JP2010150284A - Orally dissolution type or mandibulate type rhinitis treatment solid internal pharmaceutical formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable and effective rhinitis medication combining immediate and permanent effectivity. <P>SOLUTION: An orally dissolution type or mandibulate type rhinitis treatment solid internal pharmaceutical formulation containing a rhinitis medication is provided. (However, a case in which at least one selected from the group consisting of (A) belladonna alkaloid, belladonna total alkaloid, belladonna extract, datura stramonium extract and scopolia extract, and at least one selected from the group consisting of (B) chlorpheniramine maleate, hydrochloride acid isothipendyl, hydrochloride acid iproheptine, difeterol hydrochloride acid, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, triprolidine hydrochloride, tripelennamine hydrochloride, hydrochloride acid thonzylamine, hydrochloride acid promethazine, methdilazine hydrochloride, diphenhydramine salicylate and the like are contained as the rhinitis medication is excluded). <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a solid oral pharmaceutical composition for treating nasal inflammation in the mouth which has immediate effect and persistence and which is dissolved in the mouth or chewable.

Although the entrance to the nose (nasal passage) is small, there is a large space (nasal cavity) covered with mucous membranes in the back, and the nasal cavity is further connected to the pharynx at the back. Rhinitis is a condition in which inflammation occurs in the mucous membrane of the nasal cavity for some reason, and the main causes include allergies, infections caused by viruses and bacteria.
In recent years, an increasing number of patients suffer from allergic rhinitis caused by hay fever and house dust. In addition, patients who show nasal inflammation as one of the symptoms of so-called “cold” such as influenza due to viruses and colds, etc. are invariable. The typical cause of chronic rhinitis is usually allergy, but if treatment of “cold” is halfway, rhinitis may not be cured and there may be cases where chronic rhinitis is transferred. In the case of “cold” patients, rhinitis may be exacerbated by resident bacteria such as staphylococci and streptococci, because the nasal self-cleaning action decreases due to viral infection and the like.
There are various causes, but specific symptoms common to rhinitis include nasal discharge, nasal congestion, sneezing, itching of the nasal cavity, tear eyes, and sore throat. Nasal obstruction symptoms are caused by swelling of the nasal mucosa and narrowing of the nasal cavity, which may be accompanied by difficulty breathing and head feeling. In addition, nasal discharge itself causes discomfort, but can frequently cause inflammation of the nasal cavity by biting the nose. The lacrimal eye is a symptom caused by the promotion of tear secretion.

Many rhinitis patients develop the above-mentioned unpleasant symptoms more than once, repeatedly or chronically. If such a state persists for a long period of time, the quality of life (QOL) of the patient will be reduced, which will interfere with daily life. Because these nasal inflammation symptoms, particularly increased nasal congestion and nasal discharge, can be intolerable and uncomfortable, rhinitis patients have a strong tendency to seek immediate and effective treatment. For this reason, there has been a strong demand for the development of a pharmaceutical preparation excellent in immediate effect and sustainability that is not limited to alleviating the symptoms of nasal inflammation but also has enhanced nasal secretion suppression and nasal closure improvement effects.
Conventionally, pharmacological treatment for nasal inflammation is mainly administered as an antihistamine, sympathomimetic drug (vasoconstrictor), parasympatholytic agent, anti-inflammatory agent, anti-inflammatory enzyme, etc. Is done by that.

Since the nasal drops are sprayed or dripped from the nostril into the nasal cavity to reach the mucosa directly, immediate effects on nasal congestion can be expected. However, in the case of excessive nasal discharge, the nasal discharge is pushed from the nasal cavity toward the nostril due to the physiological function of the nasal cavity, so that the drug may not effectively reach the nasal cavity. In addition, it does not show sufficient effects in terms of the persistence of effects and the relief of nasal discharge, head weight and tears. On the other hand, oral preparations are useful in terms of sustained effects, treatment of nasal congestion, nasal discharge, head weight, sore throat, and tears, but cannot be expected to be effective immediately. Soft capsules for rhinitis have been provided as a more immediate solid agent for immediate use, but since this preparation also reaches the stomach quickly after taking it, there is no direct action on the nasal cavity and it is effective immediately Can not. In general, oral solids are absorbed through the gastrointestinal tract and act locally, so the effects of the drug fluctuate under the influence of the meal content, and a reliable effect cannot be expected. Only a small part of the drug reaches the target site (nasal cavity) and exhibits its effect, and there is a problem in terms of effective use of the drug.
Therefore, the development of a pharmaceutical composition that allows the administered drug to quickly reach the site of inflammation and at the same time ensure that the action lasts, has high bioavailability, and maximizes the effect of the drug. Was desired.

The inventors of the present invention have intensively and intensively studied for the purpose of providing an effective solid oral pharmaceutical composition for the treatment of rhinitis, which exhibits an immediate effect and a reliable persistence in the treatment of nasal inflammation. When the active ingredient of the present invention is allowed to act, it has been found that if it is in the mouth-dissolving or chewing form, not only the immediate effect and sustainability of the effect can be achieved, but also a high bioavailability can be achieved. It was.
That is, the present invention provides a solid pharmaceutical composition for treating rhinitis which is dissolved in the mouth or contains mastication type rhinitis.

Accordingly, the present invention provides the following.
(1) A solid oral pharmaceutical composition for treating rhinitis in the mouth, containing a therapeutic agent for rhinitis.
(2) The medicament according to item (1), wherein the rhinitis therapeutic agent is one or more medicaments selected from parasympatholytic agents, antihistamines, sympathomimetics, antiallergic agents, antiinflammatory agents and anti-inflammatory enzymes. Composition.
(3) The pharmaceutical composition according to item (2), wherein the parasympatholytic agent is selected from datsura extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, funnel extract, and iodopropamide.
(4) The pharmaceutical composition according to item (3), wherein the parasympathetic nerve blocker is selected from belladonna alkaloids, belladonna total alkaloids, and isopropamide iodide.
(5) Antihistamines are isothipenzil hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, triprolidine hydrochloride, tripelenamine hydrochloride, tonsilamine hydrochloride, promethazine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, The pharmaceutical composition according to item (2), which is selected from alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, carbinoxamine maleate, chlorpheniramine maleate (d-form, dl-form), and promethazine methylenedisalicylate.
(6) The item wherein the antihistamine is selected from isothipentyl hydrochloride, iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, alimemazine tartrate, diphenhydramine tannate and chlorpheniramine maleate (d-form, dl-form), or salts thereof (5) The pharmaceutical composition as described.
(7) The sympathomimetic drug is phenylpropanolamine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, methoxyphenamine hydrochloride, epinephrine, ephedrine hydrochloride, norepinephrine, naphazoline nitrate, gyrometazoline, middolin, methoxamine and tetrahydrozoline hydrochloride, or salts thereof The pharmaceutical composition according to item (2), which is selected from:
(8) The pharmaceutical composition according to item (7), wherein the sympathomimetic drug or the like is selected from phenylpropanolamine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride and methoxyphenamine hydrochloride, or salts thereof.
(9) Antiallergic drugs include astemizole, cyproheptadine hydrochloride, terfenadine, ibudilast, oxatomide, amlexanox, tranilast, ketotifen, azelastine, cromoglycate sodium, repirinast, emedastine, mequitazine, ozagrel, tazanolast, pemilomastin, fumarine The pharmaceutical composition according to item (2), which is selected from suplatast or a salt thereof.
(10) Antiallergic drugs are astemizole, cyproheptadine hydrochloride, amlexanox, ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate, mequitazine, clemastine fumarate and alimemazine, epinastine hydrochloride, tranilast, emedastine fumarate, oxatomide, pemirolast potassium The pharmaceutical composition according to item (9), which is selected from the salts of
(11) The pharmaceutical composition according to item (2), wherein the anti-inflammatory drug is selected from glycyrrhizic acid and salts thereof, licorice and tranexamic acid.
(12) An item in which the anti-inflammatory enzyme is selected from lysozyme chloride, bromelain, α-chymotrypsin, semi-alkaline proteinase (Seaprose S-AP), proteinase, serratopeptidase (serapeptidase), streptokinase and strepdornase ( 2) The pharmaceutical composition described.
(13) The pharmaceutical composition according to item (12), wherein the anti-inflammatory enzyme is selected from semi-alkaline proteinase, lysozyme chloride, bromelain and serratopeptidase (serapeptidase).
(14) The pharmaceutical composition according to item (1) or (2), which further contains menthol, camphor or cinerol.
(15) The pharmaceutical composition according to any one of items (1), (2), and (14), which further contains caffeine.
(16) The pharmaceutical composition according to any one of items (1) to (15), which is a chewable preparation in the mouth.

The pharmaceutical composition for treating mouth-dissolving or masticating rhinitis of the present invention is a preparation prepared by instant or gradual dissolution in the oral cavity in the presence of saliva, or partly by chewing, pulverizing and mixing with saliva. Or, it is a preparation that is taken after all is dissolved, and means a pharmaceutical composition that is used to treat allergic symptoms, nasal inflammation associated with colds such as influenza and colds.
As shown in the test examples described later, the mouth-dissolving or chewing type pharmaceutical composition of the present invention is compared with the case where the same amount of rhinitis therapeutic agent is taken as an internal tablet without dissolving or chewing in the mouth, Unexpectedly excellent therapeutic effect. As described above, the enhancement of rhinitis treatment effect is achieved by the present invention, so that all symptoms of nasal inflammation including nasal congestion, nasal discharge, headache, tears, and sore throat can be effectively eliminated for a long time immediately after administration. can do.
This excellent effect is a symptom at a site where rhinitis is in close contact with the oral cavity, and the dissolution of the drug is promoted by being mixed with saliva in the process of dissolving and / or chewing the pharmaceutical composition of the present invention in the mouth. A part of it acts directly on the nasal cavity from the pharynx side to exert immediate effect, reaches the absorption site in a state of being easily absorbed as a mixture with saliva, and is highly absorbed by the digestive tract while maintaining stability It relates to being able to exert the effect.

The pharmaceutical composition of the present invention may contain any known rhinitis therapeutic agent except for drugs that are not suitable for being dissolved or chewed in the mouth.
Examples of such rhinitis therapeutic agents include parasympatholytic agents, antihistamines, sympathomimetics, antiallergic agents, anti-inflammatory agents and anti-inflammatory enzymes, and when preparing the pharmaceutical composition of the present invention One or more drugs selected from them are used. When a plurality of drugs are used, the drugs may be the same type (when classified by action) or different types. In general, rhinitis patients often exhibit multiple symptoms such as nasal congestion, nasal discharge, head weight, and tears. Therefore, in order to obtain a comprehensive therapeutic effect, the composition of the present invention contains two or more drugs. It is preferable to use together.

  The parasympathetic nerve blocker used in the present invention is a drug having a mucus secretion inhibitory effect and a nasal discharge inhibitory effect based on blocking the antiacetylcholine action, and is useful for nasal discharge suppression. For example, datsura extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, funnel extract, iodoisopropamide, etc. More preferred is isopropamide iodide. These can be used alone or in combination of two or more. Parasympathetic blockade has the side effects of dry mouth due to suppression of salivary secretion, but by dissolving or chewing in the mouth, the effect per dose is higher than in the case of oral administration, and immediate action and high biology As a result, the occurrence of side effects can be avoided.

  The parasympatholytic agent can usually be administered to an adult in an amount of 0.01 to 100 mg as an active ingredient per day. For example, in the case of belladonna alkaloids, 0.01 to 1 mg, In the case of funnel extract, belladonna extract, and duck extract, 1-100 mg can be administered orally in the case of isopropamide iodide, 0.1-10 mg once a day or several times a day. In the case of the composition of the present invention, since the effect per dose is enhanced, the dose can be reduced. Therefore, in the case of belladonna alkaloids, 0.1 to 0.6 mg, 10-60 mg for funnel extract, belladonna extract, and duck extract, and 1-8 mg for isopropamide iodide are effective. This range is preferable in order to avoid side effects. However, the dose can be appropriately increased or decreased according to the patient's age, weight, and medical condition, and is not limited to the above range.

  Antihistamines are drugs that block the action of histamine and are, for example, isothipenzil hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, triprolidine hydrochloride, tripelamine amine hydrochloride, tondilamine hydrochloride, promethazine hydrochloride, methodiazine hydrochloride , Diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, carbinoxamine maleate, chlorpheniramine maleate (d-form, dl-form), promethazine methylenedisalicylate or salts thereof These can be used alone or in combination of two or more. Examples of the salts include hydrochloride, maleate, tartrate, salicylate, tannate, diphenyl disulfonate, theocrate, methylene disalicylate, and the like. Preferred antihistamines are istipendil hydrochloride, iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, alimemazine tartrate, diphenhydramine tannate and chlorpheniramine maleate (d form, dl form), or salts thereof. The antihistamine is usually administered to adults at a daily dose of 1 to 200 mg, preferably 1 to 100 mg, but the appropriate amount varies depending on the drug. For example, in the case of diphenhydramine hydrochloride, 1 to 100 mg is appropriate, and in the case of chlorpheniramine maleate (dl form), 1 to 10 mg is an appropriate amount and can be appropriately used depending on the drug.

  Antiallergic drugs include astemizole, cycloheptadine hydrochloride, terfenadine, ibudilast, oxatomide, amlexanox, tranilast, ketotifen, azelastine, sodium cromoglycate, repirinast, emedastine, mequitazine, ozagrel, tazanolast, pemirolastine, fumaricine, fumaricine, fumaricine, Examples thereof include suplatast and the like and salts thereof, and can be used alone or in combination of two or more. Examples of the salts include hydrochloride, maleate, tartrate, salicylate, tannate, diphenyldisulfonate, theocrate, methylenedisalicylate, nitrate, and fumarate. Preferred antiallergic drugs include astemizole, cycloheptadine hydrochloride, amlexanox, ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate, mequitazine, clemastine fumarate, epinastine hydrochloride, tranilast, emedastine fumarate, oxatomide, potassium pemirolast and alimemazine, Or a salt thereof. Antiallergic drugs are usually administered to adults in an amount of 0.01 to 300 mg per day, but the appropriate amount varies depending on the drug and can be used as appropriate within the usual range. For example, astemizole is 2.5-5 mg, ketotifen fumarate is 0.2-5 mg, epinastine hydrochloride is 2-30 mg, mequitazine is 0.5-15 mg, and alimemazine tartrate is 2-15 mg.

  Sympathomimetics (vasoconstrictors) such as phenylpropanolamine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, methoxyphenamine hydrochloride, epinephrine hydrochloride, ephedrine, norepinephrine, naphazoline nitrate, gyrometazoline, middolin, methoxamine, tetrahydrozoline hydrochloride, etc. Drugs or salts thereof may be mentioned, and these may be used alone or in combination of two or more. Examples of the salts include hydrochloride, maleate, tartrate, salicylate, tannate, diphenyl disulfonate, theocrate, methylene disalicylic acid, nitrate, and the like. Examples of the salts include hydrochloride, maleate, tartrate, salicylate, tannate, diphenyl disulfonate, theocrate, methylene disalicylic acid, nitrate, and the like. Preferred sympathomimetics (vasoconstrictors) are phenylpropanolamine hydrochloride, phenylephrine hydrochloride and methoxyphenamine hydrochloride, methylephedrine hydrochloride or salts thereof. A sympathomimetic drug (vasoconstrictor) is usually administered in an amount of 1 to 300 mg, preferably 1 to 150 mg as a daily dose for an adult. The appropriate amount varies depending on the drug, for example, phenylpropanolamine hydrochloride is 1 -120 mg, 1 to 40 mg for phenylephrine hydrochloride, 1 to 125 mg for methylephedrine hydrochloride, and 1 to 175 mg for methoxyphenamine hydrochloride, which can be appropriately increased or decreased depending on symptoms.

  Examples of the anti-inflammatory enzyme include lysozyme chloride, bromelain, α-chymotrypsin, semi-alkaline proteinase (Ceaprose S-AP), proteinase, serratopeptidase (serapeptidase), streptokinase, strepdornase and the like. Preferred anti-inflammatory enzymes are semi-alkaline proteinase, lysozyme chloride, bromelain and serratopeptidase (serapeptidase). The anti-inflammatory enzyme is usually administered to adults at a daily dose of 1.0 to 200 mg, preferably 1 to 100 mg, but the appropriate amount varies depending on the drug and can be appropriately used within the usual range. For example, in the case of lysozyme chloride, a range of 1 to 100 mg is appropriate.

  Anti-inflammatory agents include glycyrrhizic acid such as glycyrrhizic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate and diammonium glycyrrhizinate and salts thereof, licorice, tranexamic acid and the like, and these can be used alone or in combination. The anti-inflammatory drug is usually administered to an adult in a daily dose of 0.1 to 300 mg as the amount of glycyrrhizic acid, but the appropriate amount varies depending on the drug, and can be used as appropriate within the usual range.

When the central nervous system stimulant is added to the pharmaceutical composition of the present invention in addition to the rhinitis therapeutic agent, the effect on head weight due to rhinitis is further enhanced, and it is effective against sleepiness that is a side effect of certain rhinitis therapeutic agents, It may be preferable because it contributes to the improvement of the overall therapeutic effect.
Examples of the central nervous stimulant include caffeine, and specific examples include anhydrous caffeine, caffeine, sodium benzoate caffeine and the like. The dosage is preferably 12 to 300 mg per day for adults. More preferably, it is 100-200 mg.

Menthol, cinerol, and camphor can be used together in the composition of the present invention. As shown in the test examples described later, the inclusion of menthol is preferable because the immediate effect is further remarkably enhanced in addition to the improvement of compliance. Menthol may be used as menthol or as an essential oil containing menthol such as peppermint oil, spearmint oil, peppermint oil and mint oil. The dose of menthol is usually in the range of 0.001 to 40 mg per day for an adult. The preferred concentration of menthol in the composition is 0.1 to 2.25% by weight, and if it is in this range, it provides a refreshing refreshment without bitterness and is effective in improving patient compliance. Beyond the range, menthol stimulation can be uncomfortable.
Menthol is described in the literature (13th revised Japanese Pharmacopoeia, D1050 to 1058), and commercially available products can also be used. Either natural essential oil-derived or synthetic products may be used. When used in the composition of the present invention, menthol may be either l-form or dl-form. Cinerol and camphor are both described in the Japanese Pharmacopoeia, and commercially available products can also be used. Cinerol is abundant in eucalyptus oil, and may be used as cinerol or eucalyptus oil. A lot of camphor is contained in camphor oil, and it may be used as camphor or as camphor oil. In addition, the composition of the present invention, which is a dosage form that dissolves and / or chews in the mouth, has a long residence time in the mouth, and the drug directly contacts the taste buds. preferable. From such a point of view, the use of essential oils containing menthol, camphor, and cinerol and fruit flavors together helps improve patient compliance. This is preferable because a drug having a bitter taste can be masked.

In the composition of the present invention, any medicinal component can be blended according to the object of the present invention, and is not limited to the above-mentioned drugs.
Moreover, as long as the effect of treating nasal inflammation is not impaired, other substances (pharmaceuticals or quasi-drugs) commonly used in the art may be added. Such substances include vitamins, herbal medicines, antitussives, expectorants, sputum solubilizers, antipyretic analgesics, antacids and the like.
When combined with ingredients for cold medicines, it is useful for treating nasal inflammation associated with colds.

  Each of the other components described above is blended within the dose range usually used. Herbal medicines include mussels, saicin, ginger, shini, zenko, peony, etc., antitussives such as codeine phosphate, dextrometrophans, etc. as expectorants, guaifenesin, potassium guaiacol sulfonate, etc. Includes lysozyme chloride, cysteine, etc., antipyretic analgesics such as acetaminophen, etenzaamide, aspirin and the like, and antacids include magnesium silicate, magnesium oxide, magnesium hydroxide and the like.

The pharmaceutical composition of the present invention may have any dosage form as long as it is in a form that can be taken by dissolving or chewing in the mouth, such as tablets (plain tablets, sugar-coated tablets), candy (candy), gummi, nougat, etc. Illustrated. The shape and size are appropriately selected as long as there is no inconvenience for taking in the mouth.
Tablets are prepared by mixing powdered drugs and pharmaceutically acceptable excipients and compression-molding. Also, candy (gummy), gummi, nougat, etc. can be prepared by methods known in the confectionery field. Can be prepared.
For example, the tablet may be an extrusion granulation method, a pulverization granulation method, a dry compaction granulation method, a fluidized bed granulation method, a rolling granulation method, a high-speed stirring granulation method, a wet tableting method known in the art. What is necessary is just to manufacture combining a direct tableting method etc. suitably according to the objective.
A preferable dosage form for practicing the present invention is a tablet, and in particular, a chewable tablet which is a form to be taken by chewing in the mouth.

Any component that is generally used as a pharmaceutical additive can be added to the preparation of the present invention as long as the effect of the present invention is not affected. Such additives include corn starch, potato starch, sucrose, talc, kaolin, calcium sulfate, calcium carbonate, excipients such as crystalline cellulose, lubricants such as magnesium stearate and calcium stearate, carboxymethylcellulose calcium, low Degrading agents such as hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, cellulose polymers, acrylic polymers, binders such as methylcellulose, gum arabic, and polyvinyl alcohol, other sweeteners, wearing Examples include flavoring agents, coloring agents, flavoring agents, adsorbents, preservatives, wetting agents, and antistatic agents.
In addition, the composition of the present invention can control the expression of a pharmacological effect by controlling the release of a drug according to the purpose, and can be a more durable preparation.

Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1 Tablet

  According to the Japanese Pharmacopoeia General Rules for Tablets “Tablets”, tablets were produced. Specifically, the components from d-chlorpheniramine maleate to mannitol are taken, and granules (A) are prepared by a wet granulation method. On the other hand, menthol doubling (B) is prepared by mixing menthol and Avicel. Next, the granule (A), menthol trituration (B), and magnesium stearate were mixed to prepare a tableting tablet, and the tablet was made with a tableting machine with a weight of 400 mg / tablet.

Example 2 Tablet

  As in Example 1, granules (A) were prepared using ingredients from diphenhydramine hydrochloride to xylit, while ingredients from Avicel to peppermint oil were mixed to prepare menthol trituration (B). A 300 mg tablet was produced.

Example 3 Tablet

  As in Example 1, granules (A) were prepared using ingredients from diphenhydramine salicylate to mannitol, while ingredients from Avicel to mint oil or mint oil were mixed to give menthol trituration (B). 1 tablet of 400 mg was prepared.

Example 4 Tablet

  As in Example 1, granules (A) were prepared using ingredients from clemastine fumarate to sorbite, while menthol trituration (B) was prepared from L-HPC and menthol, and one tablet of 250 mg Made.

Example 5 Tablet

  As in Example 1, granules (A) were prepared using ingredients from mequitazine to mannitol, while ingredients from Avicel to mint oil or mint oil were mixed to prepare menthol trituration (B). One tablet of 500 mg was made.

Example 6 Tablet

As in Example 1, granules (A) were prepared using components from ketotifen fumarate to sorbit, while menthol trituration (B) was prepared from L-HPC and menthol. Made.
Example 7 Candy Phenylephrine hydrochloride 25.0 parts Lysozyme chloride 60.0
Sugar 2202.5
Minamata 2100.0
Citric acid 9.0
Menthol 9.0
Lemon oil 4.5
Water 90.0
4500.0
The above ingredients were mixed, and 1.5 g (dose: 3 per day) of candy was produced as usual.

Example 8 Nougat
d-Chlorpheniramine maleate 6.0 parts Phenylpropanolamine hydrochloride 90.0
Caffeine 60.0
Sugar 2677.2
Minamata 210.0
Expanded gelatin (50% gelatin) 390.0
Vegetable oil 54.0
Dye 5.4
Menthol 12.0
Grapefruit essence 5.4
540.0
The above ingredients were mixed and 1.8 g (dosage: 3 per day) of nougat was produced per unit as usual.

Example 9 Gummy diphenhydramine hydrochloride 50.0 parts Phenylpropanolamine hydrochloride 90.0
Caffeine 60.0
Powdered gelatin (180 bloom) 430.5
Sugar 120.0
Minamata 120.0
Menthol 15.0
Lemon oil 4.5
Hot water 1450.0
450.0
The above ingredients were mixed, and 1.5 g (dose: 3 per day) of gummy per one was produced as usual.

Example 10 Gum d-Chlorpheniramine maleate 6.0 parts Verazonna total alkaloid 0.4
Caffeine 60.0
Gum base 210.0
Sugar 4656.8
Glucose 90.0
Corn syrup 120.0
Glycerin 55.8
Menthol 12.0
Peppermint oil 9.0
90.0
The above ingredients were mixed, and 3.0 g (dose: 3 sheets per day) of gum was produced as usual.

Test Example 1 Dissolution Test Using the chewable tablet of Example 1 and a commercially available internal medicine for rhinitis, a test was conducted according to the dissolution test method (paddle method) which is a general test method of the Japanese Pharmacopoeia. Purified water was used as a test solution in a 500 ml test solution at 37 ° C. and a paddle rotation speed of 100 rpm. The chewable tablet of Example 1 was chewed about 5 to 15 times in the mouth and then added to the test solution as a sample. After starting the test, the eluate was collected over time, and the drug elution amount was measured using chlorpheniramine maleate blended in the chewable tablet as an indicator component.
As controls, commercially available hard capsules (commercial product 1), tablets (sugar-coated tablets) (commercial product 2), granules (commercial product 3), and soft capsules (commercial product) containing chlorpheniramine maleate as an active ingredient These were tested without chewing using 4). Chlorpheniramine maleate was measured by a conventional HPLC method. The results are shown in Table 7.

n.d.：検出限度以下
一方、日本薬局方の一般試験法である崩壊試験にある胃液を想定したｐＨ１.２又は腸液を想定したｐＨ６.８の試験液を用い、実施例１のチュアブル錠と市販の顆粒剤（市販品３）について、上記と同様の方法で薬物溶出試験を行った。結果を表８に示す。

nd: Below detection limit On the other hand, using the test solution of pH 1.2 assuming gastric juice in the disintegration test, which is a general test method of the Japanese Pharmacopoeia, or pH 6.8 assuming intestinal fluid, the chewable tablet of Example 1 and a commercially available tablet are available. About the granule (commercial item 3), the drug elution test was done by the same method as the above. The results are shown in Table 8.

From Tables 7 and 8, it can be seen that the dissolution of the drug from the chewable tablet of Example 1 is very rapid and completely dissolves in a short time (almost 100%). The dissolution rate is superior to that of a granule having a large surface area (commercial product 3). Moreover, it can be seen from Table 8 that the dissolution from the chewable tablet of Example 1 is not affected by the pH at all.
It is thought that the elution of the drug is promoted by the increase of the surface area by chewing, but compared with the granule of the commercial product 3, any condition in the stomach (pH = 1.2) or in the mouth (pH = 6.8) Even below, the composition of the present invention shows a better drug elution effect. This suggests that the dissolution enhancement in the composition of the present invention is not simply due to an increase in surface area due to chewing.
It is known that the drug release rate and its variation are closely related to the rate and amount of drug absorption in the gastrointestinal tract, and have a great influence on the manifestation of the effect of drug treatment. The above test results reveal that the preparation of the present invention exhibits an excellent dissolution rate as compared with the conventional preparation, and the preparation of the present invention has an immediate effect and a high bioavailability, It proves that it is a useful preparation that can reliably and sustainably exhibit high effects.

表９に示す錠剤Ａ−１〜Ｄは、実施例１と同様に調製した。対照としてメントールのみを含有する錠剤Ｅも同様にして調製し、試験に用いた。これらの製剤は、いずれも、含量試験、崩壊試験（ＪＰ）、含量均一性試験（ＪＰ）に適合することを確認した。鼻炎症状（くしゃみ、鼻水、鼻づまり、のどの痛み、涙目、頭重）を有する被験者１４名に薬剤を投与（一回一錠）し、症状の改善度を、薬剤服用１０分後と４時間後に評価した。
錠剤Ａ−１、Ｂ及びＥは口中で咀嚼（５から１５回）して服用し、錠剤Ａ−２は咀嚼せず溶解させ、服用した。また、錠剤ＣとＤは、１５０ｍｌの水で、口中で咀嚼又は溶解せずに嚥下内服した。試験結果を表１０及び表１１に示す。 Test Example 2 Effectiveness test

Tablets A-1 to D shown in Table 9 were prepared in the same manner as in Example 1. As a control, tablet E containing only menthol was prepared in the same manner and used in the test. All of these preparations were confirmed to meet the content test, disintegration test (JP), and content uniformity test (JP). 14 subjects with nasal inflammation (sneezing, runny nose, stuffy nose, sore throat, tears, head weight) were administered the drug (one tablet at a time), and the degree of improvement in symptoms was 10 minutes after taking the drug and 4 hours It was evaluated later.
Tablets A-1, B and E were chewed (5 to 15 times) in the mouth and taken, and tablet A-2 was dissolved without being chewed and taken. Tablets C and D were swallowed with 150 ml of water without being chewed or dissolved in the mouth. The test results are shown in Table 10 and Table 11.

When the tablets A-1, A-2, and B of the present invention are compared with the non-chewable, non-dissolving tablet C, the improvement rate after 10 minutes is significantly high, and the improvement rate after 4 hours is also excellent. It turns out that it has both immediate effect and sustainability. Further, when these preparations A-1, A-2 and B of the present invention were compared with tablet E (masticated and taken) containing no drug other than menthol, menthol was observed after 10 minutes and after 4 hours. It can be seen that it is much more effective than the single composition. On the other hand, non-chewable and non-dissolvable tablets C and D have a low improvement rate regardless of the presence or absence of menthol.
In addition, comparing the chewable (A-1) and dissolved (A-2) preparations containing menthol with the chewable (B) preparations that do not contain menthol, the former two have a higher immediate effect than the latter. (See Table 10). This indicates that when menthol is included in the chewable or dissolved preparation, the immediate effect is remarkably enhanced.
From the above results, it is clear that the dissolution type or chewing type preparation of the present invention has an immediate effect on the symptoms of nasal inflammation and a sustained effect as compared with a normal swallow type tablet. Even after 4 hours from administration, the composition of the present invention exhibits a high effect as compared with the corresponding tablet. Therefore, the composition of the present invention has a high immediate effect and a high bioavailability, and has an excellent therapeutic effect. It can be said that it is a preparation. The following points are considered as causes of these excellent actions.
1. Because it is mixed with saliva in the mouth, drug dissolution is promoted.
2. Immediate absorption and increased absorption.
3. Jaw movement promotes nasal circulation.
4. Direct action on the nasal cavity from the pharynx.

  Since the pharmaceutical composition of the present invention is held in the mouth for a long time and mixed with saliva, it can act directly on the nasal mucosa from the pharynx, so that it is immediately effective against all types of nasal inflammation including nasal discharge Indicates. This immediate effect is not limited to nasal congestion, but is effective in alleviating symptoms of rhinitis such as nasal discharge, head weight, and sore throat. At the same time, it can be absorbed from the gastrointestinal tract, ensuring a lasting effect, and achieving a sufficiently high bioavailability compared to ordinary oral tablets containing the same amount of active ingredient. . As a result, the drug can be effectively used, and the burden on the patient can be reduced and the quality of life can be improved through the reduction of the dose.

Claims (1)

  Mouth-dissolved or chewable solid oral pharmaceutical composition for treating rhinitis containing rhinitis therapeutic agent [However, rhinitis therapeutic agent comprises (A) belladonna alkaloid, belladonna total alkaloid, belladonna extract, datsura extract, and funnel extract At least one selected from the group, and (B) chlorpheniramine maleate, isothipentyl hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, triprolidine hydrochloride, tripelenamine hydrochloride, tonsilamine hydrochloride, promethazine hydrochloride, Methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teolate, potassium maleate A case of containing at least one selected from the group consisting of binoxamine, promethazine methylenedisalicylate, astemizole, cycloheptazine hydrochloride, terfenadine, oxatomide, ketotifen, azelastine, emedastine, mequitazine, clemastine fumarate, alimemazine, and epinastine except].