Pharmaceutical composition

Abstract

An object of the present invention is to provide a pharmaceutical composition that contains loxoprofen or a salt thereof and ambroxol or a salt thereof, while suppressing the decrease in the content of ambroxol or a salt thereof over time. Another object of the present invention is to provide an excellent pharmaceutical composition that contains loxoprofen or a salt thereof and ambroxol or a salt thereof, while suppressing changes in appearance. [Solution] A pharmaceutical composition characterized by containing (A) loxoprofen or a salt thereof, (B) ambroxol or a salt thereof, and (C) noscapine or a salt thereof.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition comprising loxoprofen or a salt thereof and ambroxol or a salt thereof. [Background technology]

[0002] Loxoprofen is a type of nonsteroidal anti-inflammatory drug (NSAID) and is known to be effective in reducing inflammation, pain, and fever in conditions such as rheumatoid arthritis, osteoarthritis, lower back pain, periarthritis of the shoulder, cervicobrachial syndrome, toothache, acute upper respiratory tract infections, and post-operative, post-traumatic, and post-tooth extraction conditions (Non-patent Literature 1). Due to its excellent antipyretic and analgesic effects, it is included in combination cold medicines and antipyretic analgesics. Examples of pharmaceutical compositions containing loxoprofen include Patent Documents 1 to 3. These documents describe examples of formulations or examples containing loxoprofen and ambroxol (Non-Patent Document 1). Ambroxol hydrochloride is widely known as a compound that has airway mucosal lubrication and mucolytic effects, as well as excellent expectorant properties. It is also approved as a switch OTC drug and is an ingredient in combination cold medicines and cough suppressants (Non-Patent Literature 2). It has been known that ambroxol hydrochloride can cause stability problems when combined with certain other ingredients. For example, when ambroxol hydrochloride is combined with ibuprofen, the content of ambroxol hydrochloride decreases over time and the appearance of the formulation changes. This has been improved by adding pseudoephedrine hydrochloride and at least one selected from dihydrocodeine phosphate, dextromethorphan hydrobromide, and carbocysteine ​​(Patent Document 4). Furthermore, since ambroxol degrades during storage when combined with noscapine, it is known that its stability can be improved by adding amino acids or peptides (Patent Document 5). Furthermore, it is known that mixing loxoprofen sodium and ambroxol hydrochloride causes discoloration, and that this discoloration can be suppressed by incorporating magnesium aluminosilicate or magnesium oxide (Patent Document 6). [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Publication No. 2018-090549 [Patent Document 2] Japanese Patent Publication No. 2022-008042 [Patent Document 3] Japanese Patent Publication No. 2014-12660 [Patent Document 4] Japanese Patent Publication No. 2021-195370 [Patent Document 5] Japanese Patent Publication No. 2005-350448 [Patent Document 6] Japanese Patent Publication No. 2012-106973 [Non-patent literature]

[0004] [Non-Patent Document 1] The 17th Revised Japanese Pharmacopoeia Commentary C-5998~C-6002 [Non-Patent Document 2] Abstracts of the Annual Meeting of the Pharmaceutical Society of Japan, Vol. 121, No. 3, Page 132 [Overview of the project] [Problems that the invention aims to solve]

[0005] The inventors of this invention have made the surprising discovery that when loxoprofen sodium and ambroxol hydrochloride are mixed, the content of ambroxol hydrochloride decreases over time. Furthermore, compositions containing loxoprofen sodium and ambroxol hydrochloride may undergo changes in appearance over time, indicating that there is still room for improvement in terms of storage stability. An object of the present invention is to provide a pharmaceutical composition that contains loxoprofen or a salt thereof and ambroxol or a salt thereof, while suppressing the decrease in the content of ambroxol or a salt thereof over time. Another object of the present invention is to provide an excellent pharmaceutical composition that contains loxoprofen or a salt thereof and ambroxol or a salt thereof, while suppressing changes in appearance. [Means for solving the problem]

[0006] In order to solve the above problems, the inventors conducted various studies and, surprisingly, discovered that by incorporating noscapine, the decrease in the content of ambroxol or its salt over time can be suppressed, and that a pharmaceutical composition containing loxoprofen or its salt and ambroxol or its salt with suppressed changes in appearance can be obtained.

[0007] In other words, the present invention is (1) A pharmaceutical composition characterized by containing (A) loxoprofen or a salt thereof, (B) ambroxol or a salt thereof, and (C) noscapine or a salt thereof (excluding dihydrocodeine phosphate), (2) The pharmaceutical composition according to (1), wherein the content ratio of component (A) to component (B) is 0.05 to 3.8 parts by mass of component (B) per 1 part by mass of component (A), (3) The pharmaceutical composition according to (1) or (2), wherein the content of component (C) is 0.09 to 0.7 parts by mass per 1 part by mass of the total amount of component (A) and component (B), (4) The pharmaceutical composition is a solid dosage form as described in (1) or (2), (5) Use of (C) noscapine or a salt thereof for the production of a pharmaceutical composition containing (A) loxoprofen or a salt thereof and (B) ambroxol or a salt thereof, wherein (B) ambroxol or a salt thereof is stabilized. (6) Use of (C) noscapine or salt thereof to stabilize (B) ambroxol or salt thereof in a pharmaceutical composition containing (A) loxoprofen or a salt thereof and (B) ambroxol or a salt thereof, (7)(A) Loxoprofen or a salt thereof, (B) Ambroxol or a salt thereof, (C) Noscapine or a salt thereof, and (D) does not contain dihydrocodeine phosphate, a pharmaceutical composition characterized by the above, is provided.

Effects of the Invention

[0008] According to the present invention, it has become possible to provide an excellent pharmaceutical composition containing loxoprofen or a salt thereof and ambroxol or a salt thereof, which suppresses the decomposition of ambroxol or a salt thereof over time. Further, it has become possible to provide an excellent pharmaceutical composition containing loxoprofen or a salt thereof and ambroxol or a salt thereof, in which the change in appearance is suppressed.

Modes for Carrying Out the Invention

[0009] Hereinafter, the pharmaceutical composition containing loxoprofen or a salt thereof and ambroxol or a salt thereof of the present invention will be described in detail.

[0010] In the pharmaceutical composition of the present invention, the loxoprofen or a salt thereof includes not only loxoprofen, but also pharmaceutically acceptable salts of loxoprofen, and further solvates with water, alcohol, etc. These are known compounds, which can be produced by known methods, and commercially available products can also be used. In the present invention, as the loxoprofen or a salt thereof, loxoprofen sodium hydrate and loxoprofen sodium dihydrate are preferable. The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not limited, and may be appropriately considered and determined according to, for example, the gender, age, symptoms, etc. of the user. As the daily dose, it is preferably 18 to 180 mg in terms of anhydride. The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited as long as it shows the medicinal effect, but is preferably 8 to 80% by mass, more preferably 8 to 78% by mass, still more preferably 10 to 78% by mass, and most preferably 12 to 78% by mass based on the total mass of the pharmaceutical composition.

[0011] Ambroxol or its salt used in the invention has the chemical formula C 13 H 18 The compound represented by Br2N2O or a salt thereof may be used individually or in combination of two or more. Such ambroxol or salts thereof can be produced by known methods or commercially available products can be used. Furthermore, ambroxol or salts thereof are not particularly limited as long as they are pharmaceutically acceptable, but examples of salts include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate, with hydrochloride being particularly preferred. The amount of ambroxol or its salt contained in the pharmaceutical composition of the present invention is not limited and may be determined appropriately depending on the gender, age, symptoms, etc. of the person taking the medication. Preferably, the daily dose is 4.5 to 60 mg. The amount of ambroxol or its salts in the solid composition of the invention (the total amount of two or more of ambroxol or its salts if they are included, the same applies hereinafter) is not particularly limited as long as it is in an amount that exhibits its pharmacokinetic effect, but is usually 1 to 50% by mass, preferably 1 to 48% by mass, more preferably 3 to 48% by mass, and even more preferably 4 to 48% by mass.

[0012] The noscapine or salt thereof used in this invention has the chemical formula C 22 H 23The compound indicated by NO7 or a salt thereof may be used alone or in combination of two or more. Such noscapine or salt thereof can be manufactured by known methods or commercially available products can be used. Furthermore, noscapine or its salt is not particularly limited as long as it is pharmaceutically acceptable, but examples of salts include salts of inorganic acids such as hydrochloride, hydrobromide, phenolphthalate, and phosphate, and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate, with hydrochloride being particularly preferred. The content of ambroxol or its salt in the pharmaceutical composition of the present invention is not limited and may be appropriately considered and determined according to the gender, age, symptoms, etc. of the person taking the medicine. The daily dose is preferably 4.8 to 60 mg. The amount of noscapine or its salt contained in the pharmaceutical composition of the present invention (the total amount of noscapine or its salt if two or more types are contained, the same applies hereinafter) is not particularly limited as long as it is in an amount that exhibits its pharmacological effect, but is usually 1 to 50% by mass, preferably 1 to 40% by mass, more preferably 5 to 40% by mass, and even more preferably 8 to 40% by mass.

[0013] The mixing ratio of (A) loxoprofen or a salt thereof and (B) ambroxol or a salt thereof is preferably 0.01 to 5 parts by mass, more preferably 0.05 to 4 parts by mass, and even more preferably 0.05 to 3.8 parts by mass of (B) per 1 part by mass of component (A).

[0014] The mixing ratio of (A) loxoprofen or a salt thereof, (B) ambroxol or a salt thereof, and (C) noscapine is preferably such that (C) noscapine is contained in an amount of 0.01 to 1.0 parts by mass, more preferably 0.05 to 0.75 parts by mass, and even more preferably 0.09 to 0.7 parts by mass, per 1 part by mass of the total of (A) loxoprofen or a salt thereof and (B) ambroxol or a salt thereof.

[0015] The solid composition of the present invention is not particularly limited as long as it is in a dosage form specified in the General Rules for Formulations of the Japanese Pharmacopoeia, but is preferably a tablet, powder, fine granule, granule, pill, or capsule. Tablets specified in the General Rules for Formulations of the Japanese Pharmacopoeia include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and dissolvable tablets, sugar-coated tablets, and laminated tablets. Furthermore, the tablets may be scored, marked, or engraved to improve identification. In addition, the tablets of this formulation may be round or irregularly shaped. The solid composition of the present invention may also be a mini-tablet or a dry syrup. From the viewpoint of the effects of the present invention, there is great significance in implementing it with tablets other than coated tablets.

[0016] The solid composition of the present invention may contain other commonly used active ingredients, excipients, disintegrants, binders, fluidizers, lubricants, acidulants, sweeteners, flavoring agents, cooling agents, colorants, foaming agents, surfactants, plasticizers, fragrances, coating agents, etc., within a qualitative and quantitative range that does not impair the effects of the present invention.

[0017] Other active ingredients that can be incorporated into the solid composition of the present invention include, for example, antipyretic analgesics, antihistamines, antitussives, bronchodilators, expectorants, hypnotics and sedatives, vitamins, amino acids, anti-inflammatory agents, gastric mucosal protectants, herbal medicines, Kampo prescriptions, caffeines, etc., and one or more selected from the group consisting of these may be included.

[0018] Examples of excipients that can be incorporated into the solid composition of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohols, calcium hydrogen phosphate, etc. Examples of disintegrants include low-substituted hydroxypropyl cellulose, sodium starch glycolate, crospovidone, carmellose, sodium carmellose, calcium carmellose, pregelatinized starch, etc. Examples of binders include hydroxypropyl cellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan, etc. Examples of fluidizers include light anhydrous silicic acid, hydrated silicon dioxide, etc. Examples of lubricants include sucrose fatty acid esters, hydrogenated oils, stearic acid, magnesium stearate, calcium stearate, etc.

[0019] The solid composition of the present invention preferably does not contain dihydrocodeine phosphate. This is because the presence of dihydrocodeine phosphate may reduce the stability of ambroxol hydrochloride and further deteriorate its appearance.

[0020] The present invention can be manufactured by conventional methods. Specifically, tablets of this formulation can be manufactured by mixing the active pharmaceutical ingredient and the above-mentioned additives in a suitable mixer such as a mixer to produce a tablet mixture, and then directly compressing the mixture into tablets, or by compressing granules into tablets. Granules can be manufactured by dry granulation (slug method, roller compactor method) or wet granulation. Wet granulation methods include agitation granulation, fluid bed granulation, extrusion granulation, rolling granulation, spray granulation, etc., and are preferably agitation granulation, fluid bed granulation, or extrusion granulation. From the viewpoint of manufacturability, wet granulation is preferred for this invention. As a machine for compressing the tablet mixture or the granules of the mixture, a single-shot tablet press, a rotary tablet press, etc., can be used.

[0021] Furthermore, the packaging for containing the pharmaceutical composition of the present invention is preferably an "airtight container" or "sealed container" as defined in the General Rules of the 18th Revised Japanese Pharmacopoeia. The packaging can be either fixed-shaped or irregular-shaped, and specifically, for example, bottle packaging (sealed), SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, and stick packaging are preferred. In the present invention, a combination of these may also be used, and specifically, for example, a form in which the product is packaged in PTP packaging and then further packaged in pillow packaging is also included.

[0022] <Example Test> The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.

[0023] (Preparation of solid composition) (Examples 1-6, Comparative Examples 1-3) Each raw material component was weighed according to the formulation shown in Table 1, an appropriate amount of water was added, and the mixture was uniformly mixed in a mortar. The entire mixture was then passed through a sieve (mesh size 710 μm) to obtain the mixture.

[0024] [Table 1]

[0025] (1) Change in appearance (color difference measurement) Prepared samples were stored for 7 days under 65°C conditions (packaging: approximately 3g / sealed 2K bottle). The color of the stored samples was measured using a spectrophotometer (SE6000: Nippon Denshoku Industries Co., Ltd.), and the difference between this measurement and the color of the sample immediately after preparation was calculated. The results are shown in Table 1 as the color difference (ΔE*(ab)). (ΔE*(ab)) was calculated according to Equation 1. A smaller color difference (ΔE*(ab)) indicates less discoloration and suggests an improvement effect.

[0026]

number

[0027] ΔL * = L value of the sample stored at 65°C for 7 days * - L value of the immediately after sample * value (L * : lightness + is in the white direction, - is in the black direction) Δa * = a value of the sample stored at 65°C for 7 days * - a value of the immediately after sample * value (a * : chromaticity + is in the red direction, - is in the green direction) Δb * = b value of the sample stored at 65°C for 7 days * - b value of the immediately after sample * value (b * : chromaticity + is in the yellow direction, - is in the blue direction)

[0028] (2) Appearance change (sensory evaluation) For the mixtures obtained in Examples 1 to 6 and Comparative Examples 1 to 3, the appearance change was visually observed. The evaluation was performed by relative comparison between the sample stored at 65°C for 7 days (packaging form: about 3 g / 2K bottle) and the immediately after sample, and evaluated in 5 grades: 0: no discoloration, 1: slight change is observed, 2: change is observed but acceptable, 3: obvious change is observed, 4: significant change is observed. The average value of the obtained scores was calculated.

[0029] (2) Stability test (change in the content of ambroxol hydrochloride) For the mixtures obtained in Examples 1 to 6 and Comparative Examples 1 to 3, the content of ambroxol hydrochloride in the sample stored at 65°C for 7 days (packaging form: about 3 g / 2K bottle) and the content at the start of the test were measured by HPLC method, and the residual rate was calculated. The results are shown in Table 2.

[0030] In Examples 1-6, which combined loxoprofen sodium hydrate and ambroxol hydrochloride with noscapine, the change in appearance was significantly suppressed. Regarding the color difference (ΔE*(ab)), Comparative Examples 1 and 2 showed values ​​close to 50, but the inclusion of noscapine resulted in a significantly lower value. In terms of the appearance change score, Comparative Examples 1 and 2, which did not contain noscapine, showed high scores of 3 or higher, while Examples 1-6, which contained noscapine, showed low values ​​of less than 2. Furthermore, the residual rate of ambroxol hydrochloride was higher in the Examples than in the Comparative Examples, demonstrating superior storage stability. On the other hand, in Comparative Example 3, which contained dihydrocodeine phosphate, no improvement was observed even with the inclusion of noscapine.

[0031] [Table 2]

[0032] Examples of formulation preparations are given below. Formulation Examples 1-11 Tablets, powders, or granules are manufactured using known techniques for the formulation examples listed in Table 3. The resulting powders or granules are then filled into hard capsules using known techniques to manufacture hard capsules.

[0033] [Table 3] [Industrial applicability]

[0034] According to the present invention, a pharmaceutical composition comprising loxoprofen or a salt thereof and ambroxol or a salt thereof can be provided that exhibits excellent storage stability.

Claims

1. A pharmaceutical composition characterized by containing (A) loxoprofen or a salt thereof, (B) ambroxol or a salt thereof, and (C) noscapine or a salt thereof (excluding dihydrocodeine phosphate).

2. The pharmaceutical composition according to claim 1, wherein the content ratio of component (A) to component (B) is 0.05 to 3.8 parts by mass of component (B) per 1 part by mass of component (A).

3. The pharmaceutical composition according to claim 1 or 2, wherein the content of component (C) is 0.09 to 0.7 parts by mass per 1 part by mass of the total amount of component (A) and component (B).

4. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a solid dosage form.

5. (A) loxoprofen or a salt thereof and (B) ambroxol or a salt thereof, the use of (C) noscapine or a salt thereof for the production of a pharmaceutical composition in which (B) ambroxol or a salt thereof is stabilized.

6. (A) Use of (C) noscapine or a salt thereof to stabilize (B) ambroxol or a salt thereof in a pharmaceutical composition containing loxoprofen or a salt thereof.

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