JPH10203971A - Aqueous oral solution - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an aqueous oral solution not impairing stability of phenylpropanolamine in spite of a preparation formulated with a medicine component and various preparation additives. SOLUTION: This aqueous oral solution contains stable phenylpropanolamine or its salt formulated with one or more selected from xylitol, maltitol, mannitol and erythritol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a stabilized aqueous oral solution containing phenylpropanolamine hydrochloride which is effective for rhinitis.

[0002]

2. Description of the Related Art Phenylpropanolamine hydrochloride is a sympathomimetics having a pharmacological action similar to ephedrine. It is widely used as an agent for removing nasal congestion, a therapeutic agent for cough / cold, and used as a general drug as a rhinitis agent. Tablets and capsules containing the component are marketed. Considering the absorption of the drug into the body and the ease of taking the drug, development of an aqueous oral liquid preparation in addition to these preparations is desired. However, there is an aqueous solution of phenylpropanolamine hydrochloride
It has been reported that it reacts with lactose, sucrose and the like in the pH range and changes (J. Pharm. Sci., 71, 116).
(1982)). In addition, "Study on the change of drug compounding" (Report of Toyama Pharmaceutical Research Institute, 1984/1985, 12)
7, 1987) report that lysozyme chloride, guaiacol sulfonic acid, dextromethorphan hydrobromide and the like are contraindicated. In addition, it has been reported that mixing with ibuprofen causes a change in appearance and a decrease in content even in the case of a solid preparation (Japanese Patent Application Laid-Open No. 6-9382).

[0003]

In general, phenylpropanolamine hydrochloride is stable in a single aqueous solution (Briton-Robinson buffer) irrespective of pH, but it is used as an internal medicine solution or syrup with an improved feeling of taking a drug. It is known that its stability is impaired when formulated as (Pharm. Res. No. 9 Suppl. S-86 (1
990)). There is a need for the development of a practical and stabilized aqueous oral solution containing phenylpropanolamine hydrochloride, which is an effective drug component. It is an object of the present invention to provide a pharmaceutical composition comprising phenylpropanolamine or a pharmacologically acceptable salt thereof, and other pharmaceutical ingredients and various pharmaceutical additives, in which the stability of phenylpropanolamine is not impaired. To provide a novel aqueous oral liquid preparation.

[0004]

Means for Solving the Problems According to the present invention, studies have been made on the stabilization of an aqueous preparation containing phenylpropanolamine or a salt thereof. It has been found that the decomposition is remarkably suppressed, and that the contraindicated components are stably changed mutually, thereby completing the present invention. That is, the present invention relates to (1) an aqueous oral liquid preparation containing phenylpropanolamine or a salt thereof containing one or more selected from xylitol, maltitol, mannitol and erythritol, and (2) a pH of about 3-7. The aqueous oral solution according to the above (1), wherein (3) the salt of phenylpropanolamine is phenylpropanolamine hydrochloride, and the aqueous oral solution according to the above (1); (5) an aqueous oral liquid preparation according to the above (1), which is a stabilized preparation; and (6) xylitol, maltitol, for an aqueous oral liquid preparation containing phenylpropanolamine or a salt thereof. (7) xylitol, a stabilizer comprising one or more selected from mannitol and erythritol;
The present invention relates to a method for stabilizing an aqueous oral liquid solution of phenylpropanolamine or a salt thereof comprising one or more selected from maltitol, mannitol and erythritol.

In the aqueous oral liquid preparation of the present invention, xylitol, maltitol, mannitol and erythritol are all commercially available and can be used as they are. These components can be used alone or in combination of two or more. When used alone,
Mannitol is preferred. When two or more kinds are used in combination, for example, a combination of maltitol and erythritol, mannitol and erythritol, or xylitol and erythritol is preferable. The compounding amount of these components (including a single compound or a combination of two or more compounds) is at least about 5 W / V%.
Above, preferably about 10 W / V% or more. If the amount is less than these, the stabilizing effect of phenylpropanolamine may not be obtained. When these components are expected to play a role as an excipient or a sweetener, 20 to 20
It can be added up to 50 W / V%, preferably 30 to 40 W / V%. If the compounding amount of these components is specifically shown, about 5 to 50 W / V%, preferably about 10 to 40 W / V
V%, more preferably about 10 to 30 W / V%. In the aqueous oral liquid preparation of the present invention, phenylpropanolamine or a salt thereof is blended in an amount of about 0.01 to 1.0 W / V%, preferably about 0.03 to 0.5 W / V%. When formulated as an active ingredient in a cold medicine, it is usually used in an amount of about 0.1.
01-1.0 W / V%, preferably about 0.01-0.5 W
/ V%, more preferably about 0.03-0.5 W / V%,
Most preferably, it is about 0.03-0.2 W / V%. Salts include acid addition salts, such as hydrochlorides.

[0006] The oral aqueous solution of the present invention has a pH of about 3-7.
It is adjusted to be within the range. The pH value can be appropriately selected within a range that does not impair the stability of the compounded various active ingredients. As a pH adjuster for adjusting pH, a base such as an inorganic acid or alkali, for example, hydrochloric acid,
Examples thereof include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate and the like, and further, organic acids such as citric acid, malic acid, tartaric acid, succinic acid and salts thereof. The preparation of pH may be carried out according to a method generally used in the technical field of aqueous oral liquids for adjusting pH or a method analogous thereto. The aqueous oral solution of the present invention,
Still other pharmaceutical ingredients, such as antipyretic analgesic anti-inflammatory, antihistamine, antitussive expectorant, bronchodilator, allergy agent,
An enzyme preparation, a hemostatic agent, vitamins and the like can be added.

[0007] Antipyretic analgesics and anti-inflammatory agents include, for example, acetaminophen, phenacetin, mefenamic acid, aspirin, etensamide, choline salicylate, sodium salicylate, antipyrine, phenylbutazone, sulpyrine, diclofenac sodium, aluminoprofen,
Ibuprofen, ketoprofen, naproxen, loxoprofen sodium, tinolidine hydrochloride, epilizol, tiaramid hydrochloride, indomethacin, acemethasin,
Examples of antihistamines such as graphenin, pentazocine, acetylcholine chloride, dimethothiazine mesylate, piroxicam, salicylamide, and the like include, for example, promethazine, alimemazine tartrate, triprolidine hydrochloride, dimethindene maleate, cyproheptadine hydrochloride, diphenhydramine, chlorpheniramine maleate, carbinamine maleate, Doxylamine succinate, pyrilamine maleate, diphenhydramine hydrochloride, anhydrous caffeine, caffeine, etc., as antitussive expectorants, bronchodilators, allergy agents, for example, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, Dimemorphan phosphate, pentoxiverine citrate, tipepidine hibenzate, isoaminyl citrate, cloperastine hydrochloride, noscapine, Unin water, Shazensou, Senega, Carbocysteine, Ambroxol hydrochloride, Theophylline, Aminophylline, Ephedrine hydrochloride, Epinephrine hydrochloride, Terbutaline sulfate, Salbutamol sulfate, Trimethquinol hydrochloride, Tulobuterol hydrochloride, Procaterol hydrochloride, Fenoterol hydrobromide, Fumaric acid, Fumaric acid Formoterol, oxatomide, methylephedrine hydrochloride,
Guaifenesin, bromhexine hydrochloride, etc.), enzyme preparations such as lysozyme chloride, and hemostatic agents such as
For example, tranexamic acid, sodium alginate and the like can be mentioned.

[0008] The aqueous oral liquid preparation of the present invention may contain various vitamins. The vitamin A group, e.g. retinol, retinoic acid, retinal, and examples of the vitamin B ₁ group, for example thiamine, thiamine mononitrate, thiamine hydrochloride; thiamine propyl disulfide, thiamine tetrahydrofurfuryl disulfide, thiamine-8- (methyl-6- Acetyl dihydrothioctoate) disulfide, thiamine disulfide, O-benzoyl thiamine disulfide, thiamine monophosphate disulfide, O, S-dibenzoyl thiamine, S
-Benzoylthiamine-O-monophosphate, O,
S- radical Viet carboxymethyl thiamine vitamin B ₁ derivatives and their salts, such as vitamin B ₂ group, for example riboflavin, riboflavin sodium phosphate, riboflavin butyrate and the like, as vitamin B ₆ group, for example pyridoxine, pyridoxal, pyridoxamine and these phosphoric acid or hydrochloride, etc. Examples of the vitamin B ₁₂ group, e.g. cobalamin, cyanocobalamin, methylcobalamin,
Vitamin Cs such as adenosylcobalamin and hydroxocobalamin; ascorbic acid, sodium ascorbate and calcium ascorbate; vitamin D groups such as ergocalciferol and cholecalciferol; vitamin E groups such as tocopherol , Nicotinic acid, nicotinic acid amide, and the like, as the niacin group, phytonadione, menadione, menakion, and the like, as the vitamin K group, and pantothenic acid, biotin, folic acid, and the like as the other vitamin groups. be able to. In the aqueous oral liquid preparation of the present invention, the general pharmaceutical production approval standard (19
Herbal medicines listed in the Chinese herbal prescription and Chinese herbal prescriptions listed in the 1995 edition) can be blended. Crude medicines include, for example, ephedra, spinach, calyx, and ground dragon. Examples of Kampo preparations described as Kampo formulas include Kakkonto, Keishito, Saikokeishito and the like. The herbal medicine and the Chinese medicine are preferably formulated as an extract. In the aqueous oral solution of the present invention, various additives for formulation used in general solutions, for example, flavoring agents,
Preservatives, preservatives, flavors, fragrances, fresheners, surfactants, solubilizers, emulsifiers, solvents, buffers, suspending agents, thickeners, colorants, stabilizers, solubilizers One or more bitterness masking agents and the like can be selected and blended in an amount to be blended with general oral liquid preparations.

Examples of the flavoring agent include sweeteners (eg, fructose, glucose, honey, sorbitol, aspartame, stevioside, dipotassium glycyrrhizinate, etc.) and acidulants (eg, citric acid, tartaric acid, malic acid and edible salts thereof). , Fruit juices and the like. Examples of the preservative or preservative include sodium benzoate, sodium sorbate, and parabens (for example, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, etc.). Flavoring agents, fragrances, fresheners,
For example, orange oil, menthol, various flavors (for example, strawberry flavor, cherry flavor, orange flavor, apple flavor, lemon flavor, grape flavor, coffee flavor, black tea flavor, bitter flavor, herb mint flavor, chocolate flavor, condiment flavor, etc.) And the like. Examples of the surfactant, solubilizer, emulsifier or solvent include sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate 8
0, glycerin, ethanol, propylene glycol,
Polyethylene glycols (eg, Macrogol 40
0), distilled water for injection and the like. Examples of the buffer include phosphoric acid, lactic acid, acetic acid, carbonic acid and edible salts thereof, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate and the like. Examples of the suspending agent or the thickening agent include gum arabic, crystalline cellulose, veegum, xanthan gum, gelatin, metrose and its edible salt, carmellose and its edible salt and the like. Examples of the coloring agent include caramel, β-carotene, various food colorings (food yellow No. 1, food red No. 2, etc.) and the like. Stabilizers incorporated in the present invention include, for example, edible acid edible salts, sodium chloride, edible salts of pyrosulfite and the like. Examples of the solubilizer include cyclodextrin and arginine. Examples of the bitterness masking agent include phosphatidyls (BMI-60; Kao). The aqueous oral liquid preparation of the present invention can be produced by a conventional method, and the method is not particularly limited. Usually, each component and a part of purified water are previously mixed and dissolved, and the remaining water is added to adjust the liquid volume. Further, at the time of dissolution, purified water may be heated according to a general method for preparing an oral liquid preparation, the head space may be replaced with nitrogen at the time of filling in a container, or filtration or sterilization may be performed. The aqueous liquid preparation of the present invention is useful, for example, as a liquid preparation for medical use such as a drink preparation and a syrup preparation, particularly a liquid preparation for cold medicine.

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described more specifically below with reference to examples and test examples.

【Example】

Example 1 The following components were used to prepare a cold medicine oral solution per adult daily dose [3 bottles (60 ml)]. Phenylpropanolamine hydrochloride 0.0625 W / V%
Mannitol was contained at 13.3 W / V%, respectively. Acetaminophen 900 mg dihydrocodeine phosphate 24 mg phenylpropanolamine hydrochloride 37.5 mg anhydrous caffeine 150 mg ascorbic acid 500 mg sodium citrate 500 mg sodium benzoate ... 40 mg Propylene glycol ... 2 g Macrogol 400 ... 1.5 g Ethyl parahydroxybenzoate ...・ 7 mg mannitol ・ ・ ・ ・ 8 g honey ・ ・ ・ ・ ・ ・ ・ 4 g flavor・ ・ ・ ・ ・ ・ ・ 55 μL Sodium hydroxide ・ ・ ・ Appropriate amount of hydrochloric acid・ ・ ・ ・ ・ ・ ・ ・ ・ ・ Appropriate amount Dissolve each of the above components in a part of purified water at room temperature, adjust the pH to 6.5 with sodium hydroxide, and add Was adjusted to 60 ml.

Example 2 A cold remedy was prepared in the same manner as in Example 1, except that 8 g of erythritol (13.3 W / V% based on the total amount) was used instead of 8 g of mannitol.

Example 3 In the same manner as in Example 1, except that 4 g of mannitol and 4 g of erythritol (the sum of both was 13.3 W / V% based on the total amount) were used instead of 8 g of mannitol. An oral solution was prepared.

Example 4 A cold remedy was prepared in the same manner as in Example 1 except that 12 g of mannitol (20 W / V% based on the total amount) was used instead of 8 g of mannitol.

Example 5 A cold remedy was prepared in the same manner as in Example 1 except that 18 g of mannitol (30 W / V% based on the total amount) was used instead of 8 g of mannitol.

Example 6 In Example 1, phenylpropanolamine hydrochloride 3
A cold medicine oral solution was prepared in the same manner as in Example 1 except that phenylpropanolamine hydrochloride 60 mg (0.1 W / V% based on the total amount) was used instead of 7.5 mg.

Example 7 In Example 1, phenylpropanolamine hydrochloride 3
A cold medicine oral solution was prepared in the same manner as in Example 1 except that 90 mg of phenylpropanolamine hydrochloride (0.15 W / V% based on the total amount) was used instead of 7.5 mg.

Test Example 1 Storage stability test of phenylpropanolamine in a cold medicine oral solution Briton-Robinso
n) The same components as in Example 1 were dissolved in a buffer at room temperature,
After adjusting the pH to 6.7 with sodium hydroxide, the total volume was adjusted to 60 ml. Inject 20 ml of the prepared cold solution into a 25 ml brown glass container, replace the air in the upper space of the container with nitrogen gas, and store at 50 ° C for 4 weeks or 8 weeks. The remaining amount of propanolamine was quantified and measured by high performance liquid chromatography. The results are shown in the following table.

[Table 1] From the above table, it is clear that the liquid for oral administration of the cold of Test Example 1 has a very small decrease in the content of phenylpropanolamine hydrochloride even after the lapse of 4 weeks and after the lapse of 8 weeks.

Test Example 2 Storage stability test of phenylpropanolamine hydrochloride Four components of sucrose were selected as mannitol, maltitol, xylitol and comparative components of the present invention, and the stabilizing effects of these components were examined. . That is, these four components were dissolved in a sodium hydrogen phosphate-citrate buffer to prepare a solution having a concentration of 180 mg / ml for each component (two levels of pH 4.5 and pH 6.5). Propanolamine was added to 4 mg / ml to obtain a total of eight solutions. Each of these solutions was poured into a brown glass container having a capacity of 20 ml by 10 ml,
After sealing and storing at 80 ° C. for 4 weeks, the remaining amount of phenylpropanolamine hydrochloride in each solution was quantified and measured by high performance liquid chromatography. The results are shown in the following table.

[Table 2] From the above table, it was observed that the addition of sucrose resulted in a decrease in the content of phenylpropanolamine hydrochloride in both the acidic and neutral regions, whereas D-mannitol, maltitol and xylitol resulted in a small decrease in the content and stabilization. It was observed. This tendency is particularly strong in the neutral region. In particular, mannitol exhibited excellent stabilizing action in both acidic and neutral regions.

[0019]

The aqueous oral liquid preparation of the present invention is stable for a long period of time because the content of phenylpropanolamine hydrochloride is prevented from decreasing over time.

Claims (7)

[Claims] 1. An aqueous oral liquid preparation containing phenylpropanolamine or a salt thereof, containing one or more selected from xylitol, maltitol, mannitol and erythritol. 2. The aqueous oral liquid preparation according to claim 1, wherein the pH is about 3-7. 3. The aqueous oral liquid preparation according to claim 1, wherein the salt of phenylpropanolamine is phenylpropanolamine hydrochloride. 4. The aqueous oral liquid preparation according to claim 1, which is a liquid for taking a cold medicine. 5. The aqueous oral liquid preparation according to claim 1, which is a stabilized preparation. 6. A stabilizer comprising one or more selected from xylitol, maltitol, mannitol and erythritol for use in an aqueous oral solution containing phenylpropanolamine or a salt thereof. 7. A method for stabilizing an aqueous oral liquid solution of phenylpropanolamine or a salt thereof, comprising one or more selected from xylitol, maltitol, mannitol and erythritol.