tablet

Abstract

To provide a solid preparation containing ambroxol or a salt thereof and Platycodon root, where the solid preparation barely shows a decrease in the content of ambroxol or a salt thereof.SOLUTION: A tablet contains A) ambroxol or a salt thereof and B) at least one herbal medicine selected from the group consisting of Platycodon root, ginger, Perilla herb and Pinellia tuber, where A) ambroxol or a salt thereof and B) at least one herbal medicine selected from the group consisting of Platycodon root, ginger, Perilla herb and Pinellia tuber are contained in different layers.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a solid preparation containing ambroxol or its salt and a crude drug.

Background Art

[0002] Ambroxol hydrochloride is widely known as a compound having a lubricating action on airway mucosa and a mucolytic action, and having an excellent expectorant action. It has also been approved as a switched OTC drug and is formulated in general cold medicines and cough suppressants (Non-Patent Document 1).

[0003] Platycodon root is the root of Platycodon grandiflorum A. De Candolle (Companulaceae), and is frequently used as a folk medicine and a Chinese herbal medicine for the purpose of expectoration and cough suppression (Non-Patent Document 2). The saponin component platycodin D of Platycodon root has been reported to have an expectorant action and a cough suppressant action. Platycodin D shows an expectorant action by suppressing the production and secretion of mucin that is excessively secreted due to inflammation or the like, and the action is mild (Non-Patent Documents 3 and 4). Ginger rhizome is the rhizome of Zingiber officinale Roscoe (Zingibereaceae), sometimes with the periderm removed, and is frequently used as a folk medicine and a Chinese herbal medicine for the purpose of expectoration and cough suppression (Non-Patent Document 5). The component 6-gingerol of Ginger rhizome has been reported to have a cough suppressant action (Non-Patent Document 6). Perilla leaf is the leaf and the tip of the branch of Perilla frutescens Britton var. crispa W. Deane (Labiatae), and is known to have diaphoretic, cough suppressant, and expectorant actions (Non-Patent Document 7). Pinellia tuber is the tuber of Pinellia ternate Breitenbach with the cork layer removed, and has a cough suppressant and expectorant action, and is relatively frequently formulated in prescriptions regarded as cough suppressant and expectorant drugs in Chinese herbal prescription drugs (Non-Patent Documents 8 and 9). Therefore, these combinations of active ingredients are useful for expectorant and cough suppressant treatment, and solid preparations containing ambroxol hydrochloride and Platycodon grandiflorus, and ambroxol hydrochloride and ginger are known (Patent Documents 1 and 2).

[0004] 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 vitamins, its stability decreases, which has been improved by separating the granules (Patent Document 3). Furthermore, Patent Document 4 describes that the stability of ambroxol decreases when combined with vanillin or cinnamaldehyde, and Patent Document 5 describes that it decreases when combined with ibuprofen. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] OTC Handbook 2008-09, Academic Information Distribution Center Co., Ltd., p. 235 [Non-Patent Document 2] Medical Journal, 2010, No. 46, pp. 5-11 [Non-Patent Document 3] Commentary on the 17th Edition of the Japanese Pharmacopoeia, pages D228-231 [Non-Patent Document 4] Phytomedicine 2014 No. 21 pp. 529-533 [Non-Patent Document 5] 294 Kampo Prescriptions: Explanation of Crude Drugs, 2nd Edition, Jiho, pp. 12-15 [Non-Patent Document 6] Commentary on the 17th Edition of the Japanese Pharmacopoeia, pages D477-480 [Non-Patent Document 7] 294 Kampo Prescriptions: Explanation of Crude Drugs, 2nd Edition, Jiho, pp. 17-18 [Non-Patent Document 8] 294 Kampo Prescriptions: Explanation of Crude Drugs, 2nd Edition, Jiho, pp. 232-234 [Non-Patent Document 9] Commentary on the 17th Edition of the Japanese Pharmacopoeia, pages D798-801 [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 8-337532 [Patent Document 2] Japanese Patent Application Publication No. 8-337532 [Patent Document 3] Patent No. 4899304 [Patent Document 4] Japanese Patent Publication No. 2018-177772 [Patent Document 5] Patent No. 4853818 [Overview of the project] [Problems that the invention aims to solve]

[0007] The inventors of the present invention manufactured a solid dosage form containing ambroxol hydrochloride and a specific herbal medicine and conducted thorough studies, but encountered the problem that the stability of ambroxol hydrochloride decreased over time. Therefore, the object of the present invention is to provide a solid dosage form containing ambroxol or a salt thereof and a specific herbal medicine in which the decrease in the content of ambroxol or a salt thereof is suppressed. [Means for solving the problem]

[0008] In order to solve the above problems, we conducted various studies and found that by creating a multilayer tablet with two or more layers in which ambroxol or its salt and the herbal medicine are contained in different layers within a solid preparation containing ambroxol or its salt and a specific herbal medicine, the decrease in the content of ambroxol or its salt can be suppressed, thus completing the present invention.

[0009] In other words, the present invention (1) A tablet containing ambroxol or a salt thereof, and B) at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata, A) Ambroxol or a salt thereof and B) a tablet containing at least one crude drug selected from the group consisting of Platycodon grandiflorum, Zingiber officinale, Glycyrrhiza glabra, and Coptis chinensis Franch. in different layers (2) A tablet containing A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Platycodon grandiflorum, Zingiber officinale, Glycyrrhiza glabra, and Coptis chinensis Franch., A tablet satisfying any one of the following i) or ii): i) A multilayer tablet composed of two or more layers in which A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Platycodon grandiflorum, Zingiber officinale, Glycyrrhiza glabra, and Coptis chinensis Franch. are arranged in different layers ii) A nucleated tablet in which either A) ambroxol or a salt thereof or B) at least one crude drug selected from the group consisting of Platycodon grandiflorum, Zingiber officinale, Glycyrrhiza glabra, and Coptis chinensis Franch. is a core tablet and the other is arranged in the outer layer (3) The tablet according to (1) or (2), characterized in that A) ambroxol or a salt thereof is ambroxol hydrochloride (4) The tablet according to (1) or (2), characterized in that the content of B) at least one crude drug selected from the group consisting of Platycodon grandiflorum, Zingiber officinale, Glycyrrhiza glabra, and Coptis chinensis Franch. is satisfies any one of the following i) to iv): i) When containing Platycodon grandiflorum, it contains 2 to 200 parts by mass of Platycodon grandiflorum in terms of the amount of the crude drug ii) When containing Zingiber officinale, it contains 1 to 150 parts by mass of Zingiber officinale in terms of the amount of the crude drug iii) When containing Glycyrrhiza glabra, it contains 3 to 100 parts by mass of Glycyrrhiza glabra in terms of the amount of the crude drug iv) When containing Coptis chinensis Franch., it contains 8 to 200 parts by mass of Coptis chinensis Franch. in terms of the amount of the crude drug (5) In a tablet containing A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Platycodon grandiflorum, Zingiber officinale, Glycyrrhiza glabra, and Coptis chinensis Franch., A method for suppressing the decrease in the content of ambroxol or a salt thereof, characterized by containing A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Platycodon grandiflorum, Zingiber officinale, Perilla frutescens, and Pinellia ternata in different layers. It is.

Advantages of the Invention

[0010] According to the present invention, it has become possible to provide an excellent tablet containing ambroxol or a salt thereof and a specific crude drug and suppressing the decrease in the content of ambroxol or a salt thereof.

Embodiments for Carrying Out the Invention

[0011] The tablet of the present invention can be provided as a tablet having excellent stability in a tablet containing A) ambroxol or a salt thereof (hereinafter, also referred to as "component A" in some cases) and B) at least one crude drug selected from the group consisting of Platycodon grandiflorum, Zingiber officinale, Perilla frutescens, and Pinellia ternata (hereinafter, also referred to as "component B" in some cases).

[0012] The ambroxol or a salt thereof used in the present invention is a compound represented by the chemical formula C 13 H 18 Br2N2O or a salt thereof, and one of these may be used alone or two or more thereof may be used in combination. Such ambroxol or a salt thereof can be produced by a known method, and commercially available products can also be used. Further, ambroxol or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable, and examples of the salt include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and salts of organic acids such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate. Particularly preferred is hydrochloride.

[0013] The crude drug in the present invention is an extract obtained by drying, pulverizing, or extracting using a solvent using plants in nature, and is Platycodon grandiflorum, Zingiber officinale, Perilla frutescens, and Pinellia ternata.

[0014] The balloon flower used in this invention is not particularly limited as long as it is used in pharmaceuticals, and includes powdered balloon flower, extract, extract powder, etc., and commercially available products can also be used. The balloon flower used is the dried root of Platycodon grandiflorum A. De Candolle (Campanulaceae), but it can also be used in the form of crushed powder or extract, and extract powder is preferred.

[0015] The ginger used in this invention is not particularly limited as long as it is used in pharmaceuticals, and includes powdered ginger, extract, extract powder, etc., and commercially available products can also be used. Ginger is the rhizome of Zingiber officinale Roscoe (Zingibereaceae), and sometimes the rhizome with the periderm removed can be used, but it can also be used in the form of crushed powder or extract, and extract powder is preferred.

[0016] The hibiscus used in this invention is not particularly limited as long as it is used in pharmaceuticals, and includes powdered form, extract, extract powder, etc., and commercially available products can also be used. The leaves and branch tips of Perilla frutescens Britton var. crispa W. Deane (Labiatae) can be used as hibiscus, but it can be used in the form of crushed powder or extract, and extract powder is preferred.

[0017] The Pinellia ternate used in this invention is not particularly limited as long as it is used in pharmaceuticals, and includes powdered form, extract, extract powder, etc., and commercially available products can also be used. The tuber of Pinellia ternate Breitenbach with the cork layer removed can be used, but it can be crushed into a powder or extracted, and extract powder is preferred.

[0018] Furthermore, the mixing ratio of ambroxol or its salt to platycodon is preferably 2 to 200 parts by mass of platycodon, more preferably 4.4 to 150 parts by mass, even more preferably 8.9 to 100 parts by mass, and particularly preferably 17.7 to 88.9 parts by mass, per 1 part by mass of ambroxol or its salt.

[0019] Furthermore, the mixing ratio of ambroxol or its salt to ginger is preferably 1 to 150 parts by mass of ginger in terms of crude drug equivalent per 1 part by mass of ambroxol or its salt, more preferably 2.2 to 100 parts by mass, even more preferably 4 to 80 parts by mass, and particularly preferably 22.2 to 66.7 parts by mass.

[0020] Furthermore, the mixing ratio of ambroxol or its salt to perilla is preferably 3 to 100 parts by mass of perilla (in terms of crude drug equivalent) per 1 part by mass of ambroxol or its salt, more preferably 3.5 to 75 parts by mass, even more preferably 4.4 to 50 parts by mass, and particularly preferably 36 to 44.4 parts by mass.

[0021] Furthermore, the mixing ratio of ambroxol or its salt to Pinellia ternata is preferably 8 to 200 parts by mass of Pinellia ternata per 1 part by mass of ambroxol or its salt, more preferably 9 to 150 parts by mass, even more preferably 11.1 to 120 parts by mass, and particularly preferably 100 to 111.1 parts by mass.

[0022] The tablets of the present invention contain A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata, wherein components A and B are arranged in different layers and exist in the formulation without substantially contacting each other. "Existing without substantially contacting each other in the formulation" means that when multiple drugs are present in a tablet, the drugs are not uniformly mixed, that is, they exist in the same tablet without coming into contact with each other to the extent that they do not interact with each other. Examples include tablets in the form of multilayer tablets in which the drugs are in different layers, and tablets in the form of core tablets having an inner core and an outer layer.

[0023] The tablets of the present invention are typically tablets as defined in the General Rules for Formulations of the Japanese Pharmacopoeia, and multilayer tablets or core tablets having two or more layers are particularly preferred. In addition to providing score lines, marks or inscriptions to improve identification on the tablets, they can also be sugar-coated tablets or film-coated tablets. Furthermore, the tablets of this formulation may be round tablets or irregularly shaped tablets.

[0024] The tablets of the present invention may contain other commonly used active ingredients, excipients, disintegrants, binders, fluidizers, lubricants, cooling agents, colorants (pigments), flavoring agents, fragrances, coating agents, etc., within a qualitative and quantitative range that does not impair the effects of the present invention.

[0025] Other active ingredients that can be incorporated into the tablets of the present invention include, for example, antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotics and sedatives, vitamins, anti-inflammatory agents, gastric mucosal protectants, herbal medicines, Kampo prescriptions, caffeines, etc., and one or more selected from this group may be included.

[0026] Examples of excipients that can be incorporated into the tablets of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohols, magnesium aluminometasilicate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. Examples of disintegrants include low-substituted hydroxypropylcellulose, sodium starch glycolate, crospovidone, carmellose, carmellose sodium, croscarmellose sodium, carmellose calcium, and pregelatinized starch. Examples of binders include hydroxypropylcellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, and pullulan. Examples of fluidizers include light anhydrous silicic acid and hydrated silicon dioxide. Examples of lubricants include sucrose fatty acid esters, hydrogenated oils, talc, stearic acid, magnesium stearate, and calcium stearate. Examples of cooling agents include menthol, peppermint oil, and eucalyptus oil.

[0027] The tablets of the present invention can be manufactured by conventional methods, and the method is not particularly limited, as long as A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata are arranged in different layers. For example, components A and B may be blended into separate granules, and these granules may be divided into a layer containing component A (hereinafter also referred to as "layer a") and a layer containing component B (hereinafter also referred to as "layer b") to form tablets. Alternatively, components A or B may be blended in powder form in layers a and b. Or, either layer a or layer b may be in granule form, and the other layer may be in powder form to form a tablet.

[0028] The tablets of the present invention may be manufactured by direct compression, or they may be in the form of tablets containing granules. When preparing granules, if A) granules containing ambroxol or a salt thereof and B) granules containing at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata are prepared separately, other pharmacoactive ingredients may be added to each granule as needed, and additives may be added as necessary, and the preparation may be carried out according to conventional methods. Alternatively, for example, a coating solution may be sprayed as needed to produce coated granules. The granulation method is not particularly limited and can be manufactured by wet granulation, dry granulation, or melt granulation, but wet granulation is preferred. Examples of wet granulation methods include agitation granulation, fluidized bed granulation, kneading granulation, extrusion granulation, and rolling fluidized bed granulation. Furthermore, if necessary, water, alcohol, or a mixture of water and alcohol may be used as the granulation liquid, and if necessary, active ingredients, binders, excipients, fluidizers, etc. may be dissolved or dispersed in the granulation liquid. The obtained granules may be appropriately blended with conventional additives such as the above-mentioned active ingredients and excipients. In addition, for example, a tablet containing layers a and b may be sprayed with a coating liquid as necessary to produce a film-coated tablet or a sugar-coated tablet. [Examples]

[0029] 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.

[0030] (Comparative Example 1) Ambroxol hydrochloride was mixed with an appropriate amount of water / alcohol mixture and then dried to obtain the composition. (Comparative Example 2) To 1 part by mass of ambroxol hydrochloride, 4 parts by mass of Platycodon grandiflorus dry extract powder were weighed and mixed. An appropriate amount of water / alcohol mixture was then added and mixed, and the mixture was dried to obtain the composition. Note that 1 part by mass of Platycodon grandiflorus dry extract powder is equivalent to 5 parts by mass of crude drug. (Comparative Example 3) To 1 part by mass of ambroxol hydrochloride, 4 parts by mass of ginger powder were weighed and mixed, and an appropriate amount of water / alcohol mixture was added and mixed, then dried to obtain the composition. (Comparative Example 4) To 1 part by mass of ambroxol hydrochloride, 4 parts by mass of perilla leaf extract powder were weighed and mixed, and an appropriate amount of water / alcohol mixture was added and mixed, then dried to obtain the composition. Note that 1 part by mass of perilla leaf extract powder is equivalent to 9 parts by mass of crude drug. (Comparative Example 5) To 1 part by mass of ambroxol hydrochloride, 4 parts by mass of Pinellia ternata dry extract powder were weighed and mixed, and an appropriate amount of water / alcohol mixture was added and mixed, then dried to obtain the composition. Note that 1 part by mass of Pinellia ternata dry extract powder is equivalent to 25 parts by mass of crude drug.

[0031] (Test Example 1) The compositions of Comparative Examples 1 to 5 were stored at room temperature for at least one day, then stored at 65°C for seven days, and the remaining percentage of ambroxol hydrochloride in the compositions after seven days was evaluated by HPLC. Table 1 shows the percentage of ambroxol hydrochloride remaining after 7 days of storage.

[0032] [Table 1]

[0033] (Comparative Example 6) 4.5 g of ambroxol hydrochloride, 16 g of Platycodon grandiflorus dry extract powder, 10.3 g of crystalline cellulose, and 2 g of hydroxypropyl cellulose were mixed, and granule A was obtained by granulation in a mortar. 328 mg portions of granule A were weighed out and tableted using a tablet molding machine equipped with a mortar and pestle with a small amount of magnesium stearate on the outside. (Comparative Example 7) 4.5 g of ambroxol hydrochloride, 10.3 g of crystalline cellulose, and 2 g of hydroxypropyl cellulose were mixed and granulated in a mortar to obtain granule B. Similarly, 16 g of Platycodon grandiflorus dry extract powder, 10.3 g of crystalline cellulose, and 2 g of hydroxypropyl cellulose were mixed and granules C were obtained in a mortar to obtain granule C. Mixture D, consisting of 3.36 g of granule B and 5.66 g of granule C, was weighed out in 451 mg portions and tableted using a tablet forming machine equipped with a mortar and pestle coated with a small amount of magnesium stearate. (Example 1) 168 mg of granule B and 283 mg of granule C prepared in Comparative Example 7 were weighed out, and two-layer tablets were formed in which granule B and granule C were placed in separate layers using a tablet molding machine equipped with a mortar and pestle with a small amount of magnesium stearate on the outside.

[0034] (Comparative Example 8) 0.45 g of ambroxol hydrochloride, 10 g of ginger powder, 1.22 g of crystalline cellulose, and 0.75 g of hydroxypropyl cellulose were mixed and granulated in a mortar. After granulation, a small amount of magnesium stearate was added to obtain granule E. Granule E was weighed out in 414 mg portions and formed into tablets using a tablet molding machine. (Example 2) Granule F was obtained by adding a small amount of magnesium stearate to granule B prepared in Comparative Example 7 above. Alternatively, 10 g of ginger powder, 1.22 g of crystalline cellulose, and 0.75 g of hydroxypropyl cellulose were mixed, granulated in a mortar, and then a small amount of magnesium stearate was added to obtain granule G. 56 mg of granule F and 399 mg of granule G were weighed out, and these were formed into two-layer tablets using a tablet molding machine, with granule F and granule G arranged in separate layers.

[0035] (Test Example 2) The tablets of Comparative Examples 6-8 and Examples 1-2 were each filled into bottles, sealed, and stored at 65°C for 7 days. The remaining percentage of ambroxol hydrochloride in the tablets after 7 days was evaluated by HPLC. For each comparative example and example, a sample stored at 5°C for 7 days was used as a control. The results were calculated with the remaining percentage of ambroxol hydrochloride at 5°C set to 100%. Table 2 shows the daily prescribed dose and the remaining percentage of ambroxol hydrochloride for tablets obtained by the methods described in Examples 1-2 and Comparative Examples 6-8.

[0036] [Table 2]

[0037] In a comparative example where A) ambroxol hydrochloride and B) herbal medicine were blended in the same layer, a decrease in ambroxol content was observed. On the other hand, in an example where A) ambroxol hydrochloride and B) herbal medicine were blended in separate layers, the decrease in ambroxol hydrochloride content was suppressed. [Industrial applicability]

[0038] According to the present invention, it is possible to provide tablets with improved stability that contain A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata, thereby providing an excellent pharmaceutical product.

Claims

1. A) a tablet containing ambroxol or a salt thereof, and B) at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata, A tablet that satisfies either i) or ii) below. i) Multilayer tablets consisting of two or more layers, in which A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata are arranged in different layers. ii) A core tablet in which either A) ambroxol or a salt thereof, or B) at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata, is used as the inner core, and the other is placed in the outer layer.

2. A) The tablet according to claim 1, characterized in that the ambroxol or salt thereof is ambroxol hydrochloride.

3. B) The content of at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata is, A) 1 part by mass of ambroxol or its salt, The tablet according to claim 1, characterized in that it satisfies any of the following i) to iv). i) If Platycodon grandiflorus is included, it shall contain 2 to 200 parts by mass of Platycodon grandiflorus in terms of crude drug equivalent. ii) If ginger is included, the amount of ginger shall be 1 to 150 parts by mass in terms of crude drug equivalent. iii) If it contains Perilla frutescens, it contains 3 to 100 parts by mass of Perilla frutescens in terms of crude drug equivalent. iv) If Pinellia ternata is included, it shall contain 8 to 200 parts by mass of Pinellia ternata in terms of crude drug equivalent.

4. A) a tablet containing ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata, A) A method for suppressing the decrease in content of ambroxol or its salt, characterized by containing A) ambroxol or its salt and B) at least one crude drug selected from the group consisting of Platycodon grandiflorus, Zingiber officinale, Perilla frutescens, and Pinellia ternata in different layers.

Images