Solid pharmaceutical composition

Abstract

To provide a solid preparation of Meirouin extract having resistance to discoloration.SOLUTION: A solid pharmaceutical composition contains (A) Meirouin extract, and (B) a predetermined compound selected from the group consisting of (B1) cellulose compounds, (B2) stearates, and (B3) silicate compounds. Such a solid pharmaceutical composition has resistance discoloration.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a solid pharmaceutical composition having excellent discoloration inhibitory properties.

Background Art

[0002] Meikyo-in is a Chinese herbal medicine based on "Asada's prescription" and is used for acute and chronic conjunctivitis, eye congestion, and tearing (watery eyes) in people with moderate physical strength who sometimes experience dizziness, staggering, and palpitations. Meikyo-in is commercially available, but its dosage form is a crude drug mixture and is decocted and taken at the time of use (Non-Patent Document 1, Non-Patent Document 2).

[0003] On the other hand, in general, a solid pharmaceutical preparation containing a Chinese herbal extract needs to be formulated considering the hygroscopicity of the Chinese herbal extract in order to satisfy a predetermined preparation stability. For example, Patent Document 1 discloses a formulation in which an aqueous solution obtained by adding 1 / 20 to 1 / 2 parts by weight of gelatin to a Chinese herbal extract is spray-dried to obtain a powder for preventing moisture absorption.

[0004] Furthermore, when the Chinese herbal extract incorporated in a solid pharmaceutical preparation causes significant discoloration due to hygroscopicity, a more stringent formulation design is required to suppress discoloration. For example, Patent Document 2 discloses a formulation in which polyvinyl acetate is incorporated into a Chinese herbal extract.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

[0006] [Patent Document 1] Japanese Patent Publication No. 2001-181192 [Patent Document 2] Japanese Patent Publication No. 2014-166994 [Overview of the project] [Problems that the invention aims to solve]

[0007] Since Meirōin extract is not currently available as a solid formulation, no stable formulation is known. When the inventors attempted to solidify Meirōin extract, they discovered that significant discoloration occurred.

[0008] Therefore, the object of the present invention is to provide a solid formulation of Meirōin extract in which discoloration is suppressed. [Means for solving the problem]

[0009] As a result of diligent research, the inventors of this invention have found that discoloration can be suppressed by incorporating a predetermined compound selected from the group consisting of cellulose compounds, stearates, and silicate compounds into Meirōin extract. This invention was completed by further research based on this finding.

[0010] In other words, the present invention provides inventions in the following embodiments. Item 1. A solid pharmaceutical composition comprising (A) Meirōin extract and (B) a predetermined compound selected from the group consisting of (B1) cellulose compounds, (B2) stearates, and (B3) silicate compounds. Item 2. The solid pharmaceutical composition according to Item 1, wherein the (B1) component is selected from the group consisting of cellulose, crystalline cellulose, carmellose calcium, croscarmellose calcium, and hydroxypropyl cellulose. Item 3. The solid pharmaceutical composition according to item 1 or 2, selected from the group consisting of (B3), silicon dioxide, aluminum silicate, magnesium aluminometasilicate, and talc. Item 4. The solid pharmaceutical composition according to any one of items 1 to 3, wherein the content of component (B) of claim is 0.1 to 50 parts by weight in total per 100 parts by weight of component (A). Item 5. A solid pharmaceutical composition according to any one of items 1 to 4, wherein the content of component (A) is 50 to 95% by weight. Item 6. A solid pharmaceutical composition according to any one of items 1 to 5, wherein the content of component (B) is 0.1 to 40% by weight in total. Item 7. A solid pharmaceutical composition according to any one of items 1 to 6, further comprising (C) starch and / or lactose. [Effects of the Invention]

[0011] The solid pharmaceutical composition of the present invention provides a solid formulation of Meirōin extract with suppressed discoloration. [Modes for carrying out the invention]

[0012] 1. Solid pharmaceutical composition The solid pharmaceutical composition of the present invention is characterized by comprising (A) Meirōin extract (hereinafter also referred to as "component (A)"), and (B) a predetermined compound selected from the group consisting of (B1) cellulose compounds (hereinafter also referred to as "component (B1)"), (B2) stearate (hereinafter also referred to as "component (B2)"), and (B3) silicic acid compounds (hereinafter also referred to as "component (B3)"). (Hereafter, components (B1) to (B3) will be collectively referred to as "component (B)"). The solid pharmaceutical composition of the present invention will be described in detail below.

[0013] (A) Meirōin Extract The solid pharmaceutical composition of the present invention contains Minglangyin extract as component (A). The crude drugs constituting Minglangyin are Buchu, Cyperus rotundus, Cinnamomum cassia, Magnolia officinalis, Phellodendron amurense, Glycyrrhiza glabra, and Schizandra chinensis. The crude drug preparation used for the production of Minglangyin extract consists of Buchu, Cyperus rotundus, Cinnamomum cassia, Magnolia officinalis, Phellodendron amurense, Glycyrrhiza glabra, and Schizandra chinensis. Preferred examples of the amounts of these crude drugs are 4 to 6 parts by weight of Buchu, 1.5 to 2 parts by weight of Cyperus rotundus, 3 to 4 parts by weight of Cinnamomum cassia, 1.5 to 2 parts by weight of Magnolia officinalis, 2 to 4 parts by weight of Phellodendron amurense, 2 parts by weight of Glycyrrhiza glabra, and 2 to 3 parts by weight of Schizandra chinensis.

[0014] The Minglangyin extract used in the present invention can be obtained by extracting the above-mentioned crude drug preparation by a known method. Examples of the method for extracting the crude drug preparation include adding about 10 to 20 times, preferably 10 to 15 times the amount of water to the crude drug preparation, and stirring and extracting at about 80 to 100°C, preferably 95 to 100°C for about 20 minutes to 3 hours, preferably 30 minutes to 1 hour. After extraction, it is subjected to solid-liquid separation such as centrifugation and filtration to remove solids, and if necessary, it is subjected to concentration treatment or drying treatment to obtain Minglangyin extract.

[0015] To obtain Minglangyin extract as an extract powder, the extract from which solids have been removed may be concentrated as necessary and then subjected to a drying treatment such as spray drying, vacuum concentration drying, or freeze drying. In addition, when subjected to a drying treatment (particularly drying treatment by spray drying), an excipient may be added to the extract as necessary.

[0016] The content of component (A) in the solid pharmaceutical composition of the present invention is not particularly limited, but for example, 50 to 95% by weight, preferably 52 to 80% by weight, more preferably 55 to 75% by weight, and still more preferably 60 to 70% by weight can be mentioned.

[0017] (B) A specified compound The solid pharmaceutical composition of the present invention contains, as component (B), a predetermined compound selected from the group consisting of (B1) a cellulose compound, (B2) a stearate, and (B3) a silicate compound. Component (B) suppresses discoloration during storage in the solid pharmaceutical composition containing component (A). In the present invention, as component (B), either component (B1) or component (B2) may be used alone, or component (B1) and component (B2) may be used in combination.

[0018] In the present invention, the cellulose compound as component (B1) refers to cellulose, a partially depolymerized product of cellulose, or a cellulose derivative. Examples of the partially depolymerized product of cellulose include crystalline cellulose. A cellulose derivative is a compound in which a functional group is introduced via a hydroxyl group of cellulose, and specifically, examples include cellulose ethers in which a functional group is introduced by an ether bond and cellulose esters in which a functional group is introduced by an ester bond. Among these, from the viewpoint of improving the discoloration suppressing effect, cellulose ethers are preferably used. Examples of cellulose ethers include carmellose (i.e., carboxymethyl cellulose), carmellose salts (more specifically, alkali metal salts and alkaline earth metal salts of carmellose), croscarmellose salts (i.e., crosslinked carmellose salts; more specifically, crosslinked carmellose alkali metal salts, crosslinked carmellose alkaline earth metal salts), hydroxypropyl cellulose, and the like.

[0019] These components (B1) may be used alone or in combination of two or more. Among these components (B1), from the viewpoint of efficiently obtaining the discoloration suppressing effect even in a small amount, partially depolymerized products of cellulose and cellulose derivatives are preferably used, and more preferably, partially depolymerized products of cellulose and cellulose ethers are used.

[0020] Specific examples of the stearate as component (B2) include magnesium stearate, calcium stearate, barium stearate, and zinc stearate.

[0021] These (B2) components may be used individually or in combination of multiple components. Among these (B2) components, magnesium stearate is preferred from the viewpoint of improving the discoloration suppression effect.

[0022] In the present invention, the silicate compound that is component (B3) refers to silicon dioxide or silicate. Examples of silicon dioxide include light anhydrous silicic acid and hydrated silicon dioxide. Examples of silicates include aluminum silicate, magnesium aluminometasilicate, and talc.

[0023] These (B3) components may be used individually or in combination of multiple components. Among these (B3) components, silicates are preferred from the viewpoint of efficiently obtaining a discoloration-inhibiting effect even in small amounts.

[0024] The content of component (B) in the solid pharmaceutical composition of the present invention is not particularly limited as long as the effects of the present invention are achieved, but the total amount of component (B) per 100 parts by weight of component (A) is 0.1 to 50 parts by weight.

[0025] Regarding the content of component (B1), the total amount per 100 parts by weight of component (A) is 1 to 50 parts by weight. More specifically, the content per 100 parts by weight of component (A) is, for example, 10 to 50 parts by weight for cellulose, for example, 1 to 40 parts by weight for partially depolymerized cellulose, and for example, 0.5 to 40 parts by weight for cellulose derivatives.

[0026] Furthermore, if the solid pharmaceutical composition of the present invention contains starch as component (C), the content per 100 parts by weight of component (A) is preferably 14 to 50 parts by weight, more preferably 29 to 50 parts by weight, even more preferably 35 to 50 parts by weight, even more preferably 40 to 50 parts by weight, particularly preferably 44 to 50 parts by weight or 44 to 47 parts by weight for cellulose, preferably 2 to 16 parts by weight, more preferably 4 to 12 parts by weight, even more preferably 6 to 9 parts by weight for cellulose partial depolymer, and preferably 1 to 35 parts by weight, more preferably 10 to 32 parts by weight, even more preferably 13 to 20 parts by weight for cellulose derivative.

[0027] Furthermore, when the solid pharmaceutical composition of the present invention contains lactose as component (C), the content per 100 parts by weight of component (A) is preferably 14 to 50 parts by weight, more preferably 39 to 50 parts by weight, and even more preferably 42 to 50 parts by weight for cellulose, preferably 7 to 32 parts by weight, more preferably 12 to 21 parts by weight for partially depolymerized cellulose, and preferably 7 to 35 parts by weight, more preferably 14 to 32 parts by weight for cellulose derivatives.

[0028] Regarding the content of component (B2), for example, the content per 100 parts by weight of component (A) is 0.4 to 3 parts by weight, preferably 0.6 to 2 parts by weight, and more preferably 0.7 to 1.1 parts by weight.

[0029] Regarding the content of component (B3), for example, it can be 0.3 to 50 parts by weight per 100 parts by weight of component (A). More specifically, regarding the content of silicon dioxide, for example, it can be 7 to 50 parts by weight, preferably 14 to 40 parts by weight, more preferably 18 to 35 parts by weight, and even more preferably 20 to 33 parts by weight per 100 parts by weight of component (A). Regarding the content of silicate, for example, it can be 0.3 to 20 parts by weight, preferably 0.6 to 10 parts by weight, more preferably 1 to 8 parts by weight, and even more preferably 5 to 8 parts by weight per 100 parts by weight of component (A).

[0030] The specific content of component (B) in the solid pharmaceutical composition of the present invention is determined according to the content of component (A) and the content of component (B) per 100 parts by weight of component (A), but preferably 0.1 to 50% by weight.

[0031] (B1) The specific content of the component can be, for example, 0.7 to 33% by weight in total. More specifically, the cellulose content can be, for example, 6.5 to 33% by weight, the specific content of the partially depolymerized cellulose can be, for example, 0.7 to 27% by weight, and the specific content of the cellulose derivative can be, for example, 0.3 to 27% by weight.

[0032] Furthermore, when the solid pharmaceutical composition of the present invention contains starch as component (C), the cellulose content is preferably 9 to 33% by weight, more preferably 19 to 33% by weight, even more preferably 23 to 33% by weight, even more preferably 26 to 33% by weight, and particularly preferably 29 to 33% by weight or 29 to 31% by weight. The specific content of the partially depolymerized cellulose is preferably 1.3 to 10% by weight, more preferably 2.6 to 8% by weight, and even more preferably 4 to 6% by weight. The specific content of the cellulose derivative is preferably 0.6 to 23% by weight, more preferably 6.5 to 21% by weight, and even more preferably 8.5 to 13% by weight.

[0033] Furthermore, when the solid pharmaceutical composition of the present invention contains lactose as component (C), the cellulose content is preferably 9 to 33% by weight, more preferably 26 to 33% by weight, and even more preferably 28 to 33% by weight; the cellulose partial depolymer content is preferably 4.7 to 22% by weight, more preferably 8 to 14% by weight; and the specific cellulose derivative content is preferably 4.5 to 23% by weight, more preferably 9.3 to 21.5% by weight.

[0034] (B2) Specific content of component can be, for example, 0.26 to 2% by weight, preferably 0.4 to 1.3% by weight, and more preferably 0.45 to 0.75% by weight.

[0035] (B3) The specific content of component (B3) is, for example, 0.2 to 33% by weight. More specifically, the specific content of silicon dioxide is, for example, 4.7 to 33% by weight, preferably 9 to 27% by weight, more preferably 12 to 23.5% by weight, and even more preferably 13 to 22% by weight. The specific content of silicate is, for example, 0.2 to 13% by weight, preferably 0.4 to 6.7% by weight, more preferably 0.6 to 5.5% by weight, and even more preferably 3 to 5.5% by weight.

[0036] (C) Starch and / or lactose From the viewpoint of further improving discoloration suppression, the solid pharmaceutical composition of the present invention may further contain starch and / or lactose (hereinafter also referred to as "component (C)") as component (C).

[0037] The starch is not particularly limited, but examples include corn starch and potato starch, and corn starch is preferred from the viewpoint of further improving discoloration suppression.

[0038] The content of component (C) in the solid pharmaceutical composition of the present invention is, for example, 3 to 40% by weight, preferably 10 to 35% by weight, in total.

[0039] Other ingredients The solid pharmaceutical composition of the present invention may contain additives and / or bases as other components besides the above-mentioned components, to the extent that they do not interfere with the effects of the present invention.

[0040] The additives and bases are not particularly limited as long as they are pharmaceutically acceptable, but examples include excipients (e.g., lactose), binders (e.g., sodium alginate, polyvinylpyrrolidone), disintegrants (e.g., agar), lubricants (e.g., sucrose fatty acid esters), colorants (e.g., caramel, gardenia pigment, titanium dioxide, iron oxides), preservatives (e.g., L-ascorbic acid), antiseptics (e.g., benzoates, parahydroxybenzoic acid esters), pH adjusters (e.g., potassium carbonate, sodium bicarbonate), surfactants (e.g., saponins, lecithin, sucrose fatty acid esters), and coating agents (e.g., shellac, macrogol, carnauba wax). These additives and bases may be used individually or in combination. The content of these additives and bases should be appropriately determined according to the type of additive and base used, as long as it is possible to formulate a solid pharmaceutical composition.

[0041] Furthermore, the solid pharmaceutical composition of the present invention may contain other nutritional components and pharmacological components in addition to Meirōin extract, as needed. Such nutritional components and pharmacological components are not particularly limited as long as they are pharmaceutically acceptable, but examples include antacids, stomachic agents, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives and hypnotics, antihistamines, caffeines, cardiotonic and diuretic agents, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal extracts, vitamins, menthols, and the like. These nutritional components and pharmacological components may be used individually or in combination. The content of these components may be appropriately determined depending on the type of component used.

[0042] Formulation The formulation form of the solid pharmaceutical composition of the present invention is not particularly limited as long as it is a solid formulation, and examples include tablets, pills, powders, fine granules, and granules (including granules filled into capsules). Because the solid pharmaceutical composition of the present invention has excellent discoloration suppression properties, it can effectively suppress discoloration even in the form of powders, fine granules, and granules, which have a large specific surface area.

[0043] The tablets produced from the solid pharmaceutical composition of the present invention may be uncoated tablets (unwrapped tablets) or coated tablets with a coating on the surface for purposes such as drug stabilization, flavoring, and odor masking. Because the solid pharmaceutical composition of the present invention has excellent discoloration suppression properties, discoloration can be effectively suppressed even in uncoated tablets without a surface coating.

[0044] Manufacturing method The solid pharmaceutical composition of the present invention can be manufactured using the above-mentioned components (A) and (B), and component (C) and / or other components as needed, in accordance with conventional formulation methods used in the pharmaceutical field. [Examples]

[0045] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0046] Test example 1. Preparation of Meirōin extract powder As raw materials, 4.0 parts by weight of Poria cocos, 3.0 parts by weight of Cinnamon bark, 2.0 parts by Atractylodes macrocephala, 2.0 parts by weight of Licorice, 2.0 parts by weight of Plantago asiatica, 2.0 parts by weight of Asarum sieboldii, and 2.0 parts by weight of Coptis japonica were used. After chopping these, they were extracted with 12 times their weight in water at approximately 100°C for 30 minutes, and the extract was obtained by centrifugation. The extract was concentrated under reduced pressure and dried using a spray dryer to obtain Meiroin extract powder. The drying with a spray dryer was performed by dropping the extract into an atomizer rotating at 10,000 rpm and supplying hot air at 150°C.

[0047] 2. Preparation of solid pharmaceutical composition Solid pharmaceutical compositions with the compositions shown in Tables 1 to 3 were prepared. Specifically, the Meirōin extract powder and the specified components shown in Tables 1 to 3 were mixed in a plastic bag, and then sieved to prepare a powdered solid pharmaceutical composition (powder).

[0048] 3. Discoloration Inhibition Test 3.0 g of a solid pharmaceutical composition was uniformly spread into a circle with a diameter of 10 cm and stored for 6 hours under conditions of 40°C and 75% RH. The color of the solid pharmaceutical composition was measured using a spectrophotometer (CM-700d) immediately after preparation and after storage, and the amount of color change after storage (ΔE*ab) was measured based on the following formula. The results are shown in Tables 1 to 3.

[0049]

number

[0050] Furthermore, the percentage of ΔE*ab for each example and comparative example, with ΔE*ab for Comparative Example 1 set to 100%, was derived as the "discoloration suppression index." A discoloration suppression index below 100% indicates that discoloration is suppressed, and a smaller discoloration suppression index indicates a higher discoloration suppression effect. The results are shown in Tables 1 to 3.

[0051] [Table 1]

[0052] [Table 2]

[0053] [Table 3]

[0054] As shown in Comparative Examples 1 and 5, solid pharmaceutical compositions containing Meirōin extract showed discoloration after storage. Furthermore, as shown in Comparative Examples 2 to 4 and 6 to 8, adding dextrin to Meirōin extract did not suppress discoloration; in fact, it worsened it. In contrast, as shown in Examples 1 to 33 and 34 to 48, it was found that adding specific compounds such as cellulose compounds, stearates, or silicate compounds to Meirōin extract significantly improved discoloration suppression.

Claims

1. (A) Meirōin extract and (B) A predetermined compound selected from the group consisting of (B1) cellulose, crystalline cellulose, carmellose calcium, croscarmellose sodium, and hydroxypropyl cellulose, (B2) magnesium stearate, and (B3) silicon dioxide, aluminum silicate, magnesium aluminometasilicate, and talc, A solid pharmaceutical composition containing the following:

2. The solid pharmaceutical composition according to claim 1, wherein the content of component (B) of claim (B) per 100 parts by weight of component (A) is 0.1 to 50 parts by weight in total.

3. The solid pharmaceutical composition according to claim 1 or 2, wherein the content of component (A) is 50 to 95% by weight.

4. The solid pharmaceutical composition according to any one of claims 1 to 3, wherein the content of component (B) is 0.1 to 40% by weight in total.

5. The solid pharmaceutical composition according to any one of claims 1 to 4, further comprising (C) starch and / or lactose.

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