JP2003246727A - Medicine composition for rhinitis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find an excellent medicine composition for rhinitis. <P>SOLUTION: The medicine composition contains pseudoephedrine, a halogenated isopropamide, and ambroxol and/or phenylephrine. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing pseudoephedrine and halogenated isopropamide, ambroxol and / or phenylephrine (particularly used for controlling rhinitis or sneezing or runny nose).

[0002]

BACKGROUND OF THE INVENTION Oral rhinitis medications used for allergic rhinitis such as hay fever and nasal inflammation such as common cold include sympathomimetics for the purpose of removing nasal mucosal hyperemia, and parasympathetic blockers for suppressing runny nose. , Etc. may be blended (for example, see Non-Patent Document 1).

[0003] The following are known as known formulations or combined use relating to the present invention. That is, 1) As an example of using two kinds of sympathomimetics in combination, a combination of phenylephrine hydrochloride and phenylpropanolamine hydrochloride (for example, see Non-Patent Document 2), 2) A sympathomimetic and a parasympathetic blocker were used in combination. As an example, a combination of methylephedrine hydrochloride and isopropamide iodide (see, for example, Non-Patent Document 3), 3) A combination of pseudoephedrine, a sympathomimetic, and dextromethorphan hydrobromide or guaifenesin, an expectorant (eg, Non-Patent Document 4).

However, there is no report that the nasal inflammation symptoms were synergistically improved by the combined use thereof. or,
Up to now, no drug using a parasympathetic blocker halogenated isopropamide, an expectorant ambroxol and / or a sympathomimetic phenylephrine as a concomitant drug with the sympathomimetic pseudoephedrine has been known.

[0005]

[Non-patent document 1] OTC drug manufacturing [import] approval criteria,
2000, Jiho,

[Non-patent document 2] JAPIC edition, OTC drugs, Japanese medicine collection,
2002, Jiho, p. 723

[Non-patent document 3] edited by JAPIC, General Medicine Japan Pharmaceutical Collection,
2002, Jiho, page 62

[Non-Patent Document 4] Allen, LV et al. Ed. Handbook o
f Nonprescription Drugs, 12th edition, American Pha
Table 9-2 on page 183 of the rmaceutical Association

[0006]

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, surprisingly, with respect to pseudoephedrine, a composition containing halogenated isopropamide, ambroxol and / or phenylephrine has a remarkable effect as compared with the case where each component is added alone, The present invention has been completed by finding that it is effective for the above-mentioned symptoms.

[0007]

Means for Solving the Problems The present invention is 1) a pharmaceutical composition containing pseudoephedrine and halogenated isopropamide, ambroxol and / or phenylephrine, and preferably 2) containing pseudoephedrine and halogenated isopropamide. 3) a pharmaceutical composition containing pseudoephedrine and isopropamide iodide, 4) a pharmaceutical composition containing pseudoephedrine and ambroxol, and 5) a pharmaceutical composition containing pseudoephedrine and phenylephrine. Is.

The above-mentioned medicament is preferably a pharmaceutical composition characterized by being used for suppressing rhinitis, sneezing or nasal discharge.

In the present invention, each component to be contained may be contained as a pharmacologically acceptable salt, and when such a salt has a basic functional group, for example, a fluorine salt is included. 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-
Examples thereof include amine salts such as benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt, and organic salt such as tris (hydroxymethyl) aminomethane salt. In the case of pseudoephedrine, it is preferably hydrochloride or sulfate. In the case of ambroxol it is the hydrochloride, in the case of phenylephrine it is preferably the hydrochloride.

In the case of halogenated isopropamide,
Preference is given to isopropamide bromide or isopropamide iodide, particularly preferably isopropamide iodide.

[0011]

DETAILED DESCRIPTION OF THE INVENTION Pseudoephedrine is USP.
(US Pharmacopoeia) XXIV, phenylephrine hydrochloride is listed in Japanese Pharmacopoeia XIV. Also,
Among ambroxol hydrochloride and halogenated isopropamide, isopropamide iodide is marketed as a drug, the former being WIC Co., Ltd. (Japan).
The latter is more readily available than the Procos SPA (Italy).

When the antirhinitis drug of the present invention is contained in a solid preparation, the weight% of pseudoephedrine is usually 0.01 to 50%, preferably 0.1 to 30%, and halogen. The weight percent of chlorinated isopropamide is usually 0.0005 to 2%, preferably 0.00
4 to 1%, and the weight% of ambroxol is usually 0.003 to 13%, preferably 0.0
3 to 8%, and the weight% of phenylephrine is usually 0.002 to 8%, preferably 0.
02 to 5%.

When the antirhinitis drug of the present invention is a liquid preparation, the content of pseudoephedrine is usually
0.1 to 200 mg / mL, preferably 1.0 to 100 mg / mL, and the content of halogenated isopropamide is usually 0.0005 to 4 mg / mL, preferably 0.004 To 2 mg / mL, the ambroxol content is usually 0.003 to 25 mg / mL, preferably 0.03 to 13 mg / mL, and the phenylephrine content is Usually, it is 0.002 to 16 mg / mL, and preferably 0.02 to 8 mg / mL.

In the present invention, in addition to the above active ingredients, if necessary, an antihistamine drug, an anti-inflammatory drug, caffeine,
Vitamins, crude drugs and the like can be added within a range that does not impair the effects of the present invention.

Specific dosage forms of the antirhinitis 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, hydroxypropylcellulose 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;

When the composition of the present invention is administered, the respective components of the composition can be administered simultaneously or separately at an interval.

The above-mentioned "simultaneous administration" is not particularly limited as long as it is a dosage form that can be administered at about the same time,
It is preferably administered as a single composition.

The above-mentioned "individually separated administration" is not particularly limited as long as it is an administration form that can be separately administered at different times. For example, one component is administered and then determined. The method of administering other components after a certain period of time is included.

In addition, when there are three or more components of the composition to be administered in total, "to administer at the same time or separately at a time" means to administer all of them at the same time. Method of simultaneously administering two or more kinds and simultaneously administering the rest of the medicine at a time, or method of administering two or more kinds of the same at a time and administering the rest of the medicine at the same time Including etc.

[0023]

EXAMPLES The present invention will be described in more detail below with reference to Examples, but the present invention is not limited thereto. (Example 1) Tablet (1) ingredient

[0024]

[Table 1]6 tablets (mg) 6 tablets (mg) 6 tablets (mg) Pseudoephedrine hydrochloride 180 180 90 Isopropamide iodide 7.5 − − Ambroxol hydrochloride − 45 − Phenylephrine hydrochloride − − 15 Magnesium oxide 400 400 400 Magnesium metasilicate aluminate 140 140 140 Crystalline cellulose 120 120 120 Corn starch 140 140 140 Hydroxypropyl cellulose 60 60 60 Croscarmellose sodium 15 15 15 Magnesium stearate 25 25 25 Triacetin 6 6 6Lactose Proper amount Proper amount Proper amount       Total 1400 1400 1400 (2) Manufacturing method Take the above ingredients and amounts, and add them to the "Tablets" section of the Japanese Pharmacopoeia General Regulations.
The tablets are manufactured according to the above. (Example 2) Fine granules (1) component

[0025]

[Table 2] 3 packs (mg) 3 packs (mg) 3 packs (mg) Pseudoephedrine hydrochloride 180 180 90 Isopropamide iodide 7.5-Ambroxol hydrochloride-45-Phenylephrine hydrochloride--15 Magnesium oxide 400 400 400 Magnesium aluminometasilicate 140 140 140 Purified sucrose 1400 1400 1400 Stevia extract product 15 15 15 Corn starch 1200 1200 1200 Polysorbate 80 80 80 80 Magnesium stearate 25 25 25 Lactose Suitable quantity Suitable quantity Total 4500 4500 4500 (2) Manufacturing method Above components And take an amount to prepare fine granules in accordance with the general regulations of the Japanese Pharmacopoeia, "Granules". Example (3) Capsule (1) component

[0026]

[Table 3] 6-capsules (mg) 6-capsules (mg) 6-capsules (mg) Pseudoephedrine hydrochloride 180 180 90 Isopropamide iodide 7.5 --- Ambroxol hydrochloride-45-phenylephrine hydrochloride--15 Magnesium oxide 400 400 400 Corn starch 630 630 630 Polysorbate 80 50 50 50 Magnesium stearate 25 25 25 Lactose Proper amount Proper amount Proper amount Capsules 480 480 480 Total 2500 2500 2500 (2) Manufacturing method After preparing the fine granules in the same manner, it is filled in capsules to prepare hard capsules. Example (4) Syrup (1) component

[0027]

[Table 4] 30 mL (mg) 30 mL (mg) 30 mL (mg) Pseudoephedrine hydrochloride 180 180 90 Isopropamide iodide 7.5 − − Ambroxol hydrochloride − 45 − Phenylephrine hydrochloride − − 15 Sodium benzoate 240 240 240 Citric acid 60 60 60 Sucrose 1500 1500 1500 Concentrated glycerin 1800 1800 1800 Polyvinyl alcohol 120 120 120 Hydrochloric acid Proper amount Proper amount Proper amount Sodium hydroxide Proper amount Proper amount Purified water Proper amount Proper amount Proper amount (2) Preparation method "
After preparing the syrup according to the item (1), fill a brown glass bottle to prepare the syrup. Test Example (1) Sneeze Suppressing Effect 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.

Inhibition rate (%) = [1-average number of sneezes in test substance-administered group / average number of sneezes in control group] × 100 (4) Test results Pseudoephedrine hydrochloride [P (mg / Kg)] and isopropamide iodide [ Table 5 shows the results of the sneeze inhibition rate for each of the single agents and the combination of I (mg / Kg)].

[0029]

[Table 5] P dose I dose P single agent inhibition rate% I single agent inhibition rate% P + I inhibition rate% 33 1.0 0 27 74 Excellent sneeze inhibition by combining pseudoephedrine hydrochloride and isopropamide iodide Showed the effect. Table 6 shows the results of the sneeze inhibition rate of each of the pseudoephedrine hydrochloride [P (mg / Kg)] and ambroxol hydrochloride [A (mg / Kg)] alone and in combination.

[0030]

[Table 6] P dose A dose P single agent inhibition rate% A single agent inhibition rate% P + A inhibition rate% 33 3.3 0 0 32 33 33 33 0 58 Combining pseudoephedrine hydrochloride and ambroxol hydrochloride Showed an excellent sneeze control effect. Table 7 shows the results of the sneezing inhibitory rate of each of the pseudoephedrine hydrochloride [P (mg / Kg)] and phenylephrine hydrochloride [F (mg / Kg)] alone and in combination.

[0031]

[Table 7] P dose F dose P single agent inhibition rate% F single agent inhibition rate% P + F inhibition rate% 33 1.0 0 23 47 47 33 10 0 56 77 By combining pseudoephedrine hydrochloride and phenylephrine hydrochloride, It showed excellent improvement in sneeze control effect.

[0032]

[Effects of the Invention] A drug containing pseudoephedrine of the present invention and a halogenated isopropamide, ambroxol and / or phenylephrine (particularly used for suppressing rhinitis, or sneezing or runny nose) shows a remarkable effect, It is useful as a medicine.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Yasuhiro Torizumi             3-5-1, Nihonbashihonmachi, Chuo-ku, Tokyo             Sankyo Co., Ltd. F-term (reference) 4C206 AA01 AA02 FA10 GA01 MA02                       MA03 MA43 MA55 MA57 MA61                       MA72 NA14 ZA34

Claims (8)

[Claims] 1. A pharmaceutical composition containing pseudoephedrine and halogenated isopropamide, ambroxol and / or phenylephrine. 2. The pharmaceutical composition according to claim 1, which contains pseudoephedrine and halogenated isopropamide. 3. The pharmaceutical composition according to claim 1, which contains pseudoephedrine and isopropamide iodide. 4. The pharmaceutical composition according to claim 1, which contains pseudoephedrine and ambroxol. 5. The pharmaceutical composition according to claim 1, which contains pseudoephedrine and phenylephrine. 6. The method according to any one of claims 1 to 5,
A pharmaceutical composition for use in rhinitis. 7. The method according to any one of claims 1 to 5,
A pharmaceutical composition, which is used for controlling sneezing. 8. The method according to any one of claims 1 to 5,
A pharmaceutical composition for use in controlling runny nose.