day of sensitization, 0.1% EA / physiological saline was intramuscularly administered to the thighs of the hind limbs for additional sensitization. On the 9th day after sensitization after fasting overnight, nasal mucosa pigment leakage test was performed for each of the following groups according to the following protocol.
[Group setting]
(a) VEH group: 3% gum arabic aqueous solution 10 ml / kg orally.
(b) MEQ group: 4 mg of mequitazine was suspended in 10 ml of 3% aqueous gum arabic solution to give a liquid preparation, which was orally administered at 10 ml / kg.
(c) PSE group: pseudoephedrine hydrochloride (d-pseudoephedrine hydrochloride) 75 mg was dissolved in 10 ml of 3% aqueous solution of gum arabic to obtain a liquid preparation, which was orally administered at 10 ml / kg.
(d) MEQ + PSE first group: 4 mg of mequitazine and 75 mg of pseudoephedrine hydrochloride (d-pseudoephedrine hydrochloride) were dissolved / suspended in 10 ml of 3% aqueous gum arabic solution to give a liquid preparation, which was orally administered at 10 ml / kg.
(2) Examination of nasal mucosal vascular permeability enhancing action Each test substance or control substance was forcibly orally administered 1 hour before induction. Under anesthesia, the airway of the animal was incised, a tracheal cannula was inserted into the lung side of the incised trachea, and a tube attached to a syringe pump was inserted into the nasal side. A physiological saline solution at about 37 ° C. was perfused into the nasal cavity, and a fluid flowing out from the nasal snout was collected by the following procedure.
4% Brilliant blue (brilliant blue) / physiological saline was administered from the tail vein, and physiological saline was perfused (collected) for 10 minutes. Allergy was induced by perfusion (collection) of 1% EA / physiological saline for 10 minutes, and then physiological saline was perfused (collection) for 30 minutes. Each collected perfusate was centrifuged, and the amount of Brilliant blue in the supernatant was colorimetrically determined at a wavelength of 620 nm using a spectrophotometer.
The increase in leakage dye was calculated as an index of nasal mucosal vascular permeability enhancement by antigen-antibody reaction, and the dye leakage suppression rate was calculated by the following formula as an index of nasal secretion suppression action.
[Formula 1]
Leakage dye increase (μg) =
(Amount of leaking dye for 40 minutes after the start of antigen perfusion) − (Amount of leaked dye for 10 minutes before the start of antigen perfusion) × 4
[Formula 2]
Dye leakage inhibition rate (%) =
(1-Increased amount of leakage pigment in each test substance administration group / Increase amount of leakage pigment in VEH group) x 100
(3) Test results The group administered mequitazine (MEQ group) showed only 19% nasal secretion suppression effect in the group administered Pseudoephedrine hydrochloride (PSE group) only about 13%, but mequitazine and pseudoephedrine hydrochloride were administered. In the group (MEQ + PSE first group), the nasal secretion suppression action increased to about 64%, and it was shown that the nasal secretion suppression action was synergistically improved by combining mequitazine and pseudoephedrine hydrochloride. The results are shown in FIG. In addition, the duration of the nasal secretion suppression action is more than twice as long in the MEQ + PSE group 1 as compared to the MEQ group and the PSE group. It was found that the time was extended.

Example 2 (nasal mucosa pigment leakage test)
(1) Test In the same manner as in Example 1, a nasal mucosa pigment leakage test was performed for each of the following groups.
[Group setting]
(a) VEH group: 3% gum arabic aqueous solution 10 ml / kg, orally administered.
(b) MEQ + PSE second group: mequitazine 6 mg, pseudoephedrine hydrochloride (d-pseudoephedrine hydrochloride) 60 mg was dissolved / suspended in 10 ml of 3% aqueous gum arabic solution to give a liquid preparation, which was orally administered at 10 ml / kg.
(2) Test results The group (MEQ + PSE second group) administered with 6 mg of mequitazine and 60 mg of pseudoephedrine hydrochloride showed a pigment leakage inhibition rate of about 42%. Comparing with the group (MEQ + PSE group 1) administered with 4 mg of mequitazine and 75 mg of pseudoephedrine hydrochloride in Example 1, in Example 1, the amount of mequitazine having an inhibitory action on nasal secretion was increased from 6 mg to 4 mg in Example 2. In spite of this decrease, it was confirmed that a higher nasal secretion suppression effect was obtained. From this, it can be seen that a higher nasal secretion suppression effect can be obtained by increasing the amount of pseudoephedrine or a salt thereof from 60 mg to 75 mg and making mequitazine and pseudoephedrine or a salt thereof have a specific weight ratio.

Example 3 (nasal secretion suppression test by human)
Soft capsules filled with a liquid preparation (slurry) containing 4 mg mequitazine and 75 mg pseudoephedrine hydrochloride (d-pseudoephedrine hydrochloride) per day for 22 adult men and women with nasal inflammation accompanied by runny nose in hay fever patients Each capsule was dosed with 1.33 mg of mequitazine and 25 mg of pseudoephedrine hydrochloride (d-ephedephrine hydrochloride), taking one capsule three times a day). The inhibitory effect of runny nose was evaluated according to the following 5 levels. The relationship between the evaluation and the scores is as follows: “effective” = 5 points, “effective” = 4 points, “somewhat effective” = 3 points, “not so effective” = 2 points, “not effective” = 1 It was a point. As a result of the evaluation, the average score of 20 people was 4.1 points, and 95.5% of the total respondents answered “Well effective”, “Effective” or “Slightly effective”. A high nasal secretion suppression effect was confirmed.
In the test, sleepiness was further evaluated in the following four stages. The relationship between the score and the score was “I became sleepy” = 0 points, “Slightly sleepy” = 1 point, “Slightly difficult to sleep” = 2 points, and “I did not get sleepy” = 3 points. As a result of the evaluation, the average score of 20 people was 2.8 points, and 92.3% of the total respondents answered either “It was hard to get sleepy” or “It was hard to get sleepy”. From this, it was confirmed that the combination of mequitazine and pseudoephedrine hydrochloride produced almost no sleepiness as a side effect, although a high nasal secretion suppression effect was obtained.

Example 4 (Prescription Example-Tablet)
Based on the amounts of Formulation Examples 1 to 9 in Table 1, 200 mg tablets per tablet were prepared and taken 6 tablets per day.
Moreover, based on the amounts of Formulation Examples 10 to 12 in Table 2, 255 mg tablets per tablet were prepared and taken 6 tablets per day.

Example 5 (formulation example-hard capsule)
Based on the amounts of Formulation Examples 13 to 18 in Table 3, 350 mg of hard capsule content per capsule is prepared, filled into hard capsule (No. 1) using a known technique, and taken 3 capsules per day It was.
Also, 420 mg of hard capsule content per capsule was prepared based on the amounts of Formulation Examples 19 to 22 in Table 4 and filled into a hard capsule (No. 0) using a known technique. Capsule was taken.
Also, 453.3 mg of hard capsule content per capsule was prepared based on the amount of Formulation Example 23 in Table 4, filled into hard capsules (No. 0) using known techniques, and 3 capsules per day. Capsule was taken.

Example 6 (formulation example-soft capsule)
Prepare 267 mg of soft capsule contents (liquid preparation (slurry)) per capsule based on the amounts of Formulation Examples 24-28 in Table 5, and encapsulate with a capsule base using a known technique. Soft capsules were taken, 3 capsules per day.
Also, 255 mg of soft capsule content (liquid preparation (slurry)) per capsule is prepared based on the amounts of Prescription Examples 29 to 34 in Table 6, and encapsulated with a capsule base using a known technique. Thus, soft capsules were taken, and 6 capsules were taken per day.

Example 7 (Prescription Example-Chewable Agent)
400 mg of chewable preparation was prepared based on the amount of Formulation Examples 35 to 37 in Table 7, and 3 tablets were taken per day.

  Based on the amount of formulation examples 38 to 43 in Table 8, 255 mg of soft capsule content (liquid preparation (slurry)) per capsule was prepared and encapsulated with a capsule base using a known technique. Soft capsules were taken and 6 capsules were taken per day.

Claims (6)

(A) Mequitazine,
(B) pseudoephedrine or a salt thereof, and
(C) Belladonna total alkaloid, duck extract, isopropamide iodide, lysozyme chloride, dipotassium glycyrrhizinate, and a liquid preparation for inhibiting nasal secretion containing at least one selected from the group consisting of tranexamic acid,
The (A) mequitazine content is 0.01-3 w / w%, the (B) pseudoephedrine or its salt content is 0.1-30 w / w%, and
The (A) mequitazine contains 4 mg as an adult daily dose, and the (B) pseudoephedrine or a salt thereof contains 75 mg as an adult daily dose.
A liquid preparation for nasal secretion suppression administered three times a day. The liquid preparation for nasal secretion suppression according to claim 1, wherein (B) pseudoephedrine or a salt thereof enhances the nasal secretion suppression action of mequitazine. (B) The liquid preparation for inhibiting nasal secretion according to claim 1 or 2, wherein the pseudoephedrine or a salt thereof is pseudoephedrine hydrochloride. The liquid preparation for inhibiting nasal secretion according to any one of claims 1 to 3 , which is an orally administered composition. The liquid preparation for nasal secretion suppression according to any one of claims 1 to 4 , wherein the liquid preparation is a content of a capsule. (A) in combination with mequitazine, (B) pseudoephedrine or a salt thereof, and
(C) containing at least one selected from the group consisting of belladonna total alkaloids, duck extract, isopropamide iodide, lysozyme chloride, dipotassium glycyrrhizinate, and tranexamic acid, (A) liquid for enhancing nasal secretion inhibition action of mequitazine A preparation comprising:
The mequitazine content is 0.01-3 w / w%, the pseudoephedrine or its salt content is 0.1-30 w / w%, and
The (A) mequitazine contains 4 mg as an adult daily dose, and the (B) pseudoephedrine or a salt thereof contains 75 mg as an adult daily dose.
Liquid preparation administered three times a day.

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