JP2022120384A - Medicine containing isopropamide iodide - Google Patents

Abstract

To provide means for preventing a pharmaceutical containing isopropamide iodide from discoloring with time.SOLUTION: A pharmaceutical contains the following components (A) and (B): (A) isopropamide iodide and (B) at least one compound selected from sodium bicarbonate, synthetic hydrotalcite, glycine, arginine and alanine.SELECTED DRAWING: None

Description

The present invention relates to medicaments containing isopropamide iodide.

Isopropamide iodide is a type of anticholinergic drug that suppresses the secretion of runny nose by blocking the parasympathetic nerves. However, there was a problem that the content decreased and discoloration occurred over time.

JP-A-08-325142 Japanese Patent Application Laid-Open No. 2004-143141

Under the above background, it has been proposed to add polyvinylpyrrolidone or a sugar alcohol to a solid preparation containing isopropamide iodide in order to suppress the decrease in the content of isopropamide iodide over time (Patent Document 1). , 2) achieves suppression of discoloration of medicines containing isopropamide iodide.
In order to cover up the above-mentioned discoloration, it is common practice to apply a film coating to the drug product. There is a demand for a material in which discoloration is not observed even in such cases.

An object of the present invention is to provide means for suppressing discoloration over time of a drug containing isopropamide iodide.

As a result of intensive studies by the present inventors, discoloration over time can be suppressed by using isopropamide iodide in combination with one or more compounds selected from sodium hydrogen carbonate, synthetic hydrotalcite, glycine, arginine and alanine. I found that I could do it, and completed the present invention.

That is, the present invention provides the following <1> to <7>.
<1> A medicament containing the following components (A) and (B).
(A) isopropamide iodide (B) one or more compounds selected from sodium bicarbonate, synthetic hydrotalcite, glycine, arginine and alanine

<2> The medicament according to <1>, wherein the component (B) is sodium hydrogen carbonate.
<3> The medicament according to <1> or <2>, wherein the content mass ratio of component (B) to component (A) [(B)/(A)] is 0.001 or more and 200 or less.
<4> The medicament according to <1> or <2>, wherein the content mass ratio of component (B) to component (A) [(B)/(A)] is 5 or more and 200 or less.

<5> The medicament according to any one of <1> to <4>, wherein the dosage form is a solid preparation.
<6> The pharmaceutical according to any one of <1> to <5>, wherein the dosage form is granules, fine granules, powders, tablets, pills, capsules or dry syrups.

<7> A method for inhibiting discoloration of a medicament, which comprises the step of adding one or more compounds selected from sodium hydrogen carbonate, synthetic hydrotalcite, glycine, arginine and alanine to a medicament containing isopropamide iodide.

ADVANTAGE OF THE INVENTION According to this invention, the time-dependent discoloration of the medicament containing isopropamide iodide can be suppressed.

[Pharmaceuticals]
(Component (A))
The medicament of the present invention contains (A) isopropamide iodide.
Isopropamide iodide can be produced by a known method, and a commercially available product can also be used.
The content of component (A) is preferably 0.01% by mass or more and 80% by mass or less, more preferably 0.05% by mass or more and 60% by mass or less, in the pharmaceutical of the present invention, from the viewpoint of discoloration suppressing effect, etc. 0.1% by mass or more and 30% by mass or less is more preferable, and 0.5% by mass or more and 15% by mass or less is particularly preferable.

(Component (B))
The medicament of the present invention contains (B) one or more compounds selected from sodium hydrogen carbonate, synthetic hydrotalcite, glycine, arginine and alanine. These compounds can be produced by known methods, and commercially available products can also be used. Arginine and alanine may be D-, L-, or DL-forms, but arginine is preferably L-arginine, and alanine is preferably DL-alanine.
Among component (B), sodium hydrogen carbonate, synthetic hydrotalcite, and glycine are preferred, and sodium hydrogen carbonate is more preferred, from the viewpoint of moldability, disintegrability, and the like.

The content of the component (B) is preferably 20% by mass or more and 99.99% by mass or less, more preferably 40% by mass or more and 99.95% by mass or less, in the medicament of the present invention from the viewpoint of discoloration suppression effect, etc. 70% by mass or more and 99.9% by mass or less is more preferable, and 85% by mass or more and 99.5% by mass or less is particularly preferable.

In addition, the content mass ratio of component (B) to component (A) [(B)/(A)] is 0.001 or more and 200 or less from the viewpoint of discoloration suppression effect, moldability, disintegration property, stability, etc. It is preferably 0.1 or more and 175 or less, more preferably 1 or more and 150 or less, still more preferably 5 or more and 125 or less, and particularly preferably 10 or more and 100 or less. When the content mass ratio [(B)/(A)] is 10 or more and 100 or less, discoloration is further suppressed for a long period of time.

In addition to components (A) and (B), the medicament of the present invention contains one or more selected from drugs other than components (A) and (B) (hereinafter also referred to as other drugs) and pharmaceutical excipients. You can stay.
Other drugs include, for example, anticholinergics (except isopropamide iodide), antacids (except sodium bicarbonate, synthetic hydrotalcite and glycine), anti-inflammatory agents, sedative hypnotics, antitussive expectorants, caffe Ins, antihistamines, antiallergic agents, vitamins, muscle relaxants, herbal medicines, and the like. One of these may be used alone, or two or more may be used in combination.

Examples of the anticholinergic drug include roth extract, roth root, belladonna total alkaloids, scopolamine hydrobromide, butyl scopolamine bromide, methylbenactidium bromide, thymepidium bromide, pirenzepine and the like. One of these may be used alone, or two or more may be used in combination.
The content of the anticholinergic drug (excluding isopropamide iodide) in the pharmaceutical of the present invention is usually 0% by mass or more and 10% by mass or less, preferably 0% by mass or more and 1% by mass or less, more preferably 0% by mass or more and 0% by mass. 0.1% by mass or less, more preferably 0% by mass or more and 0.01% by mass or less, and particularly preferably 0% by mass.

Examples of the antacid include precipitated calcium carbonate, calcium silicate, synthetic aluminum silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide/hydrogen carbonate. Examples include sodium coprecipitate, magnesium hydroxide/aluminum potassium sulfate coprecipitate, magnesium silicate, dihydroxyaluminum aminoacetate, magnesium carbonate, and the like. One of these may be used alone, or two or more may be used in combination.
The content of antacids (excluding sodium bicarbonate, synthetic hydrotalcite and glycine) in the medicament of the present invention is usually 0% by mass or more and 10% by mass or less, preferably 0% by mass or more and 1% by mass or less, and more It is preferably 0% by mass or more and 0.1% by mass or less, more preferably 0% by mass or more and 0.01% by mass or less, and particularly preferably 0% by mass.

Examples of the anti-inflammatory agent include ibuprofen and its salts, glycyrrhizic acid and its salts, tranexamic acid, glycyrrhetinic acid, sodium azulene sulfonate, aspirin, and salicylamide. One of these may be used alone, or two or more may be used in combination.

Examples of the hypnotic sedative include allylisopropylacetylurea, bromovalerylurea and the like. One of these may be used alone, or two or more may be used in combination.

Examples of the antitussive expectorant include ambroxol hydrochloride, L-ethylcysteine hydrochloride, potassium guaiacolsulfonate, potassium cresolsulfonate, guaifenesin, bromhexine hydrochloride, L-carbocysteine, codeine phosphate hydrate, dihydrocodeine Phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalate, dimemorphan phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride , dl-methylephedrine saccharin salt and the like. One of these may be used alone, or two or more may be used in combination.

Examples of the caffeine include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and the like. One of these may be used alone, or two or more may be used in combination.

Examples of the above antihistamines and antiallergic agents include mequitazine, azelastine hydrochloride, fexofenadine hydrochloride, epinastine hydrochloride, loratadine, cetirizine hydrochloride, olopatadine hydrochloride, alimemazine tartrate, carbinoxamine maleate, clemastine fumarate. acid salts, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, diphenhydramine hydrochloride and the like. One of these may be used alone, or two or more may be used in combination.

Examples of the vitamins include vitamin B1, vitamin B1 derivatives, vitamin B2, vitamin B2 derivatives, vitamin C, vitamin C derivatives, hesperidin, hesperidin derivatives, and salts thereof. One of these may be used alone, or two or more may be used in combination.

Examples of muscle relaxants include methocarbamol, chlorzoxazone, pridinol mesylate, chlorphenesin carbamate, eperisone hydrochloride, afloqualone, tizanidine hydrochloride and the like. One of these may be used alone, or two or more may be used in combination.

Examples of the herbal medicines include jiryu, cinnamon, licorice, peony, botanpi, chinpi, ginger, sansho, bellflower, ephedra, kyonin, hangge, chazensou, senega, rhinoceros, and shin'i. One of these may be used alone, or two or more may be used in combination.

The total content of other drugs in the medicament of the present invention is generally 0% by mass to 75% by mass, preferably 0% by mass to 50% by mass, more preferably 0% by mass to 10% by mass, and still more preferably is 0% by mass or more and 1% by mass or less.

Examples of the pharmaceutical additives include excipients such as lactose, lactose hydrate, sucrose, glucose, mannitol, sorbitol, xylitol, corn starch, and crystalline cellulose; croscarmellose sodium, carmellose, carmellose calcium, crospovidone , low-substituted hydroxypropylcellulose, disintegrants such as sodium carboxymethyl starch; surfactants such as sodium lauryl sulfate, sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol; gelatin, sodium alginate, hydroxypropylmethylcellulose, polyvinylpyrrolidone , carmellose sodium; lubricants such as talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerol fatty acid ester; fluidizers such as light anhydrous silicic acid and hydrous silicon dioxide; One of these may be used alone, or two or more may be used in combination. Further, solubilizing agents, buffering agents, preservatives, flavoring agents, pigments, sweeteners, corrigents and the like can be used as necessary.

The total content of pharmaceutical additives in the pharmaceutical of the present invention is usually 0% by mass or more and 99% by mass or less, preferably 0% by mass or more and 90% by mass or less, more preferably 0% by mass or more and 50% by mass or less, and particularly preferably is 0% by mass or more and 25% by mass or less.

The dosage form of the medicament of the present invention includes solid preparations (eg, granules, fine granules, powders, tablets, pills, capsules (soft capsules, hard capsules, etc.), dry syrups, etc.) or semi-solid preparations. (for example, jelly preparations, etc.) are preferable, and solid preparations are more preferable. Moreover, the medicament of the present invention is preferably for oral use. The average particle size of the granules is preferably 50-1000 μm, more preferably 50-500 μm. The average particle size can be measured by a sieving method.
Among the above dosage forms, granules, tablets and capsules are preferred, and granules and tablets are more preferred. Examples of tablets include uncoated tablets, film-coated tablets, sugar-coated tablets, orally disintegrating tablets, and chewable tablets. In addition, even in the case of a non-coated solid preparation such as an uncoated tablet, the medicament of the present invention is less likely to undergo discoloration over time and tends to maintain the color tone of its appearance.

The dosage of the medicament of the present invention is preferably such that 0.1 to 7.5 mg of isopropamide iodide can be taken per day, more preferably 3 to 7.5 mg per day. Also, the amount of isopropamide iodide is preferably 0.1 to 7.5 mg per dose, more preferably 1 to 2.5 mg per dose.

[Method for producing pharmaceutical, method for suppressing discoloration]
The medicament of the present invention comprises (A) a medicament containing isopropamide iodide and (B) a step of adding one or more compounds selected from sodium hydrogen carbonate, synthetic hydrotalcite, glycine, arginine and alanine (hereinafter referred to as (also referred to as step 1). According to this method, it is possible to easily produce a medicament that is resistant to discoloration over time despite containing isopropamide iodide.
In addition, in the manufacturing method of the medicine and the method for suppressing discoloration, the meaning of various terms, the compounding amount of each component, etc. are the same as those described for the medicine of the present invention.

(Step 1)
In step 1, the order in which the components (A) and (B) are added to the medicine does not matter.
As step 1, a step of mixing components (A) and (B) and, if necessary, other components (the drugs and pharmaceutical additives described above) is preferable. Specifically, a method of mixing components (A) and (B) and optionally other components to form a mixture, or mixing components (A) and (B) and optionally other components Alternatively, the obtained mixture may be kneaded with a solvent such as water or hydrous alcohol, if necessary, and then granulated by a known method to form granules.
The content mass ratio [(B)/(A)] in the composition obtained in step 1 is the same as the content mass ratio [(B)/(A)] in the desired pharmaceutical of the present invention. Preferably.

Further, when the granules are obtained in step 1, after step 1, drying, pulverization, sieving, spheroidizing treatment with marumerizer, coating with saccharides or polymers, and the like may be performed. Moreover, when the granular material is obtained in step 1, the obtained granular material can be used as it is as granules, fine granules, and powders. Tablets can be obtained by compressing the granules in a conventional manner, and capsules can be obtained by filling capsules with the granules in a conventional manner.

In addition, the medicament of the present invention obtained as described above is less likely to undergo discoloration over time in spite of containing isopropamide iodide.
The medicament of the present invention is extremely useful as a cold medicine, rhinitis medicine, anti-vertigo medicine, gastrointestinal medicine and the like.

EXAMPLES The present invention will be described in detail below with reference to Examples, but the present invention is not limited to these Examples.

[Test Example 1 Stability test]
After preparing each sample of the examples and comparative examples shown below, about 3 g of the sample was placed on a plastic tray and dried in a box dryer (PH-202/manufactured by Espec) at 60 ° C. under conditions without humidity control. After standing overnight, the presence or absence of discoloration of the sample was evaluated according to the following criteria. The results are shown in Tables 1-3.

-Example 1-
A sample of Example 1 was obtained by mixing 1.5 g of isopropamide iodide and 1.5 g of sodium hydrogencarbonate and kneading in a mortar while adding an appropriate amount (0.4 g) of purified water as kneading water.
- Examples 2 to 12, Comparative Examples 1 to 22 -
Samples of Examples 2 to 12 and Comparative Examples 1 to 22 were obtained in the same manner as in Example 1 except that the types and amounts of each component were changed to those shown in Tables 1 to 3.
-Comparative Example 23-
A sample of Comparative Example 23 was 1.5 g of isopropamide iodide.

(Stability evaluation criteria in Test Example 1)
A: White immediately after the start of storage and after standing overnight, no discoloration B: White immediately after the start of storage, but after standing overnight, the color changes from white to pale yellow C: White immediately after the start of storage However, after standing overnight, the color changes from white to yellow. D: White immediately after the start of storage, but after standing overnight, the color changes from white to deep yellow.

[Test Example 2 Stability test]
After the samples of Examples 5 and 6 and Comparative Example 23 were prepared in the same manner as in Test Example 1, about 3 g of the sample was placed on a plastic tray and dried at 60°C with a box dryer (PH-202/manufactured by ESPEC). After allowing to stand overnight in a dry condition, it was further allowed to stand in an open system at 30°C for one week. The presence or absence of discoloration of the sample after standing was evaluated according to the following criteria. Table 4 shows the results.

(Stability evaluation criteria in Test Example 2)
A: White immediately after the start of storage and after standing overnight + 1 week, no discoloration B: White immediately after the start of storage, but after standing overnight + 1 week, the color changes from white to pale yellow C: Start of storage White immediately after, but after standing overnight + 1 week, the color changes from white to yellow. D: White immediately after the start of storage, but after standing overnight + 1 week, the color changes from white to dark yellow.

[Formulation Example 1 Granules]
To 300 g of ibuprofen, 3.75 g of chlorpheniramine maleate, 3 g of isopropamide iodide, 30 g of dl-methylephedrine hydrochloride, 300 g of low-substituted hydroxypropylcellulose, 69.25 g of lactose hydrate and 30 g of sodium bicarbonate, purified water is added. After addition, 736 g of granulated powder was obtained after wet granulation by a conventional method, followed by drying and sizing.

[Formulation example 2 uncoated tablet]
155 g of crystalline cellulose, 25 g of light anhydrous silicic acid, 7 g of talc, and 7 g of magnesium stearate were added to the granulated powder obtained in Formulation Example 1, and mixed uniformly to obtain a powder for tableting. This powder for tableting was compression-molded by a rotary tableting machine in a conventional manner using a mortar and pestle with a diameter of 9.5 mm so that each tablet weighed 310 mg, to obtain uncoated tablets.

[Formulation Example 3 Hard Capsule]
To 248 g of the granulated powder obtained in Formulation Example 1, 2 g of talc was added and mixed uniformly, and the hard capsules (No. 2) of the Japanese Pharmacopoeia were filled so that the filling mass per capsule was 250 mg. got the drug.

Claims (7)

A medicament containing the following components (A) and (B).
(A) isopropamide iodide (B) one or more compounds selected from sodium bicarbonate, synthetic hydrotalcite, glycine, arginine and alanine 2. The medicament according to claim 1, wherein component (B) is sodium bicarbonate. The medicament according to claim 1 or 2, wherein the content mass ratio of component (B) to component (A) [(B)/(A)] is 0.001 or more and 200 or less. The medicament according to claim 1 or 2, wherein the content mass ratio of component (B) to component (A) [(B)/(A)] is 5 or more and 200 or less. The pharmaceutical according to any one of claims 1 to 4, wherein the dosage form is a solid preparation. The pharmaceutical according to any one of claims 1 to 5, wherein the dosage form is granules, fine granules, powders, tablets, pills, capsules or dry syrups. A method for inhibiting discoloration of a medicament, which comprises the step of adding one or more compounds selected from sodium hydrogen carbonate, synthetic hydrotalcite, glycine, arginine and alanine to a medicament containing isopropamide iodide.