JP2022166832A - tablet - Google Patents

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 The present invention relates to solid preparations containing ambroxol or a salt thereof and herbal medicines.

Ambroxol hydrochloride is widely known as a compound having airway mucosal lubricating action and mucolytic action and excellent expectorant action. It is also approved as a switch OTC drug, and is compounded in common cold medicines and cough medicines (Non-Patent Document 1).

Platycodon grandiflorum A. De Candolle (Companulaceae) is the root of Platycodon grandiflorum A. De Candolle (Companulaceae). Platycodin D, a saponinic component of Bellflower, has been reported to have expectorant and antitussive effects. is relaxation (Non-Patent Documents 3, 4).
Ginger is the rhizome of ginger Zingiber officinale Roscoe (Zingibereaceae), sometimes with the pericarp removed, and is often used as a folk medicine or Chinese herbal medicine for the purpose of expectoration and antitussive (Non-Patent Document 5). 6-shogaol, a component of ginger, has been reported to have an antitussive effect (Non-Patent Document 6).
Soyou is Perilla frutescens Britton var. crispa W. It is a leaf and branch tip of Deane (Labiatae), and is known to have sweating, antitussive, and expectorant actions (Non-Patent Document 7).
Hange is a tuber of Pinellia ternate Breitenbach from which the cork layer has been removed. , 9).
Therefore, the combination of these active ingredients is useful for expectorant/antitussive therapy, and solid preparations containing ambroxol hydrochloride and bellflower, and ambroxol hydrochloride and ginger are known. (Patent Documents 1 and 2).

Ambroxol hydrochloride has been known to cause stability problems when co-formulated with certain ingredients. For example, when ambroxol hydrochloride and vitamins are blended, the stability of ambroxol hydrochloride is lowered, which is improved by separate granulation (Patent Document 3). Further, Patent Document 4 describes that ambroxol and vanillin or cinnamaldehyde, and Patent Document 5 describes that simultaneous blending of ambroxol and ibuprofen decreases the stability of ambroxol. .

OTC Handbook 2008-09 Academic Information Distribution Center Co., Ltd. Page 235 Pharmaceutical Journal 2010 No. 46 pp. 5-11 Japanese Pharmacopoeia 17th Edition Commentary D228-231 Phytomedicine 2014 No. 21, pp. 529-533 Kampo 294 Prescriptions Herbal Medicine Commentary 2nd Edition Jiho Pages 12-15 Japanese Pharmacopoeia 17th Edition Commentary D477-480 Kampo 294 Prescriptions Herbal Medicine Commentary 2nd Edition Jiho Pages 17-18 Kampo 294 Prescriptions Herbal Medicine Commentary 2nd Edition Jiho Pages 232-234 Japanese Pharmacopoeia 17th Edition Manual D798-801

JP-A-8-337532 JP-A-8-337532 Japanese Patent No. 4899304 JP 2018-177772 A Japanese Patent No. 4853818

The present inventors produced a solid formulation containing ambroxol hydrochloride and a specific herbal medicine, and when they conducted intensive studies, they faced the problem that the stability of ambroxol hydrochloride decreased over time. Accordingly, it is an object of the present invention to provide a solid preparation containing ambroxol or a salt thereof and a specific herbal medicine in which a decrease in the content of ambroxol or a salt thereof is suppressed.

As a result of various investigations to solve the above problems, in a solid preparation containing ambroxol or its salt and a specific crude drug, ambroxol or its salt and the crude drug are contained in different layers in the preparation. The present inventors have found that the decrease in the content of ambroxol or a salt thereof can be suppressed by forming a multi-layered tablet having two or more layers, and have completed the present invention.

That is, the present invention provides a tablet containing (1) A) ambroxol or a salt thereof, and B) at least one crude drug selected from the group consisting of Bellflower, Ginger, Soyou and Hange,
A) a tablet containing ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange 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 Bellflower, Ginger, Soyou and Hange,
A tablet that satisfies either of the following i) or ii),
i) A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Bellflower, Ginger, Soyou and Hange are arranged in different layers ii) A) A multi-layered tablet consisting of two or more layers A dry-coated tablet comprising one of xol or a salt thereof and B) at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange as an inner core and the other as an outer layer (3) A) the tablet according to (1) or (2), wherein ambroxol or a salt thereof is ambroxol hydrochloride;
(4) B) the content of at least one herbal medicine selected from the group consisting of Bellflower, Ginger, Soyou and Hange is A) based on 1 part by mass of ambroxol or a salt thereof,
The tablet according to (1) or (2), characterized by satisfying any of the following i) to iv),
i) When containing bellflower, containing 2 to 200 parts by mass of bellflower in terms of crude drug equivalent ii) When containing ginger, containing 1 to 150 parts by mass of ginger in terms of crude drug iii) When containing soyo , containing 3 to 100 parts by mass of soybean as an amount equivalent to the original herbal medicine; In a tablet containing at least one crude drug selected from the group consisting of Bellflower, Ginger, Soyou and Hange,
A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange are contained in different layers. Content decrease suppression method,
is.

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide an excellent tablet containing ambroxol or a salt thereof and a specific herbal medicine and suppressing a decrease in the content of ambroxol or a salt thereof.

The tablet of the present invention comprises: A) ambroxol or a salt thereof (hereinafter sometimes referred to as "ingredient A"); Hereinafter, it may be referred to as "ingredient B" depending on the case).

Ambroxol or a salt thereof used in the present invention is a compound represented by the chemical formula C ₁₃ H ₁₈ Br ₂ N ₂ O or a salt thereof. may be used. Such ambroxol or a salt thereof can be produced by a known method, or commercially available products can be used. In addition, ambroxol or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. And organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, etc. Hydrochloride is particularly preferred.

The crude drug in the present invention is an extract obtained by drying, pulverizing, or extracting using a solvent using plants in the natural world, and summer).

Bellflowers used in the present invention are not particularly limited as long as they are used for pharmaceuticals, and include powdered ones, extracts, powdered extracts, etc. Commercially available products can also be used. Bellflower is Platycodon grandiflorum A. The dried root of De Candolle (Campanulaceae) can be used, but it can be pulverized into powder or extracted, preferably the extract powder.

Ginger used in the present invention is not particularly limited as long as it is used for pharmaceuticals, and includes powdered ones, extracts, powdered extracts, etc. Commercially available products can also be used. Ginger is the rhizome of ginger Zingiber officinale Roscoe (Zingibereaceae), sometimes the pericarp can be removed, but it can be crushed into powder or extracted, preferably It is the extract powder.

The soy sauce used in the present invention is not particularly limited as long as it is used for pharmaceuticals, and includes powdered ones, extracts, powdered extracts, etc. Commercially available products can also be used. Soyou is Perilla frutescens Britton var. crispa W. The leaves and branch tips of Deane (Labiatae) can be used, but they can be pulverized into powder or extracted, preferably the powdered extract.

The hange used in the present invention is not particularly limited as long as it is used for pharmaceuticals, and includes powdered ones, extracts, powdered extracts, etc., and commercially available products can also be used. The tuber of Pinellia ternate Breitenbach from which the cork layer has been removed can be used as the hange.

In addition, the compounding ratio of ambroxol or its salt and bellflower is preferably 2 to 200 parts by mass, more preferably 4.4 to 1 part by mass of bellflower in terms of crude drug equivalent, per 1 part by mass of ambroxol or its salt. 150 parts by mass, more preferably 8.9 to 100 parts by mass, particularly preferably 17.7 to 88.9 parts by mass.

In addition, the compounding ratio of ambroxol or its salt and ginger is preferably 1 to 150 parts by mass, more preferably 1 part by mass of ginger in terms of crude drug, per 1 part by mass of ambroxol or its salt. 2 to 100 parts by mass, more preferably 4 to 80 parts by mass, particularly preferably 22.2 to 66.7 parts by mass.

In addition, the compounding ratio of ambroxol or a salt thereof and soy sauce is preferably 3 to 100 parts by mass, more preferably 3.5 to 100 parts by mass in terms of crude drug equivalent of soy sauce per 1 part by mass of ambroxol or a salt thereof. 75 parts by mass, more preferably 4.4 to 50 parts by mass, particularly preferably 36 to 44.4 parts by mass.

In addition, the compounding ratio of ambroxol or a salt thereof and hange is preferably 8 to 200 parts by mass, more preferably 9 to 150 parts by mass, based on 1 part by mass of ambroxol or a salt thereof, in terms of crude drug equivalent. parts, more preferably 11.1 to 120 parts by mass, particularly preferably 100 to 111.1 parts by mass.

The tablet of the present invention contains A) ambroxol or a salt thereof and B) at least one herbal medicine selected from the group consisting of bellflower, ginger, soybean and hange, and the layer where component A and component B are different are arranged in the formulation and exist substantially without contact with each other in the formulation. “Exists in the formulation without substantial contact” means that when multiple drugs, etc. are present in a tablet, the drugs do not exist in a homogeneous mixture, i.e., the drugs do not interact with each other. It refers to a state that exists in the same tablet so as not to contact to the extent that it does not develop. For example, there are tablets in the form of multilayer tablets in which drugs are present in different layers, and tablets in the form of dry-coated tablets having an inner core and an outer layer.

The tablet of the present invention is usually a tablet defined in the General Rules for Pharmaceutical Preparations of the Japanese Pharmacopoeia, and is preferably a multilayer tablet having two or more layers or a dry-coated tablet. In addition to providing a score line, a mark for improving identification, and an engraving on the tablet, sugar-coated tablets and film-coated tablets can also be used. In addition, the tablet of the present formulation may be a round tablet or an irregularly shaped tablet.

The tablet of the present invention contains other commonly used active ingredients, excipients, disintegrants, binders, fluidizers, lubricants, and cooling agents within a qualitative and quantitative range that does not impair the effects of the present invention. agents, coloring agents (pigments), flavoring agents, fragrances, coating agents, and the like can be added.

Other active ingredients that can be incorporated into the tablet of the present invention include, for example, antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, sedative hypnotics, vitamins, anti-inflammatory agents, gastric mucosa protective agents, Herbal medicines, herbal medicines, caffeines, etc. may be mentioned, and one or more selected from the group consisting of these may be contained.

Examples of excipients that can be incorporated into the tablet 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 hydroxypropyl cellulose, sodium starch glycolate, crospovidone, carmellose, carmellose sodium, croscarmellose sodium, carmellose calcium, pregelatinized starch, etc. Binders include hydroxypropyl. cellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan, etc.; Oil, talc, stearic acid, magnesium stearate, calcium stearate, etc., and cooling agents include menthol, peppermint oil, eucalyptus oil, and the like.

The tablet of the present invention can be produced by a conventional method as long as A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange are arranged in different layers. It can be manufactured, and the method is not particularly limited. For example, the A component and the B component are each blended into separate granules, and the granules are a layer containing the A component (hereinafter also referred to as "layer a") and a layer containing the B component (hereinafter also referred to as "layer b") ), may be a tablet that is separately blended, it may be a tablet that is blended separately powdery component A or B into layer a and layer b, or one of layer a and layer b is made into granules. , the other layer may be made into a tablet as it is.

As a method for preparing the tablet of the present invention, a direct compression method may be used, or a tablet containing granules may be used. When preparing granules, when A) granules containing ambroxol or a salt thereof and B) granules containing at least one crude drug selected from the group consisting of Bellflower, Ginger, Soybean and Hange are separately prepared If necessary, each granule may be blended with other medicinal ingredients and, if necessary, additives may be added, and prepared according to a conventional method. Alternatively, for example, a coating liquid may be sprayed as necessary to obtain coated granules. The granulation method is also not particularly limited, and can be produced by a wet granulation method, a dry granulation method, a melt granulation method, or the like, but the wet granulation method is preferred. Wet granulation methods include, for example, stirring granulation, fluid bed granulation, kneading granulation, extrusion granulation, and rolling fluidized granulation. In addition, if necessary, water, alcohol, or a mixture of water and alcohol may be used as the granulation liquid. You can disperse it. Usual additives such as the above active ingredients and excipients may be appropriately blended with the obtained granules. Alternatively, for example, a tablet containing layer a and layer b may be sprayed with a coating liquid as necessary to form a film-coated tablet or sugar-coated tablet.

EXAMPLES 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.

(Comparative example 1)
An appropriate amount of water/alcohol mixture was added to ambroxol hydrochloride, mixed, and then dried to obtain a composition.
(Comparative example 2)
To 1 part by mass of ambroxol hydrochloride, 4 parts by mass of dry extract powder of Bellflower was weighed and mixed, and an appropriate amount of water/alcohol mixture was added thereto and mixed, followed by drying to obtain a composition. Note that 1 part by mass of dried extract powder of Bellflower is 5 parts by mass in terms of raw herbal medicine.
(Comparative Example 3)
4 parts by mass of ginger powder was weighed out and mixed with 1 part by mass of ambroxol hydrochloride, and an appropriate amount of water/alcohol mixture was added thereto and mixed, followed by drying to obtain a composition.
(Comparative Example 4)
To 1 part by mass of ambroxol hydrochloride, 4 parts by mass of dried Soyo extract powder was weighed and mixed, and an appropriate amount of water/alcohol mixture was added and mixed, followed by drying to obtain a composition. In addition, 1 part by mass of Soyo dried extract powder is 9 parts by mass in terms of crude drug.
(Comparative Example 5)
4 parts by weight of dry extract powder was weighed and mixed with 1 part by weight of ambroxol hydrochloride, and an appropriate amount of water/alcohol mixture was added thereto and mixed, followed by drying to obtain a composition. It should be noted that 1 part by mass of the dry extract powder is 25 parts by mass in terms of crude drug.

(Test example 1)
After storing the compositions of Comparative Examples 1 to 5 at room temperature for 1 day or more, they were stored at 65° C. for 7 days, and after 7 days the residual rate of ambroxol hydrochloride in the compositions was evaluated by HPLC.
Table 1 shows the residual rate (%) of ambroxol hydrochloride after storage for 7 days.

(Comparative Example 6)
4.5 g of ambroxol hydrochloride, 16 g of dry extract powder of Bellflower, 10.3 g of crystalline cellulose, and 2 g of hydroxypropyl cellulose were mixed, and granulated product A was obtained by mortar granulation. 328 mg of the granule A was weighed out and tableted with a tableting machine equipped with a mortar and pestle externally lubricated with a small amount of magnesium stearate.
(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 material B was obtained by mortar granulation. Further, 16 g of dry extract powder of Bellflower, 10.3 g of crystalline cellulose, and 2 g of hydroxypropyl cellulose were mixed, and granulated product C was obtained by mortar granulation. 451 mg of mixture D, which was a mixture of 3.36 g of granules B and 5.66 g of granules C, was weighed out and tableted with a tableting machine equipped with a die and pestle externally lubricated 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 above were weighed, and granulated using a tableting machine equipped with a mortar and pestle externally lubricated with a small amount of magnesium stearate. A bilayer tablet was formed in which product B and granulated product C were arranged in separate layers.

(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. . 414 mg of the granulated product E was weighed out and tableted with a tableting machine.
(Example 2)
Granule F was obtained by adding a small amount of magnesium stearate to Granule B prepared in Comparative Example 7 above. Further, 10 g of ginger powder, 1.22 g of crystalline cellulose, and 0.75 g of hydroxypropyl cellulose were mixed, and after granulation in a mortar, a trace amount of magnesium stearate was added to obtain granules G. 56 mg of granules F and 399 mg of granules G were each weighed out, and tableted into a double-layer tablet in which granules F and granules G were arranged in different layers with a tableting machine. .

(Test example 2)
The tablets of Comparative Examples 6 to 8 and Examples 1 to 2 were each filled in bottles, sealed, stored at 65° C. for 7 days, and after 7 days the residual rate of ambroxol hydrochloride in the tablets was evaluated by HPLC. did. For each comparative example and example, a sample stored at 5°C for 7 days was used as a control. The results were calculated based on the residual rate of ambroxol hydrochloride at 5°C as 100%.
Table 2 shows the prescribed amount per day and residual rate of ambroxol hydrochloride for the tablets obtained by the methods described in Examples 1-2 and Comparative Examples 6-8.

In the comparative example in which A) ambroxol hydrochloride and B) herbal medicine were blended in the same layer, a decrease in ambroxol content was confirmed. On the other hand, in the example in which A) ambroxol hydrochloride and B) herbal medicine were blended in different layers, the decrease in ambroxol hydrochloride content could be suppressed.

According to the present invention, it is possible to provide a tablet with improved stability containing A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of bellflower, ginger, soybean, and hangge. As a result, we can provide excellent pharmaceutical products.

Claims (5)

A) ambroxol or a salt thereof, and B) a tablet containing at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange,
A tablet containing, in different layers, A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange. A) ambroxol or a salt thereof, and B) a tablet containing at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange,
A tablet that satisfies either i) or ii) below.
i) A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of Bellflower, Ginger, Soyou and Hange are arranged in different layers ii) A) A multi-layered tablet consisting of two or more layers A dry-coated tablet in which one of xol or a salt thereof and B) at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange is used as an inner core and the other is disposed as an outer layer. A) The tablet according to claim 1 or 2, wherein ambroxol or a salt thereof is ambroxol hydrochloride. B) the content of at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange is A) per 1 part by mass of ambroxol or a salt thereof,
3. The tablet according to claim 1 or 2, which satisfies any one of the following i) to iv).
i) When containing bellflower, containing 2 to 200 parts by mass of bellflower in terms of crude drug equivalent ii) When containing ginger, containing 1 to 150 parts by mass of ginger in terms of crude drug iii) When containing soyo , containing 3 to 100 parts by mass of soybean as an amount equivalent to the original herbal medicine; A) ambroxol or a salt thereof and B) a tablet containing at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange,
A) ambroxol or a salt thereof and B) at least one crude drug selected from the group consisting of bellflower, ginger, soybean and hange are contained in different layers. A method for suppressing a decrease in content.