JP2003221324A - Composition for rhinitis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To discover an excellent composition for rhinitis. <P>SOLUTION: A medicine containing pseudoephedrine and antihistamines contains pseudoephedrine and epinastine and/or ketotifen, wherein either or both the pseudoephedrine and these antihistamines are contained at amounts that cannot exert medicinal effects alone. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to pseudoephedrine and antihistamines (particularly chlorpheniramine).
A drug containing (particularly, one used for suppressing rhinitis, or sneezing or runny nose), characterized in that either or both of the pseudoephedrine and the antihistamine are blended in such amounts that the single compound is not effective. And a drug containing pseudoephedrine and epinastine or ketotifen (particularly those used for controlling rhinitis or sneezing or runny nose).

[0002]

BACKGROUND OF THE INVENTION Oral medicines for rhinitis used for allergic rhinitis such as hay fever and nasal inflammation such as common cold include sympathomimetics for the purpose of removing decongestion of nasal mucosa and antihistamine for suppressing allergic reaction. May be mixed with drugs. The reason why these drugs are used in combination is that a decongestant for nasal mucosa is effective for nasal obstruction, while an antihistamine is effective for itching of the nose (feeling of sneezing), sneezing, and runny nose. This is because they expect a complementary effect (for example, see Non-Patent Document 1). The following are known as the compounding of such pseudoephedrine and the antihistamine. That is, 1) an oral drug for rhinitis containing pseudoephedrine and chlorpheniramine or triprolidine (for example,
See Non-Patent Document 2. ), 2) Divide into prescriptions containing pseudoephedrine and chlorpheniramine for night use and no antihistamine drug for morning use, and fill them in the same package to prevent the side effects of antihistamine drugs from drowsiness or sedation during the daytime. The drug for rhinitis that was avoided in the above (for example, refer to Patent Document 1), 3) a combination of pseudoephedrine and cetirizine (for example, refer to Non-Patent Document 3), and 4) a formulation of pseudoephedrine and diphenhydramine (for example, refer to Patent Document 2). , 5) Combination use of pseudoephedrine and terfenadine (for example, see Non-Patent Document 4), 6) Combination use of pseudoephedrine and acrivastine (for example, Non-Patent Document 5), 7) Combination use of pseudoephedrine and fexofenadine (for example, non-patent document) See Patent Document 6), 8) Combined use of pseudoephedrine and astemizole. (E.g., see Non-Patent Document 7.), And, 9) a combination of pseudoephedrine and loratadine (e.g., see Non-Patent Document 8.). However, up to now, a drug using pseudoephedrine in combination with epinastine or ketotifen has not been known. In each of these combination examples, the compounding amount was set based on the dose of each single agent, and no combination agent was known that could reduce the amount of either or both of pseudoephedrine and antihistamine.

[Patent Document 1] International Publication No. 9921556 Pamphlet

[Patent Document 2] US Patent No. 1995530449

[Non-Patent Document 1] Handbook of Nonprescription Drugs,
12th edition, American Pharmaceutical Association

[Non-Patent Document 2] Handbook of Nonprescription Drugs,
12th edition, American Pharmaceutical Association

[Non-Patent Document 3] Eur J Clin Pharm, Vol.41, 1991 P.32
1-324

[Non-Patent Document 4] Rhinology, Vol.35, 1997, P.67-73

[Non-Patent Document 5] Annals of Allergy, Asthma, & Immun
ology, Vol.76, 1996 P.432-438

[Non-Patent Document 6] J Allergy Clin Immunol, Vol. 104, 199
9 P.100-106

[Non-Patent Document 7] Rhinology, Vol.34, 1996 p21-23

[Non-Patent Document 8] Ear Nose Throat J, Vol.79, 2000 P.
254-460

[0003]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention
Various drugs were investigated as the drugs that can be used for controlling sneezing and runny nose. As a result, a combination of a reduced amount of pseudoephedrine and an antihistamine (particularly, chlorpheniramine), and a combination of pseudoephedrine and epinastine or ketotifen have a remarkable effect as compared with the case where each component is blended alone, The present invention has been completed by finding that it is effective for the above-mentioned symptoms.

[0004]

Means for Solving the Problems The present invention is characterized in that: 1) a drug containing a pseudoephedrine and an antihistamine, wherein the content of either or both of the pseudoephedrine and the antihistamine is such that it does not exhibit a medicinal effect alone. 2) In 1), the antihistamine is chlorpheniramine. Furthermore, the present invention is 3) a pharmaceutical agent containing pseudoephedrine and epinastine, and 4) a pharmaceutical agent containing pseudoephedrine and ketotifen. Among the above-mentioned medicines, the medicine is preferably used for suppressing rhinitis, sneezing or nasal discharge.

In the above, the term "amount which does not show a medicinal effect alone" means an amount which is below the limit amount which shows an effect when the drug is administered alone, and such an amount can be determined by those skilled in the art. If there is, it can be determined using a well-known test method, for example, it can be determined using the inhibitory effect test for sneezing against antigen stimulation described in Test Example 1 below, in chlorpheniramine maleate. The amount is preferably 0.1 mg / kg or less, and the amount of pseudoephedrine hydrochloride is preferably 33 mg / kg or less.

In the above, "antihistamine" means
There is no particular limitation as long as it has a histamine H1 receptor antagonistic action, for example, diphenhydramine, promethazine, chlorpheniramine, ketotifen, azelastine, oxatomide, mequitazine, terfenadine, astemizole, cetirizine, epinastine, ebastine,
Examples thereof include emedastine, and preferred are chlorpheniramine, ketotifen, and epinastine.

In the present invention, each of the components contained may be contained as a pharmacologically acceptable salt, and such a salt may be, for example, a fluorine-containing salt when the component has a basic functional group. Hydrohalides such as hydrochloride, hydrochloride, hydrobromide and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates and phosphates; methanesulfonic acid Lower organic sulfonates such as salts, trifluoromethanesulfonate, ethanesulfonate; arylsulfonates such as benzenesulfonate, p-toluenesulfonate, etc .; ornithine salt, glutamate salt, etc. Amino acid salts; and fumaric acid, succinic acid, citric acid,
Examples thereof include carboxylic acid salts such as tartaric acid, oxalic acid and maleic acid. When the component has an acidic functional group,
Alkali metal salts such as sodium salts, potassium salts and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts. Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-
Methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt,
N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-
Benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt, amine salts such as organic salts such as tris (hydroxymethyl) aminomethane salt can be mentioned, and in the case of pseudoephedrine, it is preferably hydrochloride or sulfate. In the case of chlorpheniramine it is preferably the maleate, in the case of epinastine it is preferably the hydrochloride and in the case of ketotifen it is the fumarate.

[0008]

DETAILED DESCRIPTION OF THE INVENTION Pseudoephedrine is USP.
(US Pharmacopoeia) XXIV, chlorpheniramine maleate is listed in Japanese Pharmacopoeia XIV. Further, epinastine hydrochloride and ketotifen fumarate are commercially available as pharmaceuticals and can be easily obtained.

The weight% of pseudoephedrine contained in the case of the solid preparation of the antirhinitis drug of the present invention is usually 0.01 to 50%, preferably 0.1 to 30%. The weight percent of phenylamine is usually
0.0003 to 2%, preferably 0.003 to 1%, and the weight% of epinastine is usually
0.0005 to 3%, preferably 0.005 to 2%, and the weight% of ketotifen is usually 0.0001 to 1%, preferably 0.00
It is 1 to 0.5%.

When the antirhinitis drug of the present invention is a liquid preparation, the content of pseudoephedrine is usually
It is 0.01 to 100 mg / mL, preferably 0.1 to 50 mg / mL, and the content of chlorpheniramine is usually 0.003 to 5 mg / mL, preferably 0.0
3 to 3 mg / mL, and the content of epinastine is usually 0.005 to 10 mg / mL, and preferably,
It is 0.05 to 5 mg / mL, and the content of ketotifen is usually 0.001 to 2 mg / mL, preferably 0.01 to 1 mg / mL.

In the present invention, in addition to the above active ingredients, if necessary, a parasympathetic nerve blocker, an anti-inflammatory drug, caffeines, vitamins, herbal medicines, etc. may be added within a range that does not impair the effects of the present invention. it can.

Specific dosage forms of the anti-cold drug of the present invention include, for example, tablets, fine granules (including powders), capsules,
Examples thereof include liquids (including syrups) and the like, which can be manufactured according to the usual methods described in the Japanese Pharmacopoeia and the like, using additives and base materials suitable for each dosage form as appropriate.

In each of the above dosage forms, various commonly used additives may be used depending on the dosage form.

For example, in the case of tablets, lactose, crystalline cellulose and the like are used as excipients, magnesium aluminometasilicate or magnesium oxide and the like are used as stabilizers, hydroxypropyl cellulose and the like are used as coating agents, and magnesium stearate and the like are used as lubricants. It can be used as a bulking agent, and in the case of fine granules and capsules, lactose, purified sucrose, etc. are used as excipients, magnesium aluminometasilicate or magnesium oxide, etc. are used as stabilizers, and corn starch etc. are adsorbed. As an agent, hydroxypropyl cellulose or the like can be used as a binder.

In each of the above dosage forms, if necessary, a disintegrating agent such as crospovidone; a surfactant such as polysorbate;
It is also possible to add an adsorbent such as calcium silicate; a coloring agent such as iron sesquioxide and caramel; a stabilizer such as sodium benzoate; a pH adjusting agent;

[0016]

EXAMPLES The present invention will be described in more detail below by showing Examples, but the scope of the present invention is not limited to these. (Example 1) Tablet (1) ingredient

[0017]

[Table 1]

(2) Manufacturing method Using the above ingredients and amounts, tablets are manufactured in accordance with the Japanese Pharmacopoeia General Rules "Tablets". (Example 2) Fine granule (1) component

[0019]

[Table 2]

(2) Manufacturing method Taking the above-mentioned components and amounts, fine granules are manufactured in accordance with the general regulations of the Japanese Pharmacopoeia, "Granules". (Example 3) Capsule (1) component

[0021]

[Table 3]

(2) Manufacturing method Taking the above-mentioned components and amounts, fine granules are prepared according to the general regulations of the Japanese Pharmacopoeia, "Granules", and then filled into capsules to prepare hard capsules. (Example 4) Syrup agent (1) component

[0023]

[Table 4]

(2) Manufacturing method Taking the above ingredients and amounts, the Japanese Pharmacopoeia General Rules "Syrup"
After preparing the syrup according to the item (1), fill a brown glass bottle to prepare the syrup. (Test Example 1) Inhibitory effect of sneezing on antigen stimulation (1) Test substance The test substance was used as a suspension with 0.5% tragacanth solution on the day of the test. The amount of test substance administered is 2.
The control group was given 0 mL, and the same amount of 0.5% tragacanth solution was administered. (2) Test animal Hartley male guinea pig 5 weeks old (purchased from Japan SLC)
Was fed with solid feed and tap water in an environment-controlled breeding apparatus (manufactured by CLEA Japan, Inc.) having a temperature of 20 to 26 ° C. and a humidity of 35 to 65%, and preliminarily breeded under the condition of lighting time of 7:00 to 19:00. Used later. (3) Test Method Preparation of Actively Sensitized Guinea Pigs 6-week-old guinea pigs are immunized subcutaneously and intraperitoneally with 0.5 mL of the antigen solution (50 mg / mL of ovalbumin: Sigma Chemical Co.). One week later, the same amount of antigen is similarly administered to give a booster immunization. Seven to nine days after the booster immunization, the animals are fasted for about 24 hours and subjected to the test as active sensitized guinea pigs. Induction of sneezing by antigen Anti-health of the animals is checked and selected. Then, 0.1 mL of the antigen solution (50 mg / mL) is intranasally applied to both nasal cavities of the guinea pig. After that, the symptom is observed for 15 minutes, and the number of times of sneezing is measured to determine the intensity of the antigen-induced nasal symptom. Inhibitory action of test substance The test substance is administered using an oral probe 1 hour before nasal administration of the antigen described in the preceding paragraph. The sneeze suppression rate (%) is calculated from the following formula.

[0025]

[Equation 1] Inhibition rate (%) = [1-average number of sneezes in test substance administration group / average number of sneezes in control group] x 100 (4) Test results pseudoephedrine hydrochloride [P (mg / Kg)] and chlor maleate Table 5 shows the results of the sneeze inhibition rate of each of pheniramine [C (mg / Kg)] alone and in combination.

[0026]

[Table 5]

Pseudoephedrine hydrochloride or chlorpheniramine maleate alone showed an excellent sneeze-inhibiting effect by combining the two even at a low dose that did not exhibit the sneezing-inhibiting effect. Pseudoephedrine hydrochloride [P (mg / Kg)] and epinastine hydrochloride [E (m
Table 6 shows the results of the sneeze inhibition rate for each single agent and combination of g / Kg)].

[0028]

[Table 6]

Pseudoephedrine hydrochloride or epinastine hydrochloride alone exhibited an excellent sneeze-suppressing effect by combining the two even at low doses that did not exhibit a sneeze-suppressing effect. Pseudoephedrine hydrochloride [P (mg / Kg)] and ketotifen fumarate [K (mg / K
Table 7 shows the results of the sneeze inhibition rate for each of the single agents and the combination of g)].

[0030]

[Table 7]

The combination of pseudoephedrine hydrochloride and ketotifen fumarate showed an improvement in the sneeze inhibiting effect.

[0032]

[Effects of the Invention] A pharmaceutical containing pseudoephedrine and an antihistamine (particularly, chlorpheniramine) of the present invention (particularly used for suppressing rhinitis or sneezing or runny nose), wherein either pseudoephedrine or an antihistamine is used or Those characterized in that both compounded amounts are not effective by themselves, and
A drug containing pseudoephedrine and epinastine or ketotifen (particularly used for suppressing rhinitis or sneezing or runny nose) shows a remarkable effect and is useful as a drug.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 11/02 A61P 11/02 27/16 27/16 43/00 121 43/00 121 (72) Inventor Torizumi Yasuhiro 3-5-1, Nihonbashi Honcho, Chuo-ku, Tokyo Sankyo Co., Ltd. F-term (reference) 4C084 AA01 AA02 AA03 AA17 MA02 MA23 MA35 MA37 MA41 NA05 NA11 ZA34 ZB08 4C086 AA01 AA02 BB02 BC16 BC17 CB11 GA04 GA07 MA02 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA23 MA37 MA41 NA05 NA11 ZA34 ZB08 4C206 AA01 AA02 FA10 MA02 MA37 MA43 MA55 MA57 MA61 MA72 NA05 NA11 ZA34 ZB08

Claims (7)

[Claims] 1. A medicine containing pseudoephedrine and an antihistamine, wherein the content of either or both of the pseudoephedrine and the antihistamine is such an amount that does not show a medicinal effect alone. 2. The medicine according to claim 1, wherein the antihistamine is chlorpheniramine. 3. A medicine containing pseudoephedrine and epinastine. 4. A medicine containing pseudoephedrine and ketotifen. 5. A medicine according to any one of claims 1 to 4, which is used for rhinitis. 6. A medicine according to any one of claims 1 to 4, which is used for suppressing sneezing. 7. A medicine according to any one of claims 1 to 4, which is used for suppressing runny nose.