JP2014070055A - Liquid pharmaceutical composition for oral administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a liquid pharmaceutical composition for oral administration in which the bitterness caused by bromhexine and/or salt thereof is masked.SOLUTION: In a pharmaceutical composition containing 0.05 wt.% or more of (A) bromhexine and/or salt thereof, 0.1 pts.wt. or more of (B) acesulfame potassium is blended with respect to 1 pts.wt. of the (A) component.

Description

  The present invention relates to a liquid pharmaceutical composition for oral administration in which the bitter taste by bromhexine and / or a salt thereof is masked.

  Bromhexine and its salts are pharmacologically active ingredients developed based on the active ingredients of Adhatoda vasica, an Indian herbal medicine, and are usually used in the form of bromhexine hydrochloride. Bromhexine has the effect of increasing serous secretions in the respiratory tract to facilitate sputum, and has an expectorant effect. For the purpose of expectoration of respiratory diseases, symptoms such as colds, rough throats, and coughs It is considered effective against. In addition, bromhexine hydrochloride may be used as a general cold medicine in combination with other antitussive expectorant, bronchodilator, anti-inflammatory enzyme, anti-inflammatory drug and the like.

  Drugs are prepared in various dosage forms depending on the type of active ingredient and the age of the patient to which they are applied. However, antitussive expectorant tends to be preferred because it is relatively easy to take. is there. However, bromhexine has a strong bitter taste, and the bitterness is further emphasized particularly when prepared as a liquid preparation. Therefore, various studies have been made to mask the bitter taste derived from bromhexine. One of them is a method of blending sucrose with bromhexine. However, since a large amount of sucrose is required to mask the strong bitterness derived from bromhexine, it is difficult to maintain the balance between bitterness masking and sweetness, and the excessive sweetness causes a problem that the feeling of administration is impaired. It was. Moreover, there also existed a problem that sugar content and a calorie became high by mix | blending a large amount of sucrose. In addition, as a technique for masking the bitter taste of bromohexine, there is known a method in which a sweetener such as maltitol, erythritol, thaumatin and the like are combined with bromohexine hydrochloride (for example, see Patent Documents 1 to 3). However, both of these techniques are effective when the content of bromohexine hydrochloride is 0.1% by weight or less, and a sufficient bitter taste masking effect in a pharmaceutical composition containing a higher concentration of bromohexine hydrochloride. It was difficult to realize.

  In order to mask the bitter taste of the target drug within an appropriate sweetness range, a method of reducing the concentration of bromhexine in a single dose can be considered. However, reducing the concentration of the active ingredient and obtaining a medicinal effect inevitably increases the dose and frequency of administration of the liquid, resulting in increased patient burden. In addition, when the single dose is large, the size of the product becomes large, the portability of the product is poor, and a new problem has arisen that it is difficult to take while away from home.

  As means for improving the convenience of taking the liquid agent, there is a method using a container provided with a discharge device (for example, Patent Document 4). Since such a container is excellent in portability and easy to take on the go, it is useful for solving the above-mentioned problems of the liquid agent. However, when taking such a device, since the discharge amount is limited, it is necessary to concentrate the chemical solution, and in the case of a liquid agent containing bromohexine, there is a better bitterness masking technology. Necessary.

  From the background as described above, there has been a demand for a liquid pharmaceutical composition that is effective in masking bitterness while having a relatively high concentration of bromhexine, and that has excellent dosing properties.

JP-A 63-313725 JP-A-10-36292 Japanese Patent Laid-Open No. 10-306038 JP 2007-277125 A

  The main object of the present invention is to provide a liquid pharmaceutical composition for oral administration in which the bitter taste of bromhexine and / or a salt thereof is masked.

  As a result of intensive studies to solve the above problems, the present inventors have effectively masked the bitterness of a liquid pharmaceutical composition for oral administration containing a combination of bromohexine and / or a salt thereof and acesulfame potassium. I found out that Further, the present inventors have found that an even better bitterness masking effect can be obtained by further blending aspartame or monoterpene with the above composition. Furthermore, the present inventors have found that such a liquid pharmaceutical composition is a formulation suitable for taking a medicine directly injected into the oral cavity. The present invention has been completed as a result of further research based on these findings.

That is, this invention provides the liquid pharmaceutical composition and pharmaceutical product for oral administration of the following aspect.
Item 1. A liquid pharmaceutical composition for oral administration comprising (A) bromhexine and / or a salt thereof and (B) acesulfame potassium,
The oral administration, wherein the content of the component (A) is 0.05% by weight or more, and the blending ratio of the component (B) is 0.1 parts by weight or more with respect to 1 part by weight of the component (A). Liquid pharmaceutical composition.
Item 2. Item 2. The liquid pharmaceutical composition for oral administration according to Item 1, wherein the content of the component (A) is 0.05 to 2% by weight.
Item 3. The liquid pharmaceutical composition for oral administration according to Item 1 or 2, further comprising (C) aspartame.
Item 4. Item 4. The liquid pharmaceutical composition for oral administration according to any one of Items 1 to 3, further comprising (D) a monoterpene.
Item 5. Item 5. The liquid pharmaceutical composition for oral administration according to any one of Items 1 to 4, wherein the monoterpene is menthol.
Item 6. Item 6. The liquid pharmaceutical composition for oral administration according to any one of Items 1 to 5, wherein the blending ratio of the component (C) is 0.1 to 1 part by weight with respect to 1 part by weight of the component (A).
Item 7. Item 7. The liquid pharmaceutical composition for oral administration according to any one of Items 1 to 6, wherein the content of the component (D) is 0.0025 to 0.025% by weight.
Item 8. Item 8. The liquid pharmaceutical composition for oral administration according to any one of Items 1 to 7, which is for antitussive expectorant.
Item 9. Item 9. A pharmaceutical product, wherein the liquid pharmaceutical composition for oral administration according to any one of Items 1 to 8 is contained in a container equipped with a discharge device.

  According to the present invention, there is provided a liquid pharmaceutical composition for oral administration which is easy to take, having a bitter taste masked effectively while containing bromhexine and / or a salt thereof at a high concentration of 0.05% by weight or more. . Furthermore, the pharmaceutical composition of the present invention not only masks the bitter taste of bromohexine by acesulfame potassium, but also exhibits a good feeling of taking in which the balance between bitterness and sweetness is maintained without causing excessive sweetness. . Conventionally, liquid pharmaceutical products are generally taken after being transferred from a container to a measuring cup or the like, but the pharmaceutical composition of the present invention can be carried in a container equipped with a discharge device. Since there is no need to measure it occasionally, it is excellent in portability and convenience for taking and can be stored hygienically. Since the bitterness of the pharmaceutical composition of the present invention is effectively masked, it is difficult to feel the bitterness even if it is ejected as droplets from a container equipped with such a discharge device, and the feeling of taking is good. Presents.

1. Liquid pharmaceutical composition for oral administration The liquid pharmaceutical composition for oral administration of the present invention comprises (A) bromohexine and / or a salt thereof and (B) acesulfame potassium,
The content of the component (A) is 0.05% by weight or more, and the blending ratio of the component (B) is 0.1 part by weight or more with respect to 1 part by weight of the component (A). To do. In the present specification, the liquid pharmaceutical composition for oral administration of the present invention may be abbreviated as “the pharmaceutical composition of the present invention” or “the liquid pharmaceutical composition”.

Component (A): Bromohexine and / or its salt Bromohexine is a known compound having antitussive expectorant action. In the present invention, a salt of bromhexine can be similarly used as the component (A). Here, examples of the salt include inorganic acid salts such as sulfates, hydrochlorides, carbonates and phosphates; organic acid salts such as malic acid, tartaric acid, citric acid and gluconic acid, preferably inorganic acid salts, Preferably, hydrochloride is used. In the present invention, commercially available bromhexine and / or a salt thereof can be used.

  In the present invention, as the component (A), one kind selected from the bromohexyne and its salt may be used alone, or two or more kinds may be used in combination.

  The content of the component (A) in the pharmaceutical composition of the present invention is 0.05% by weight or more, preferably 0.05-2% by weight, more preferably 0.05-1% by weight, still more preferably 0.05-0.5 weight%, More preferably, 0.05-0.2 weight% is mentioned. The liquid pharmaceutical composition containing the component (A) at such a concentration usually feels a strong bitter taste when taken, but in the present invention, it is bitter by combining the component (B) described later. Is effectively masked and does not impair the feeling of taking.

Component (B): Acesulfame potassium Acesulfame potassium is a compound known as a high-intensity sweetener. In the present invention, commercially available acesulfame potassium can be used.

  The blending ratio of acesulfame potassium is 0.1 parts by weight or more, preferably 0.1 to 10 parts by weight, preferably 0.1 to 5 parts by weight, more preferably 1 part by weight of the component (A). Is 0.1 to 1 part by weight. By blending acesulfame potassium in the above ratio with respect to the component (A), an even better bitterness masking effect is exhibited. In addition, by blending acesulfame potassium in such a range, the balance between the bitterness and sweetness of the liquid pharmaceutical composition can be kept good, and the ingestion feeling of the pharmaceutical composition of the present invention can be further improved. .

  The content of acesulfame potassium in the pharmaceutical composition of the present invention is 0.005 to 0.1% by weight, preferably 0.005 to 0.075% by weight, more preferably 0.01 to 0.075% by weight. %.

(C) Component: Aspartame The pharmaceutical composition of the present invention may further contain aspartame. By blending aspartame, an even better bitterness masking effect can be obtained. Aspartame is a compound known as a high intensity sweetener. In the present invention, commercially available aspartame can be used.

  The mixing ratio of aspartame is 0.05 to 2 parts by weight, preferably 0.05 to 1 part by weight, and more preferably 0.1 to 1 part by weight with respect to 1 part by weight of the component (A). The content of aspartame in the pharmaceutical composition of the present invention is 0.005 to 0.2% by weight, preferably 0.005 to 0.1% by weight, more preferably 0.005 to 0.075% by weight. Is mentioned. By setting the aspartame content in the above range, effective masking of bitterness is realized.

(D) Component: Monoterpene The pharmaceutical composition of the present invention may further contain a monoterpene. By blending monoterpene, an even better bitterness masking effect can be obtained.

  Terpenes are also called isoprenoids or terpenoids, and are usually compounds in which a plurality of isoprene units (5 carbon atoms) are bonded. Monoterpenes have a structure containing two isoprene units.

  Specific examples of monoterpenes include limonene, menthone, pinene, menthol, geraniol, linalool, thymol, borneol, perylaldehyde, citral, citronellal, camphor, cineole, and preferably menthol.

  In the present invention, when an optical isomer exists in monoterpene, any of d-form, l-form, and dl-form may be used. The monoterpene may be used alone or in combination of two or more.

  The monoterpene content in the pharmaceutical composition of the present invention is 0.0025 to 0.025% by weight, preferably 0.0025 to 0.02% by weight, more preferably 0.005 to 0.02% by weight. Can be mentioned. By setting the monoterpene content in the above range, the bitterness masking effect derived from the component (A) can be further enhanced. Moreover, if it is in the said range, there is no possibility of giving an excessive irritation | stimulation and an astringent feeling to an intraoral area by a terpenoid, and it can provide a favorable taking feeling.

Preferred Embodiment The pharmaceutical composition of the present invention is orally used together with the above-mentioned components (A) to (D), together with pharmaceutically acceptable carriers, additives and the like which are usually used in liquid pharmaceutical compositions for oral administration. It is prepared as a solution.

  As the carrier, those commonly used in liquid pharmaceutical compositions for oral administration can be used, and are not particularly limited. Examples thereof include water (ion-exchanged water, distilled water, purified water, etc.), physiological saline and the like. It is done. In the present invention, the content of these carriers is adjusted so as to correspond to the balance other than the above components (A) to (D) and other optional components.

  Additives include flavoring agents, preservatives, preservatives, flavoring agents, fragrances, refreshing agents, surfactants, solubilizers, emulsifiers, solvents, buffering agents, suspending agents, thickening agents, coloring agents. , Stabilizers, solubilizers, pH adjusters, sweeteners and the like.

  Examples of the corrigent include sour agents (for example, 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 (eg, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, etc.) and the like. 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.). Surfactants, solubilizers, emulsifiers or solvents include, for example, sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil, polysorbate 80, glycerin, D-sorbitol, ethanol, propylene glycol, polyethylene glycols (eg, macro Goal 400), 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 thickening agent include gum arabic, crystalline cellulose, bee gum, xanthan gum, gelatin, metrose and edible salts thereof, carmellose and edible salts thereof. Examples of the colorant include caramel, β-carotene, various food colors (food yellow No. 1, food red No. 2, etc.) and the like. Examples of the stabilizer blended in the present invention include an edible salt of edetic acid, sodium chloride, and an edible salt of pyrosulfite. Examples of the solubilizer include cyclodextrin and arginine.

  Examples of the pH adjuster include phthalic acid, phosphoric acid, citric acid, succinic acid, acetic acid, fumaric acid, malic acid, carbonic acid and potassium salts, sodium salts or ammonium salts thereof, sodium hydroxide, and the like. The pH of the pharmaceutical composition of the present invention is not particularly limited as long as it does not cause safety problems in the oral cavity and the human body. For example, 1 g of the pharmaceutical composition of the present invention is dissolved in 100 mL of water at 25 ° C. In this case, the pH is 3.0 to 6.0. The pharmaceutical composition of this invention can be adjusted to the said range using the said pH adjuster as needed.

  Moreover, the pharmaceutical composition of this invention may contain sweeteners other than the said (B) and (C) component in the range which does not impair the effect of this invention. Examples of the sweetener include stevia extract, licorice extract, and saccharin sodium. The compounding quantity of these sweeteners is 0.0001 to 1 weight%, for example, Preferably it is 0.0001 to 0.5 weight%, More preferably, 0.005 to 0.1 weight% is mentioned.

  The content of the additive in the pharmaceutical composition of the present invention can be appropriately set according to the amount of each component contained, the carrier, the type of additive, etc., but the total amount of the additive is 1 to 50% by weight. Can be mentioned.

  In addition, the pharmaceutical composition of the present invention contains pharmacologically active ingredients such as antitussives, bronchodilators, expectorants, antiphlogistics, antipyretic analgesics, antihistamines, bactericides, etc., as long as the effects of the active ingredients are not impaired. Further, it may be included.

  Antitussives include, for example, codeine phosphate, dihydrocodeine phosphate, hydrocodone, hydromorphone, methadone, morphine, oxymethebanol, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate, tipepidine citrate, dibutate sodium, hydrogen bromide Acid dextromethorphan, dextromethorphan, phenolphthalic acid, tipepidine hibenzate, cloperastine fendizoate, noscapine, maou, nantenjitsu, clofedanol, levopropoxyphene, hominoben, oxeradin, pentoxyberine, benproberine, dimemorphan, dipranate, epradinone , Carbetapentane and isoaminyl.

  Examples of bronchodilators include α-adrenergic receptor stimulators (eg, phenylpropanolamine, pseudoephedrine, phenylephrine, norepinephrine, methoxamine, naphazoline, xylometazoline, clonidine, etc.), β-adrenergic receptor stimulators (eg, trihydrochloride hydrochloride). Metoquinol, methoxyphenamine hydrochloride, dl-methylephedrine hydrochloride, tyramine, ephedrine, methylephedrine saccharinate, amphetamine, methamphetamine, methoxyphenamine, orciprenaline, chlorprenalin, isoproterenol, dopamine, dobutamine, isoprenaline, salbutamol, Terbutaline, hexoprenalin, tubuterol, fenoterol, procaterol, pyrbuterol, clenbuterol, ma Buterol, formoterol, salmeterol, etc.), xanthine derivatives (eg, aminophylline, diprophyrin, theophylline, proxyphylline, xanthine, theobromine, pentoxyphyllin, etc.) or salts thereof, anticholinergic agents (eg, datsura extract, belladonna alkaloid, belladonna total alkaloid, Belladonna extract, funnel extract, etc.) and parasympathomimetic blocking agents (eg, isopropamide iodide, ipratropium, furtropium, oxitropium, etc.).

  Examples of expectorants include, for example, ammonium chloride, ammonia fennel, lysozyme chloride, ethyl cysteine hydrochloride, methyl cysteine hydrochloride, potassium guaiacol sulfonate, guaifenesin, potassium cresol sulfonate, ambroxol hydrochloride, L-carbocysteine, fudosteine, etc. Is mentioned.

  Examples of the anti-inflammatory agent include lysozyme chloride, glycyrrhizic acid, dipotassium glycyrrhizinate, and sodium azulene sulfonate.

  Examples of antipyretic analgesics include acetaminophen, ibuprofen, aspirin, etenzaamide and the like.

  Antihistamines include, for example, istipendil hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyralin hydrochloride, diphenhydramine hydrochloride, triprolidine hydrochloride, tripelamine hydrochloride, tonsilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, and tartaric acid tartaric acid. , Diphenhydramine tannate, phenetazine tannate, diphenylpyraline teuroate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, chlorpheniramine maleate, dipheterol phosphate, and the like.

  Examples of the disinfectant include cetylpyridinium chloride, decalinium chloride, chlorhexidine hydrochloride, and the like.

  The content of the pharmacologically active ingredient in the pharmaceutical composition of the present invention can be appropriately set according to the amount of each ingredient contained, the carrier, the effective amount of the pharmacologically active ingredient, and the like. 0001 to 10% by weight.

  Since the pharmaceutical composition of the present invention contains bromhexine and / or a salt thereof as component (A) at a high concentration of 0.05% by weight or more, it can exhibit an excellent antitussive expectorant action by bromhexine. That is, the pharmaceutical composition of the present invention is preferably used for general cold medicine, antitussive expectorant, internal medicine for rhinitis, antipyretic analgesic and the like, and particularly useful for antitussive expectorant.

  The daily dose of the pharmaceutical composition of the present invention is not particularly limited as long as the effect of the component (A) is obtained. The amount of the active ingredient contained in the pharmaceutical composition, the age of the patient, and the degree of symptoms It can be appropriately determined depending on the like. From the viewpoint of the number of administrations per day and convenience during administration, the daily dose is, for example, 5 to 100 mL, preferably 5 to 60 mL, and more preferably 5 to 15 mL. Since the pharmaceutical composition of the present invention is characterized by containing the active ingredient (A) at a high concentration, the necessary amount of the active ingredient can be ingested with a relatively small dose.

  The number of doses per day of the pharmaceutical composition of the present invention can be appropriately changed according to the above-mentioned dose per day, for example, 1 to 10 times per day, preferably 3 to 6 times per day. Since the pharmaceutical composition of the present invention contains the active ingredient at a high concentration, the burden on the patient due to frequent administration can be reduced.

2. Pharmaceutical Product The present invention provides a pharmaceutical product in which the liquid pharmaceutical composition is contained in a container equipped with a discharge device. In such a pharmaceutical product, administration is carried out by ejecting the liquid pharmaceutical composition directly or indirectly from the discharge device onto or around the tongue in the oral cavity. Here, on or around the tongue includes, for example, dentition, gums, cheeks, and the floor of the mouth. Inflow to the urine is prevented, and oral administration can be performed safely. Preferably in the pharmaceutical product of the present invention, the liquid pharmaceutical composition is injected onto the tongue for administration.

  In the pharmaceutical product of the present invention, the discharge device is urged by an elastic force so as to close the discharge port of the discharge device, and moves against the elastic force when the liquid pharmaceutical composition is discharged, thereby causing the discharge device to move. You may provide a valve member made into an open state.

  That is, in the pharmaceutical product of the present invention, the container includes a storage unit and a discharge device that store the liquid pharmaceutical composition, and is configured to be able to send the liquid pharmaceutical composition stored in the storage unit to the discharge device. Yes. Further, the discharge device is provided with a valve member configured to be openable and closable in response to pressure from the outside, pressurization in the container, and the like. Therefore, by applying pressure to a predetermined portion of the container, the valve member is opened and the liquid pharmaceutical composition inside the container can be discharged. Further, the valve member is closed when pressure is not applied to a predetermined portion of the container, and leakage of the liquid pharmaceutical composition is avoided.

  The discharge device may include a pump. Further, the pump may include a cylinder suspended in the container, and a stem having a cylindrical piston at a lower end portion and urged upward from the inside of the cylinder. The pressure of the liquid stored in the internal space between the upper valve on the stem side and the lower valve on the cylinder side increases, and the liquid pharmaceutical composition passes through the upper valve and the discharge unit provided above the stem. The liquid ejected from the jet port may be configured to suck up the liquid in the container through the lower valve by the rise of the stem into the cylinder.

  Examples of the discharge device in the pharmaceutical product of the present invention include a so-called trigger type discharge device, a so-called push pump type discharge device, and the like. More specifically, for example, JP 2002-326054 A, JP 2001-171864 A, JP 2004-359242 A, JP 2004-359241 A, JP 2004-359238 A, The discharge devices described in JP 2004-352343 A, JP 2004-352333 A, and the like can be used.

  As another aspect of the discharge device in the present invention, for example, a discharge device having a pressing head described in Japanese Patent Application Laid-Open No. 2004-834 can be cited. In the present invention, by using a discharge device including such a pressing head, alteration can be prevented by preventing the liquid pharmaceutical composition contained in the container from coming into contact with the outside air. In addition, according to the discharge device having such a structure, dripping can be prevented, so that it can be continuously used in a sanitary manner. Further, since the liquid pharmaceutical composition can be cut well, fluctuations in the amount of the liquid pharmaceutical composition to be discharged can be suppressed.

  In the pharmaceutical product of the present invention, the discharge amount from the discharge device by one injection is not particularly limited, but is, for example, 0.03 to 3 mL, preferably 0.1 to 2 mL, and more preferably 0.3 to 1 mL. Here, the “injection amount from one injection / discharge device” refers to the amount of the liquid pharmaceutical composition discharged from the discharge port by one push in the case of a push pump type discharge device, for example. In addition, even when a discharge device of another aspect (for example, a trigger-type discharge device) is used, a desired discharge amount based on the amount of liquid pharmaceutical composition discharged by one push in the push pump type What is necessary is just to design a discharge outlet etc. so that liquid pharmaceutical composition of this may be discharged.

  In addition, the droplet particles at the time of ejection preferably have a certain particle diameter from the viewpoint of preventing inflow into the trachea and lung, for example, 100 to 5500 μm, preferably 100 to 3600 μm, and more preferably 100 to 1600 μm. Can be mentioned. The particle diameter of the droplet can be appropriately adjusted by selecting the nozzle of the ejection device or the configuration of the flow path near the ejection port.

  The container used in the present invention is not particularly limited as long as it is usually used as a container for a liquid pharmaceutical composition. For example, a brown light-shielding glass container or the like can be used.

  As a container provided with such a discharge device, for example, a container disclosed in Japanese Patent Application Laid-Open No. 2007-277125 is a preferable example.

  The viscosity of the pharmaceutical composition when the pharmaceutical composition of the present invention is stored in such a container is not particularly limited as long as it can be quantitatively ejected from the discharge device, for example, 0.8 to 500 cP, Preferably 0.9-100 cP, More preferably, it is 1.00-50.0 cP, More preferably, it is 1.00-25 cP, Most preferably, it is 1.00-2.5 cP. Here, the viscosity of the pharmaceutical composition of the present invention is a value measured with a UL adapter under a condition of 25 ° C. using a B-type viscometer (for example, a digital viscometer DV-II + manufactured by Brookfield). .

  The medicinal product of the present invention can be administered with a dose that is simply and accurately measured by adopting the above configuration. In addition, when a liquid pharmaceutical composition having a strong bitterness is sprayed as droplets in the oral cavity, the bitterness is further emphasized, making it extremely difficult to take. However, the pharmaceutical composition of the present invention is effective in masking the bitter taste of bromohexine and having excellent balance of bitterness and sweetness. Even when administered in the form of an injection, it is prepared so as not to feel unpleasant bitterness. Moreover, in the pharmaceutical composition of the present invention, since bromohexine, which is an active ingredient, is contained at a high concentration, the dose per dose may be small, and the container size can be designed small. Therefore, the pharmaceutical product of the present invention is excellent in portability and convenience for taking.

  Hereinafter, the present invention will be specifically described with reference to examples and the like. However, the present invention is not limited to these.

  The components shown in Tables 2 to 8 below were mixed in purified water and dissolved uniformly to prepare a liquid pharmaceutical composition of each formulation. The pH of the liquid pharmaceutical composition was set to pH 4.5 using hydrochloric acid or sodium hydroxide. Sensory evaluation was carried out on the bitterness and sweetness of each liquid pharmaceutical composition by 10 adult male and female panelists. Evaluation was carried out according to the following evaluation criteria, including 10 ml of each liquid pharmaceutical composition in the mouth for 20 seconds. The results are shown in Tables 2-8.

(Evaluation criteria)
(sweet taste)
0: Not sweet 1: Slightly sweet 2: Slightly sweet 3: Sweet 4: Very sweet (bitter taste)
0: not bitter 1: slightly bitter 2: slightly bitter 3: bitter 4: very bitter

The total score of sweetness and bitterness evaluation obtained based on the above evaluation criteria was used as the sweetness evaluation score and bitterness evaluation score of each formulation. A sweetness rating score of less than 30 indicates that the liquid pharmaceutical composition for oral administration is not too sweet. Moreover, if a bitterness evaluation score is less than 30, it will show that the bitterness masking effect is acquired.
(Sweetness evaluation)
× Sweetness score 30 points or more ○ Sweetness score less than 30 points

(Bitter taste evaluation)
× Bitterness evaluation point 30 points or more ○ Bitterness evaluation point 20 points or more and less than 30 points ◎ Bitterness evaluation point 10 points or more and less than 20 points ★ Bitterness evaluation point less than 10 points

  In order to accurately evaluate the masking effect by the sweetener, the blending amount of the sweetener was adjusted based on the sweetness shown in Table 1 so that the sweetness in each formulation was equal.

In addition, the following products were used as bromhexine hydrochloride and l-menthol.
Bromhexine hydrochloride: Japanese Pharmacopoeia Bromhexine hydrochloride (Watanabe Chemical Co., Ltd.)
l-Menthol: Japanese Pharmacopoeia L-Menthol (Nagaoka Jitsugyo Co., Ltd.)

Comparing the results of Reference Examples 1 and 2 shown in Table 2 with Comparative Examples 1 to 3, the liquid pharmaceutical composition containing 0.05% by weight or more of bromohexine hydrochloride has a bitterness evaluation score of 30 or more. It was revealed that the bitterness is very strong and causes problems when taking. The amount of bromhexine hydrochloride to be blended in a conventional liquid pharmaceutical composition for oral administration is generally 0.01 to 0.02% by weight.

  As shown in Table 3, when stevia, glycyrrhizin, thaumatin, sucralose, or aspartame was blended with a liquid pharmaceutical composition having a strong bitterness containing 0.05% by weight of bromohexine hydrochloride, in the case of these sweeteners, It was shown that the masking effect was not obtained (Comparative Examples 4 to 13). In addition, when the concentration of the sweetener was increased in anticipation of the enhancement of the masking action, not only the bitterness masking effect was not obtained, but the sweetness became too strong, resulting in a decrease in dosage. 9, 11 and 13). Furthermore, it was shown that aspartame as the component (C) of the present invention and l-menthol as the component (D) alone cannot provide a bitter taste masking effect (Comparative Examples 12, 13 and 15). Moreover, when acesulfame potassium which is (B) component of this invention is mix | blended, it was shown that the bitterness masking effect is not acquired in 0.06 weight part with respect to 1 weight part of bromohexine hydrochloride (Comparative Example 14). ).

  Table 4 shows that even when 0.05% by weight of bromohexine hydrochloride is contained, bitterness is effectively masked when acesulfame potassium is added in an amount of 0.1 parts by weight or more per 1 part by weight of bromohexine hydrochloride. Was shown to be. In addition, in the case of acesulfame potassium, even if the amount was increased, the sweetness became too strong and the dosing property did not decrease.

  Furthermore, when 0.1 to 5 parts by weight of acesulfame potassium was contained with respect to 1 part by weight of bromohexine hydrochloride, an even better bitterness masking effect was expressed. In particular, when 0.1 to 1 part by weight of acesulfame potassium was contained with respect to 1 part by weight of bromohexine hydrochloride, a more remarkable bitterness masking effect was obtained.

  From Tables 5 to 7, the bitterness masking effect could be further enhanced by blending (C) component aspartame and / or (D) component 1-menthol in addition to bromohexine hydrochloride and acesulfame potassium (implementation) Examples 10-29). In particular, when all of the components (A) to (D) were included, an even more remarkable bitter taste masking effect was exhibited, and the balance with sweetness was good (Examples 23 to 29).

  Moreover, the masking effect of the bitterness which was excellent when 0.1-1 weight part of aspartame was contained with respect to 1 weight part of bromohexine hydrochloride (Examples 10-15) was obtained. Furthermore, when the liquid pharmaceutical composition contained 0.005 to 0.02% by weight of 1-menthol, the masking effect of bitterness was further enhanced (Examples 16 to 19).

Formulation Example A liquid pharmaceutical composition (9 ml per day) for oral administration having the formulation shown in Table 8 below was prepared. Specifically, each component was mixed with purified water and dissolved uniformly, and then adjusted to pH 4.5 using hydrochloric acid or sodium hydroxide to prepare a liquid pharmaceutical composition. When the sensory evaluation of bitterness and sweetness was performed on the composition of the following formulation, the bitterness was effectively masked and the liquid pharmaceutical composition had a good balance of sweetness. Furthermore, a pharmaceutical product containing such a liquid pharmaceutical composition in a container equipped with a discharge device is excellent in convenience and portability for taking.

Claims (9)

A liquid pharmaceutical composition for oral administration comprising (A) bromhexine and / or a salt thereof and (B) acesulfame potassium,
The oral administration, wherein the content of the component (A) is 0.05% by weight or more, and the blending ratio of the component (B) is 0.1 parts by weight or more with respect to 1 part by weight of the component (A). Liquid pharmaceutical composition.   The liquid pharmaceutical composition for oral administration according to claim 1, wherein the content of the component (A) is 0.05 to 2% by weight.   The liquid pharmaceutical composition for oral administration according to claim 1 or 2, further comprising (C) aspartame.   The liquid pharmaceutical composition for oral administration according to any one of claims 1 to 3, further comprising (D) a monoterpene.   The liquid pharmaceutical composition for oral administration according to any one of claims 1 to 4, wherein the monoterpene is menthol.   The liquid pharmaceutical composition for oral administration according to any one of claims 1 to 5, wherein the blending ratio of the component (C) is 0.1 to 1 part by weight with respect to 1 part by weight of the component (A).   The liquid pharmaceutical composition for oral administration according to any one of claims 1 to 6, wherein the content of the component (D) is 0.0025 to 0.025% by weight.   The liquid pharmaceutical composition for oral administration according to any one of claims 1 to 7, which is for antitussive expectorant.   A pharmaceutical product comprising the liquid pharmaceutical composition for oral administration according to any one of claims 1 to 8 accommodated in a container provided with a discharge device.