Pharmaceutical composition

Abstract

To provide a pharmaceutical formulation capable of inhibiting discoloration of a pharmaceutical composition containing ambroxol and / or a salt thereof.SOLUTION: Discoloration can be inhibited by combining dextromethorphan and / or a salt thereof with a pharmaceutical composition containing ambroxol and / or a salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing ambroxol and / or a salt thereof, with suppressed discoloration.

Background Art

[0002] Ambroxol hydrochloride is known as an airway lubricating expectorant and is sold in dosage forms such as tablets, oral solutions, syrups, dry syrups, coated tablets, etc. (Non-Patent Document 1).

[0003] Ambroxol and its salts are widely used, particularly for the treatment and relief of cold symptoms. Furthermore, ambroxol and its salts are formulated together with other active ingredients that contribute to the treatment and relief of cold symptoms and are also commercially available as over-the-counter cold medications that can be kept at home.

[0004] It is known that preparations containing ambroxol and its salts have reduced stability when formulated with other active ingredients, and formulations for improving formulation stability are being investigated.

[0005] For example, by including pseudoephedrine or its salt in a solid composition containing ibuprofen, ambroxol, or its salt, it is known that the appearance change compared to storage at 5°C is suppressed after storage at 65°C for 12 days (Patent Document 1).

[0006] Also, it is known that by further including magnesium oxide in a cold pharmaceutical composition containing ibuprofen and ambroxol hydrochloride, discoloration after storage at 70°C for 24 hours is suppressed (Patent Document 2).

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0009] Conventional formulations for improving the stability of formulations containing ambroxol and / or its salts are limited to those in the presence of antipyretics. On the other hand, the inventor has faced the problem that ambroxol and / or its salts discolor upon exposure to light when alone. However, there has been insufficient consideration of pharmaceutical formulations that improve the photo-instability of ambroxol and / or its salts alone, regardless of the co-formulation with other components other than antipyretics.

[0010]

Means for Solving the Problems

[0011] As a result of intensive studies, the inventor has found that discoloration due to light is suppressed by formulating ambroxol and / or its salts with dextromethorphan and / or its salts.

[0012] That is, the present invention provides an invention in the following aspects. Item 1. A pharmaceutical composition comprising (A) ambroxol and / or its salt, and (B) dextromethorphan and / or its salt, and not containing an antipyretic analgesic. Item 2. The pharmaceutical composition according to Item 1, further comprising (C) pseudoephedrine, methylephedrine, and / or a salt thereof. Item 3. The pharmaceutical composition according to Item 1 or 2, comprising (D) tranexamic acid and / or (E) chlorpheniramine and / or a salt thereof. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, comprising 0.1 part by weight or more of the component (B) per 1 part by weight of the component (A). Item 5. The pharmaceutical composition according to any one of Items 2 to 4, comprising 0.25 part by weight or more of the component (C) per 1 part by weight of the component (A). Item 6. The pharmaceutical composition according to any one of Items 3 to 5, comprising 5 parts by weight or more of the component (D) per 1 part by weight of the component (A). Item 7. The pharmaceutical composition according to any one of Items 3 to 5, comprising 0.05 part by weight or more of the component (E) per 1 part by weight of the component (A). Item 8. The pharmaceutical composition according to any one of Items 1 to 7, comprising 0.1 to 10% by weight of the component (A). Item 9. The pharmaceutical composition according to any one of Items 1 to 8, which is a granule, fine granule, powder, troche, or tablet.

Advantages of the Invention

[0013] According to the present invention, a formulation prescription capable of suppressing discoloration of a pharmaceutical composition containing ambroxol and / or a salt thereof by light is provided.

Modes for Carrying Out the Invention

[0014] The pharmaceutical composition of the present disclosure contains (A) ambroxol and / or its salts (hereinafter also referred to as "(A) component" or "ambroxols"), and (B) dextromethorphan and / or its salts (hereinafter also referred to as "(B) component" or "dextromethorphans"). The pharmaceutical composition of the present disclosure can further contain (C) pseudoephedrine, methylephedrine, and / or their salts (hereinafter also referred to as "(C) component" or "ephedrines"). The pharmaceutical composition of the present disclosure can further contain (D) tranexamic acid (hereinafter also referred to as "(D) component"), and / or (E) chlorpheniramine and / or its salts (hereinafter also referred to as "(E) component" or "chlorpheniramines"). The pharmaceutical composition of the present disclosure can suppress discoloration by light.

[0015] Hereinafter, the 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 the 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.

[0016] (A) Ambroxol compounds The pharmaceutical composition of the present disclosure contains ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol) and / or its salts as the (A) component. Ambroxols are components known as airway lubricating expectorants. The (A) component alone exhibits discoloration with respect to light, but the pharmaceutical composition of the present disclosure is suppressed in discoloration with respect to light.

[0017] The salts of ambroxol are not particularly limited as long as they are 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.

[0018] In the pharmaceutical composition of the present disclosure, as the component (A), one kind may be used alone or a plurality of kinds may be used in combination from the above components. Preferably, as the component (A) in the pharmaceutical composition of the present disclosure, salts of ambroxol are exemplified, more preferably inorganic acid salts of ambroxol, and even more preferably hydrochloride salts of ambroxol.

[0019] Regarding the specific content of the component (A) in the solid pharmaceutical composition of the present disclosure, for example, 0.1% by weight or more, preferably 0.5% by weight or more, more preferably 0.75% by weight or more, even more preferably 1.0% by weight or more, and still more preferably 1.2% by weight or more can be mentioned. The specific content of the component (A) is not particularly limited even at its upper limit, but for example, 10% by weight or less, 7% by weight or less, 6% by weight or less, 5% by weight or less, 4% by weight or less, or 3.5% by weight or less can be mentioned.

[0020] (B) Dextromethorphan compounds The pharmaceutical composition of the present disclosure contains dextromethorphan and / or its salt as the component (B). Dextromethorphans are components known as non-narcotic antitussives. By formulating the component (B), the present disclosure's pharmaceutical composition can suppress discoloration caused by the component (A).

[0021] The salt of dextromethorphan is not particularly limited as long as it is pharmaceutically acceptable, and examples include hydrobromide, phenolphthalein salt, etc. Also, the salt of dextromethorphan may be a solvate with water or alcohol, etc.

[0022] As the component (B), one kind may be used alone or a plurality of kinds may be used in combination from the above components. Preferably, as the component (B) in the pharmaceutical composition of the present disclosure, dextromethorphan salts are exemplified, more preferably dextromethorphan hydrobromide, and even more preferably dextromethorphan hydrobromide hydrate.

[0023] In the pharmaceutical composition of the present disclosure, the content of component (B) is not particularly limited and can be appropriately set according to the degree of discoloration suppression effect required. For example, the content of component (B) per 1 part by weight of component (A) is, for example, 0.1 part by weight or more, and from the viewpoint of further enhancing the discoloration suppression effect, preferably 0.5 part by weight or more, more preferably 0.8 part by weight or more, still more preferably 1 part by weight or more, and even more preferably 1.2 part by weight or more. The content of component (B) per 1 part by weight of component (A) is not particularly limited even in terms of its upper limit, but examples include 14 parts by weight or less, preferably 8 parts by weight or less, 6 parts by weight or less, 4 parts by weight or less, 2 parts by weight or less, or 1.5 parts by weight or less.

[0024] Regarding the specific content of component (B) in the pharmaceutical composition of the present disclosure, for example, 0.1% by weight or more or 0.5% by weight or more, preferably 1% by weight or more, more preferably 2% by weight or more, still more preferably 3% by weight or more, and even more preferably 4% by weight or more can be mentioned. The specific content of component (B) is not particularly limited even in terms of its upper limit, but examples include 10% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, or 5% by weight or less.

[0025] (C) Ephedrine compounds The pharmaceutical composition of the present disclosure can contain, as component (C), 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. By further blending component (C), the discoloration suppression property of the pharmaceutical composition of the present disclosure can be improved.

[0026] The salts of pseudoephedrine and methylephedrine are not particularly limited as long as they are 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.

[0027] (C) As a component, one of the above components may be used alone, or a plurality of components may be used in combination. Preferably, as the component (C) in the pharmaceutical composition of the present disclosure, methylphenidate and its salts are mentioned, more preferably methylphenidate salts are mentioned, still more preferably inorganic acid salts of methylphenidate are mentioned, and even more preferably hydrochloride salts of methylphenidate are mentioned.

[0028] In the pharmaceutical composition of the present disclosure, the content of the component (C) is not particularly limited and can be appropriately set according to the degree to which the discoloration suppression effect is required. For example, the content of the component (C) per 1 part by weight of the component (A) is, for example, 0.25 part by weight or more. From the viewpoint of further enhancing the discoloration suppression effect, it is preferably 0.5 part by weight or more or 1 part by weight or more, more preferably 1.3 parts by weight or more, still more preferably 1.5 parts by weight or more. The content of the component (C) per 1 part by weight of the component (A) is not particularly limited even in terms of its upper limit, but is, for example, 25 parts by weight or less, preferably 10 parts by weight or less, 5 parts by weight or less, or 2.5 parts by weight or less.

[0029] Regarding the specific content of the component (C) in the 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, even more preferably 1.8% by weight or more, 1.9% by weight or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, or 5% by weight or more. The specific content of the component (C) is not particularly limited even in terms of its upper limit, but is, for example, 9% by weight or less, 8% by weight or less, 7% by weight or less, or 6% by weight or less.

[0030] (D) Tranexamic acid The pharmaceutical composition of the present disclosure can contain tranexamic acid as the component (D). Tranexamic acid is a component known as an anti-hemorrhagic agent, an anti-allergic agent, and an anti-inflammatory agent. By further blending the component (D), the discoloration suppression property of the pharmaceutical composition of the present disclosure can be improved.

[0031] In the pharmaceutical composition of the present disclosure, the content of component (D) is not particularly limited and can be appropriately set according to the degree of discoloration suppression effect required. For example, the content of component (D) per 1 part by weight of component (A) is, for example, 5 parts by weight or more. From the viewpoint of further enhancing the discoloration suppression effect, it is preferably 10 parts by weight or more, more preferably 13 parts by weight or more, and still more preferably 15 parts by weight or more. The content of component (D) 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 20 parts by weight or less.

[0032] Regarding the specific content of component (D) in the pharmaceutical composition of the present disclosure, for example, it is 5% by weight or more, preferably 7% by weight or more or 8% by weight or more, more preferably 10% by weight or more, still more preferably 13% by weight or more, even more preferably 15% by weight or more, even more preferably 18% by weight or more, particularly preferably 19% by weight or more, 20% by weight or more, 40% by weight or more, or 55% by weight or more. The specific content of component (D) is not particularly limited even at its upper limit, but examples include 90% by weight or less, 80% by weight or less, 70% by weight or less, or 65% by weight or less.

[0033] (E) Chlorpheniramine compounds The pharmaceutical composition of the present disclosure can contain chlorpheniramine (3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine) and / or a salt thereof as component (E). Chlorpheniramines are components known as antihistamines. By further blending component (E), the discoloration suppression property of the pharmaceutical composition of the present disclosure can be improved.

[0034] 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.

[0035] In the pharmaceutical composition of the present disclosure, as the component (E), one of the above components may be used alone or a plurality of components may be used in combination. Preferably, as the component (E) in the pharmaceutical composition of the present disclosure, salts of chlorpheniramine are mentioned, more preferably organic acid salts of chlorpheniramine, and even more preferably maleate salts of chlorpheniramine.

[0036] In the pharmaceutical composition of the present disclosure, the content of the component (E) is not particularly limited and can be appropriately set according to the degree of discoloration suppression effect required. For example, the content of the component (E) per 1 part by weight of the component (A) is, for example, 0.05 part by weight or more. From the viewpoint of enhancing the discoloration suppression effect, it is preferably 0.1 part by weight or more, more preferably 0.15 part by weight or more, even more preferably 0.2 part by weight or more, still more preferably 0.25 part by weight or more. The content of the component (E) 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, 0.4 part by weight or less, or 0.3 part by weight or less.

[0037] Regarding the specific content of the component (E) in the pharmaceutical composition of the present disclosure, for example, it is 0.01% by weight or more or 0.05% by weight or more, preferably 0.1% by weight or more, more preferably 0.3% by weight or more, even more preferably 0.5% by weight or more, still more preferably 0.7% by weight or more, and even more preferably 0.8% by weight or more. The specific content of the component (E) is not particularly limited even at its upper limit, but is, for example, 2% by weight or less, 1.5% by weight or less, or 1% by weight or less.

[0038] Antipyretic and analgesic agents In order not to impair the discoloration suppression effect, the solid pharmaceutical composition of the present disclosure does not contain an antipyretic analgesic. The antipyretic analgesic 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.

[0039] Other components In the pharmaceutical composition of the present disclosure, within the range that does not interfere with the effects of the present invention, in addition to the aforementioned components (A) to (E), other pharmacological components may or may not be included as necessary. The types of pharmacological components regardless of such inclusion are not particularly limited. For example, antacids, stomachic agents, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory and analgesic agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzyme agents, sedative hypnotics, antihistamines, anticholinergic agents (such as belladonna total alkaloids, etc.), cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, crude drug powders or crude drug extracts (such as platycodon grandiflorum or its extract, etc.), vitamins, etc. may be mentioned. These pharmacological components may be used alone or in combination of two or more. Also, 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 pharmaceutical composition, etc.

[0040] In the pharmaceutical composition of the present disclosure, for the purpose of preparing into a desired dosage form, other pharmaceutically acceptable bases and / or additives, etc. may or may not be included as necessary. Examples of such other bases and additives regardless of such inclusion include excipients, binders, disintegrants, lubricants, tonicity agents, plasticizers, dispersants, emulsifiers, solubilizing agents, wetting agents, stabilizers, suspending agents, adhesives, coating agents, brightening 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 preventives, 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 component used and / or the dosage form of the pharmaceutical composition, etc.

[0041] Among the above-mentioned bases and additives, the pharmaceutical composition of the present disclosure preferably contains talc used as an excipient, lubricant, etc. from the viewpoint of further enhancing the discoloration suppression effect. When the pharmaceutical composition of the present disclosure contains talc, the content of talc is not particularly limited. For example, it may be 10 to 95% by weight, preferably 15 to 95% by weight, more preferably 20 to 95% by weight, still more preferably 25 to 95% by weight, 20 to 90% by weight, 20 to 60% by weight, 20 to 40% by weight, or 20 to 30% by weight.

[0042] Formulation and packaging The dosage form of the pharmaceutical composition of the present disclosure is not particularly limited and may be either a liquid preparation or a solid preparation, preferably a solid preparation. Specific examples of solid preparations include tablets (tablets with a light-transmitting (preferably transparent) coating and uncoated tablets), troches (troches with a light-transmitting (preferably transparent) coating and uncoated troches), capsules (capsules filled with light-transmitting (preferably transparent) capsules), powders, fine granules, granules (including dry syrups). Since the pharmaceutical composition of the present disclosure is excellent in discoloration suppression or discoloration suppression and moisture absorption suppression, suitable dosage forms include tablets with a light-transmitting (preferably transparent) coating, uncoated tablets, troches with a light-transmitting (preferably transparent) coating, uncoated troches, capsules filled with light-transmitting (preferably transparent) capsules, powders, fine granules, granules, more preferably uncoated tablets, uncoated troches, powders, fine granules, granules, and still more preferably powders, fine granules, granules.

[0043] To prepare the pharmaceutical composition of the present disclosure in the above dosage form, the components (A) and (B), and the components (C), (D), (E) and / or other components that are formulated as required can be used to formulate according to the usual formulation methods employed in the pharmaceutical field.

[0044] The packaging of the pharmaceutical composition of the present disclosure is not particularly limited, and examples include PTP packaging, strip packaging, blister packaging, loose packaging, etc. Since the pharmaceutical composition of the present disclosure is excellent in discoloration suppression, it is preferable that some or all of these packaging materials are made of a translucent (preferably transparent) plastic. Further, since the pharmaceutical composition of the present disclosure is excellent in discoloration suppression, as a suitable example of the packaging, loose packaging with a large number of exposures to light can be mentioned.

[0045] Furthermore, among the packaging materials in which the pharmaceutical composition of the present disclosure is packaged, it may be filled with air or may be filled with an inert gas such as nitrogen. Since the pharmaceutical composition of the present disclosure is excellent in discoloration suppression, in a preferred form, the inside of the packaging material may be filled with air.

Examples

[0046] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0047] Test example 1 The components shown in Tables 1 and 2 were mixed in a mortar to prepare a pharmaceutical composition in the form of a powder. 13 g of the prepared pharmaceutical composition was placed in a transparent petri dish (without filling with an inert gas), covered with a glass lid, and exposed to direct sunlight for 1 week. The outside air temperature during storage was 20 to 25°C.

[0048] Three panelists scored the degree of discoloration of the pharmaceutical composition of Comparative Example 1 on a visual analog scale (VAS) where the degree of discoloration is 10 points and no discoloration is 1 point, and the average value of these scores was derived as the "discoloration score". The larger the discoloration score, the greater the degree of discoloration and the lower the discoloration suppression ability, and the smaller the discoloration score, the smaller the degree of discoloration and the higher the discoloration suppression ability. The results are shown in Tables 1 and 2.

Table 1

[0049]

Table 2

[0050] As shown in Comparative Example 1, the pharmaceutical composition containing component (A) undergoes discoloration upon exposure to light. However, as shown in Example 1, by additionally blending component (B), the discoloration was suppressed. As shown in Reference Example 1, component (B) itself also undergoes some degree of discoloration upon exposure to light, but when co-blended with component (A), unexpectedly, the discoloration was significantly suppressed.

[0051] In Examples 1 to 5, even when the content ratio of component (B) was reduced (for example, reduced to 0.5 parts by weight per 1 part by weight of component (A)), the discoloration suppression effect was obtained. However, Examples 1 to 5 clearly showed a superior discoloration suppression effect. Also, in Examples 1 to 5, even when component (B) was changed to dextromethorphan phthalate, the discoloration suppression effect was obtained. However, Examples 1 to 5 showed a superior discoloration suppression effect.

[0052] As shown in Examples 2 to 5, by further additionally blending component (C) into the pharmaceutical composition containing components (A) and (B), the discoloration was further suppressed. As shown in Reference Example 2, component (C) itself also undergoes some degree of discoloration, but when co-blended with components (A) and (B), unexpectedly, the discoloration was further reduced. Furthermore, as shown in Examples 3 to 5, by further additionally blending component (D) and / or component (E) into the pharmaceutical composition containing components (A) and (B), the discoloration was further suppressed. As shown in Reference Examples 3 and 4, components (D) and (E) also undergo some degree of discoloration themselves, but when co-blended with components (A) and (B), unexpectedly, the discoloration was further reduced.

[0053] Also, in Examples 2 to 5, when ephedrine hydrochloride was replaced with pseudoephedrine hydrochloride, the discoloration suppression effect was similarly obtained.

[0054] On the one hand, as shown in Reference Examples 5 and 6, although neither ibuprofen nor acetaminophen causes much discoloration, as shown in Comparative Examples 2 and 3, when additionally formulated into the composition of Example 5, the discoloration became significantly stronger. This tendency of enhanced discoloration was similarly observed with common analgesics such as loxoprofen sodium and aspirin.

Claims

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

2. The pharmaceutical composition according to claim 1, further comprising (C) pseudoephedrine, methylephedrine, and / or a salt thereof.

3. The pharmaceutical composition according to claim 1, comprising (D) tranexamic acid and / or (E) chlorpheniramine and / or a salt thereof.

4. The pharmaceutical composition according to claim 1, wherein the component (B) is contained in an amount of 0.1 part by weight or more per 1 part by weight of the component (A).

5. The pharmaceutical composition according to claim 2, wherein the component (C) is contained in an amount of 0.25 part by weight or more per 1 part by weight of the component (A).

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

7. The pharmaceutical composition according to claim 3, wherein the component (E) is contained in an amount of 0.05 part by weight or more per 1 part by weight of the component (A).

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

9. The pharmaceutical composition according to claim 1, which is a granule, fine granule, powder, troche, or tablet.

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