Oral pharmaceutical composition

Abstract

To provide a pharmaceutical formulation that can reduce the bitterness of an oral pharmaceutical composition containing ambroxol and / or a salt thereof by utilizing an active ingredient.SOLUTION: Incorporating pseudoephedrine, methylephedrine, and / or a salt thereof into an oral pharmaceutical composition containing ambroxol and / or a salt thereof enables reduction in bitterness.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an oral pharmaceutical composition containing ambroxol and / or a salt thereof, in which bitterness is suppressed.

Background Art

[0002] Ambroxol hydrochloride is known as an expectorant of the airway lubricating type and is formulated in many over-the-counter cold medicines.

[0003] Since ambroxol hydrochloride has bitterness, a decrease in patient compliance becomes a problem. For oral preparations containing ambroxol hydrochloride, as a formulation design for reducing bitterness, it is common to add sweeteners, fragrances, and other additives with a masking effect.

[0004] Specifically, as a formulation design for reducing the bitterness of oral preparations containing ambroxol hydrochloride, the blending of magnesium aluminum silicate (Patent Document 1) and the blending of vanillin (Patent Document 2) can be mentioned.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0006] The addition of sweeteners and / or fragrances for the purpose of reducing the bitterness of an oral preparation containing ambroxol hydrochloride adds the flavor of the added sweeteners and / or fragrances to the bitterness of the active ingredient, but the masking effect of the bitterness itself is not sufficient. In addition, the addition of an additive with a masking effect increases the bulk of the preparation itself, resulting in an increase in the dose per administration, which can have an adverse effect on compliance. Therefore, if the bitterness of an oral preparation containing ambroxol hydrochloride can be reduced by formulating other active ingredients instead of additives, it will be possible to efficiently administer multiple active ingredients along with the reduction of bitterness, which is considered to greatly contribute to the improvement of compliance.

[0007] Therefore, an object of the present invention is to provide a formulation prescription that can reduce the bitterness of an oral pharmaceutical composition containing ambroxol and / or its salts (hereinafter also referred to as "ambroxols") by co-formulating other active ingredients.

Means for Solving the Problems

[0008] As a result of intensive studies, the present inventors have found that the bitterness is reduced by formulating a pseudoephedrine, methyl ephedrine, and / or their salts (hereinafter also referred to as "ephedrines") in an oral pharmaceutical composition containing ambroxols without formulating an antipyretic analgesic. Although ephedrines themselves are drugs that exhibit bitterness, it was extremely unexpected that the bitterness of an oral pharmaceutical composition containing ambroxols could be reduced. In addition, it has also been found that the bitterness can be further reduced by further formulating tranexamic acid or further formulating chlorpheniramine and / or its salts (hereinafter also referred to as "chlorpheniramines"). Although these tranexamic acid and chlorpheniramines themselves are drugs that exhibit bitterness, it was also extremely unexpected that the bitterness of an oral pharmaceutical composition containing ambroxols and ephedrines could be further reduced. The present invention has been completed by further studies based on these findings.

[0009] That is, the present invention provides an invention in the following aspects. Item 1. An oral pharmaceutical composition containing (A) ambroxol and / or a salt thereof, and (B) pseudoephedrine, methylephedrine, and / or a salt thereof, and not containing an antipyretic analgesic. Item 2. The oral pharmaceutical composition according to Item 1, further containing (C) tranexamic acid. Item 3. The oral pharmaceutical composition according to Item 1 or 2, further containing (D) chlorpheniramine and / or a salt thereof. Item 4. The oral pharmaceutical composition according to any one of Items 1 to 3, containing 0.5 parts by weight or more of the component (B) per 1 part by weight of the component (A). Item 5. The oral pharmaceutical composition according to any one of Claims 2 to 4, containing 3 parts by weight or more of the component (C) per 1 part by weight of the component (A). Item 6. The oral pharmaceutical composition according to any one of Items 3 to 5, containing 0.05 parts by weight or more of the component (D) per 1 part by weight of the component (A). Item 7. The oral pharmaceutical composition according to any one of Items 1 to 6, containing 0.1 to 10% by weight of the component (A).

Advantages of the Invention

[0010] According to the present invention, a formulation prescription is provided that can reduce the bitterness of an oral pharmaceutical composition containing ambroxol by co-formulating other active ingredients.

Modes for Carrying Out the Invention

[0011] The oral pharmaceutical composition of the present disclosure contains (A) ambroxol and / or its salts (hereinafter also referred to as the “(A) component”), and (B) pseudoephedrine, methylephedrine, and / or their salts (hereinafter also referred to as the “(B) component”), and is characterized by not containing an antipyretic analgesic. The oral pharmaceutical composition of the present disclosure may further contain (C) tranexamic acid (hereinafter also referred to as the “(C) component”), and / or (D) chlorpheniramine and / or its salts (hereinafter also referred to as the “(D) component”). Despite containing ambroxol, the oral pharmaceutical composition of the present disclosure has reduced bitterness.

[0012] Hereinafter, the oral pharmaceutical composition of the present disclosure will be described in detail. In this specification, a numerical range indicated by two numerical values and “~” shall include those two numerical values as the lower limit value and the upper limit value. For example, the notation of 2~15% by weight means 2% by weight or more and 15% by weight or less.

[0013] (A) Ambroxol compounds The oral pharmaceutical composition of the present disclosure contains ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol) and / or its salts as the (A) component. Ambroxol is a component known as an airway lubricating expectorant. The (A) component is a component that exhibits bitterness, but the oral pharmaceutical composition of the present disclosure has reduced bitterness.

[0014] The salts of ambroxol are not particularly limited as long as they are pharmaceutically acceptable. Examples include inorganic acid salts such as hydrochloride, hydrobromide, and phosphate; organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate.

[0015] In the oral pharmaceutical composition of the present disclosure, as the component (A), one of the above components may be used alone or a plurality of components may be used in combination. Preferably, as the component (A) in the oral pharmaceutical composition of the present disclosure, salts of ambroxol are mentioned, more preferably inorganic acid salts of ambroxol, and even more preferably hydrochloride salts of ambroxol.

[0016] The blending amount of the component (A) in the oral pharmaceutical composition of the present disclosure is not particularly limited, and for example, 0.1 to 10% by weight can be mentioned. From the viewpoint of further reducing bitterness, preferably 0.1 to 7% by weight, more preferably 0.1 to 5% by weight, even more preferably 0.1 to 4% by weight, still more preferably 0.1 to 3% by weight can be mentioned. Further, since the oral pharmaceutical composition of the present disclosure is excellent in the bitterness reducing effect, even when the blending amount of the component (A) is such that bitterness is originally felt more strongly, bitterness can be effectively reduced. From such a viewpoint, preferred blending amounts of the component (A) include preferably 0.3 to 10% by weight, more preferably 0.5 to 10% by weight, even more preferably 0.7 to 10% by weight, still more preferably 1 to 10% by weight, and particularly preferably 1.2 to 10% by weight.

[0017] (B) Ephedrine compounds The oral pharmaceutical composition of the present disclosure contains, as the component (B), pseudoephedrine (1-phenyl-2-methylaminopropanol-1), methylephedrine (1-phenyl-2-dimethylaminopropanol-1), and / or salts thereof. Ephedrines are components known as bronchodilators and central cough suppressants. Although the component (B) is a component that exhibits bitterness by itself, the bitterness can be reduced by co-blending with the component (A) in the oral pharmaceutical composition of the present disclosure.

[0018] The salts of pseudoephedrine and methylephedrine are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, and phosphate; organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate.

[0019] (B) As a component, one kind may be used alone or a plurality of kinds may be used in combination from the above components. Preferably, as the (B) component in the oral pharmaceutical composition of the present disclosure, from the viewpoint of enhancing the bitterness-reducing effect, methylphenidate and its salts are mentioned, more preferably methylphenidate salt is mentioned, still more preferably an inorganic acid salt of methylphenidate is mentioned, and even more preferably hydrochloride of methylphenidate is mentioned.

[0020] In the oral pharmaceutical composition of the present disclosure, the content of the (B) component is not particularly limited and can be appropriately set according to the required degree of the bitterness-reducing effect. For example, the content of the (B) component per 1 part by weight of the (A) component is, for example, 0.5 part by weight or more. From the viewpoint of further enhancing the bitterness-reducing effect, preferably 0.6 part by weight or more, more preferably 0.7 part by weight or more, still more preferably 0.8 part by weight or more, and even more preferably 1.2 part by weight or more. The content of the (B) component per 1 part by weight of the (A) component is not particularly limited even at its upper limit, but for example, 10 parts by weight or less, preferably 7 parts by weight or less, 5 parts by weight or less, or 2.5 parts by weight or less.

[0021] Regarding the specific content of the (B) component in the oral pharmaceutical composition of the present disclosure, for example, 0.1% by weight or more, preferably 0.5% by weight or more or 0.8% by weight or more, more preferably 1.0% by weight or more, still more preferably 1.2% by weight or more, even more preferably 1.5% by weight or more, still even more preferably 1.6% by weight or more, 1.7% by weight or more, 1.8% by weight or more, 1.9% by weight or more, or 2.0% by weight or more. The specific content of the (B) component is not particularly limited even at its upper limit, but for example, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, 5% by weight or less, or 4.5% by weight or less.

[0022] (C) Tranexamic acid The oral pharmaceutical composition of the present disclosure may or may not contain tranexamic acid as component (C). Tranexamic acid is a component known as an anti-hemorrhagic agent, anti-allergic agent, anti-inflammatory agent, etc. By further blending component (C), the bitter taste reducing effect of the oral pharmaceutical composition of the present disclosure can be further reduced.

[0023] In the oral pharmaceutical composition of the present disclosure, the content of component (C) is not particularly limited and can be appropriately set according to the degree to which the bitter taste reducing effect is required. For example, the content of component (C) per 1 part by weight of component (A) is, for example, 3 parts by weight or more. From the viewpoint of further enhancing the bitter taste reducing effect, it is preferably 4 parts by weight or more, more preferably 5 parts by weight or more, still more preferably 6 parts by weight or more, and even more preferably 10 parts by weight or more. The content of component (C) per 1 part by weight of component (A) is not particularly limited even at its upper limit, but examples include 60 parts by weight or less, preferably 55 parts by weight or less, 50 parts by weight or less, or 25 parts by weight or less.

[0024] Also, in the oral pharmaceutical composition of the present disclosure, the content of component (C) per 1 part by weight of component (B) is, for example, 1 part by weight or more. From the viewpoint of further enhancing the bitter taste reducing effect, it is preferably 3 parts by weight or more, more preferably 6 parts by weight or more, still more preferably 8 parts by weight, and even more preferably 9 parts by weight or more. The content of component (C) per 1 part by weight of component (B) is not particularly limited even at its upper limit, but examples include 20 parts by weight or less, preferably 17 parts by weight or less, 14 parts by weight or less, or 12 parts by weight or less.

[0025] Regarding the specific content of component (C) in the oral pharmaceutical composition of the present disclosure, for example, it may be 5% by weight or more, preferably 7% by weight or more, 8% by weight or more, more preferably 10% by weight or more, still more preferably 12% by weight or more, even more preferably 13% by weight or more, even more preferably 14% by weight or more, particularly preferably 15% by weight or more, 16% by weight or more, 18% by weight or more, or 20% by weight or more. The specific content of component (C) is not particularly limited even at its upper limit, and examples include 90% by weight or less, 80% by weight or less, 70% by weight or less, 60% by weight or less, 50% by weight or less, or 45% by weight or less.

[0026] (D) Chlorpheniramine compounds The oral pharmaceutical composition of the present disclosure may or may not contain chlorpheniramine (3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine) and / or its salt as component (D). Chlorpheniramines are compounds known as antihistamines. When the oral pharmaceutical composition of the present disclosure does not contain component (C), by further blending component (D), the bitter taste reducing effect of the oral pharmaceutical composition of the present disclosure can be further reduced.

[0027] The salt of chlorpheniramine is not particularly limited as long as it is pharmaceutically acceptable, and examples include inorganic acid salts such as hydrochloride, hydrobromide, and phosphate; organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate.

[0028] In the oral pharmaceutical composition of the present disclosure, as component (D), one of the above components may be used alone, or a plurality of components may be used in combination. Preferably, as component (D) in the oral pharmaceutical composition of the present disclosure, the salt of chlorpheniramine is mentioned, more preferably the organic acid salt of chlorpheniramine, and still more preferably the maleate salt of chlorpheniramine.

[0029] In the oral pharmaceutical composition of the present disclosure, the content of the component (D) is not particularly limited and can be appropriately set according to the degree of the required bitter taste reduction effect. For example, the content of the component (D) per 1 part by weight of the component (A) is, for example, 0.05 part by weight or more, and from the viewpoint of further enhancing the bitter taste reduction effect, preferably 0.1 part by weight or more, more preferably 0.11 part by weight or more, and still more preferably 0.13 part by weight or more. The content of the component (D) per 1 part by weight of the component (A) is not particularly limited even at its upper limit, but is, for example, 1 part by weight or less, preferably 0.6 part by weight or less, 0.5 part by weight or less, 0.4 part by weight or less, or 0.3 part by weight or less.

[0030] Further, the content of the component (D) per 1 part by weight of the component (B) is, for example, 0.01 part by weight or more, and from the viewpoint of further enhancing the bitter taste reduction effect, preferably 0.03 part by weight or more, more preferably 0.06 part by weight or more, still more preferably 0.08 part by weight, even more preferably 0.09 part by weight or more. The content of the component (D) per 1 part by weight of the component (B) is not particularly limited even at its upper limit, but is, for example, 0.2 part by weight or less, preferably 0.17 part by weight or less, 0.14 part by weight or less, or 0.12 part by weight or less.

[0031] Regarding the specific content of the component (D) in the oral pharmaceutical composition of the present disclosure, for example, it is 0.01% by weight or more, preferably 0.05% by weight or more or 0.08% by weight or more, more preferably 0.1% by weight or more, still more preferably 0.12% by weight or more, even more preferably 0.13% by weight or more, still even more preferably 0.14% by weight or more, 0.15% by weight or more, 0.16% by weight or more, 0.18% by weight or more, or 0.2% by weight or more. The specific content of the component (D) is not particularly limited even at its upper limit, but is, for example, 0.9% by weight or less, 0.8% by weight or less, 0.7% by weight or less, 0.6% by weight or less, 0.5% by weight or less, or 0.45% by weight or less.

[0032] Antipyretic and analgesic agents The oral pharmaceutical composition of the present disclosure does not contain an antipyretic analgesic agent so as not to impair the bitter taste reducing effect. The antipyretic analgesic agent is not particularly limited, and examples thereof include acetaminophen, loxoprofen or its salt, ibuprofen, ethenzamide, aspirin or its salt, salicylamide, sodium salicylate, salicylamide, lactylphenetidine, salsalate, isopropylantipyrine and the like.

[0033] Other components The oral pharmaceutical composition of the present disclosure may or may not contain other pharmacological components as necessary, in addition to the components (A) to (D) described above, as long as the effects of the present invention are not impaired. The types of pharmacological components, regardless of whether or not they are contained, are not particularly limited. For example, antacids, stomachics, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory analgesics, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzyme agents, sedative hypnotics, antihistamines, cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, crude drugs, crude drug extract powders, vitamins and the like can be mentioned. These pharmacological components may be used alone or in combination of two or more. Further, the content of these pharmacological components may be appropriately set according to the type of pharmacological component used and / or the dosage form of the oral pharmaceutical composition.

[0034] The oral pharmaceutical composition of the present disclosure may or may not contain pharmaceutically acceptable bases and / or additives, etc. as necessary for preparing into a desired dosage form. Examples of bases and additives regardless of such inclusion or not include, for example, excipients, binders, disintegrants, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, solubilizing agents, wetting agents, stabilizers, suspending agents, adhesives, coating agents, gloss agents, water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, ultraviolet ray inhibitors, preservatives, flavoring agents, fragrances, powders, thickeners, pigments, chelating agents, etc. These bases and additives may be used alone or in combination of two or more. Also, the content of these bases and / or additives may be appropriately set according to the type of additive components to be used and / or the dosage form of the oral pharmaceutical composition, etc.

[0035] Among the above bases and additives, the oral pharmaceutical composition of the present disclosure preferably contains starch used as an excipient, binder, disintegrant, etc. from the viewpoint of further enhancing the bitter taste reducing effect. When the oral pharmaceutical composition of the present disclosure contains starch, the content of starch is not particularly limited, and examples thereof include 20 to 95% by weight, preferably 30 to 95% by weight, more preferably 40 to 95% by weight, still more preferably 45 to 95% by weight, 45 to 80% by weight, 45 to 70% by weight, or 50 to 60% by weight.

[0036] Formulation and packaging Regarding the dosage form of the oral pharmaceutical composition of the present disclosure, any solid preparation capable of oral administration (oral ingestion) is acceptable. Specific dosage forms of the oral pharmaceutical composition of the present disclosure may be either a liquid preparation or a solid preparation, but preferably a solid preparation. Specific examples of the solid preparation include powders, fine granules, granules (including dry syrups), troches, tablets, capsules, etc.

[0037] To prepare the oral pharmaceutical composition of the present disclosure in the above dosage form, the components (A) and (B) above, and the components (C), (D) and / or other components that are formulated as necessary can be used to formulate according to the usual formulation methods employed in the pharmaceutical field.

Examples

[0038] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0039] Test Example 1 The components shown in Tables 1 and 2 were mixed in a mortar to prepare an oral pharmaceutical composition in the form of a powder. For 150 mg of the prepared oral pharmaceutical composition, a professional panelist evaluated the taste.

[0040] Four professional panelists scored the degree of bitterness of each comparative example and each example using a Visual Analog Scale (VAS) where the degree of bitterness of the oral pharmaceutical composition of Comparative Example 2 was 5 points and no bitterness was 1 point, and the average value of these scores was derived as the "average bitterness". The smaller the value of the average bitterness, the higher the bitterness reduction effect. Also, four professional panelists scored the degree of saltiness of the oral pharmaceutical composition of Example 3 using a VAS where the degree of saltiness was 5 points and no saltiness was 1 point, and the average value of these scores was derived as the "average saltiness". The larger the value of the average saltiness, the higher the salt addition effect. The results are shown in Tables 1 and 2.

[0041]

Table 1

[0042]

Table 2

[0043] As shown in Comparative Example 1, the oral pharmaceutical composition containing the component (A) has a strong bitterness. However, as shown in Example 1, by additionally blending the component (B), the bitterness was reduced. As shown in Reference Example 1, although the component (B) itself has a strong bitterness, when co-blended with the component (A), the bitterness was unexpectedly reduced. In Example 1, even when the content ratio of the component (B) was reduced (for example, reduced to 1 part by weight per 1 part by weight of the component (A)), the bitterness-reducing effect was obtained, but the bitterness-reducing effect in Example 1 was clearly higher.

[0044] As shown in Examples 2 and 3, by further adding the component (C) or the component (D) to the oral pharmaceutical composition containing the components (A) and (B), the bitterness was further reduced. As shown in Reference Example 2, the component (C) itself has a strong bitterness, and as shown in Reference Example 3, the component (D) also has a certain degree of bitterness itself. However, in both cases, when co-blended with the components (A) and (B), the bitterness was unexpectedly further reduced. Furthermore, as shown in Example 4, by further adding the components (C) and (D) to the oral pharmaceutical composition containing the components (A) and (B), the bitterness was further reduced. When the component (B) was absent from the compositions of Examples 2 to 4, an effective bitterness-reducing effect was not obtained compared with Comparative Example 1. Also, when the component (A) was absent from the composition of Example 4, the bitterness became stronger than that of Example 4.

[0045] Also, when ephedrine hydrochloride was replaced with pseudoephedrine hydrochloride in Examples 1 to 4, the bitterness-reducing effect was similarly obtained.

[0046] On the other hand, as shown in Comparative Example 2, when acetaminophen was additionally blended into the composition of Example 4, the bitterness became significantly stronger. All of the professional panelists answered that the bitterness of the oral pharmaceutical composition of Comparative Example 2 was very strong. As shown in Reference Example 4, acetaminophen itself has a strong bitterness, and when added to the composition of Example 4, the bitterness was enhanced. This tendency of bitterness enhancement was similarly observed for common analgesics such as ibuprofen and sodium loxoprofen.

[0047] In addition, as shown by the comparison between Comparative Example 1, Reference Examples 1 to 3 and Examples 1 to 4, it was confirmed that while the bitterness was reduced, the saltiness was enhanced. That is, it is considered that the combined individual bitterness of the components (A) to (D) constituting Examples 1 to 4 shifted the taste to saltiness, thereby making it less likely to feel bitterness. However, as shown in Comparative Example 2, when an antipyretic analgesic is included, although the saltiness is also enhanced, the effect of enhancing the bitterness due to the combination of antipyretic analgesics is remarkable, so the effect of making it less likely to feel bitterness could not be obtained.

Claims

1. An oral pharmaceutical composition comprising (A) ambroxol and / or a salt thereof, and (B) pseudoephedrine, methylephedrine, and / or a salt thereof, and not containing an antipyretic analgesic.

2. The oral pharmaceutical composition according to Claim 1, further comprising (C) tranexamic acid.

3. The oral pharmaceutical composition according to Claim 1, further comprising (D) chlorpheniramine and / or a salt thereof.

4. The oral pharmaceutical composition according to Claim 1, wherein the component (B) is contained in an amount of 0.5 parts by weight or more per 1 part by weight of the component (A).

5. The oral pharmaceutical composition according to Claim 2, wherein the component (C) is contained in an amount of 3 parts by weight or more per 1 part by weight of the component (A).

6. The oral pharmaceutical composition according to Claim 3, wherein the component (D) is contained in an amount of 0.05 parts by weight or more per 1 part by weight of the component (A).

7. The oral pharmaceutical composition according to Claim 1, wherein the component (A) is contained in an amount of 0.1 to 10% by weight.

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