Solid pharmaceutical composition

Abstract

To provide a solid preparation of Saikatsugekito extract that is less prone to discoloration.SOLUTION: A solid pharmaceutical composition contains (A) Saikatsugekito extract, and (B) light silicic anhydride and / or cellulose compound. The composition has high resistance to 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] Kakkatokyokito (Asada family formula) is a combined formula obtained by removing ginseng and jujube from the combined formula of Shochikoto and Kakkonto and adding gypsum. From the description of the composition and source of the formula, it is considered that it should be applied to the concurrent disease of taiyang disease and interior shaoyang syndrome (Non-Patent Document 1).

[0003] In recent years, while actively elucidating the pathogenesis and developing new drugs and vaccines for unknown infectious diseases such as COVID-19, traditional Chinese medicine treatment is also clinically applied. Among them, regarding Kakkatokyokito, it has been proposed that it should be prescribed when fever that cannot be treated with Kakkonto or Maekishito is recognized in the prevention of severe exacerbation of mild COVID-19 patients (Non-Patent Document 2).

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, the formulation stability of the solid preparation of Kakkatokyokito extract has not been sufficiently studied so far. As a result of the study by the present inventor, it has been found that the solid preparation of Kakkatokyokito extract is particularly likely to discolor during storage.

[0006] Therefore, an object of the present invention is to provide a solid preparation of Kakkatokyokito extract having excellent discoloration inhibitory properties. [Means for solving the problem]

[0007] As a result of diligent research, the inventors of this invention have found that by combining the extract of Saikatsukaijito with light anhydrous silicic acid and / or a cellulose compound, a solid formulation exhibiting excellent discoloration inhibition is obtained. This invention was completed by further research based on this finding.

[0008] In other words, the present invention provides inventions in the following embodiments. Item 1. A solid pharmaceutical composition comprising (A) Saikatsukaito extract and (B) light anhydrous silicic acid and / or a cellulose compound. Item 2. The solid pharmaceutical composition according to Item 1, wherein the cellulose compound is a carmellose salt. Item 3. The solid pharmaceutical composition according to item 1 or 2, wherein the content of component (A) is 50 to 95% by weight. Item 4. The solid pharmaceutical composition according to any one of items 1 to 3, wherein the herbal preparation used to extract component (A) contains 3 to 5 parts by weight of ginger per 100 parts by weight of the herbal preparation. Item 5. A solid pharmaceutical composition according to any one of items 1 to 4, wherein the content of component (B) is 0.5 to 50% by weight in total. Item 6. A solid pharmaceutical composition according to any one of items 1 to 5, wherein the total amount of component (B) per 100 parts by weight of component (A) is 1 to 70 parts by weight. Item 7. A solid pharmaceutical composition according to any one of items 1 to 6, further comprising (C) starch, lactose and / or dextrin. Item 8. A discoloration inhibitor for solid pharmaceutical compositions containing Saikatsukaito extract, comprising light anhydrous silicic acid and / or a cellulose compound. [Effects of the Invention]

[0009] The solid pharmaceutical composition of the present invention provides a solid formulation of Saikatsukaito extract that exhibits excellent discoloration suppression. [Modes for carrying out the invention]

[0010] 1. Solid pharmaceutical composition The solid pharmaceutical composition of the present invention is characterized by comprising (A) Saikatsukaito extract (hereinafter also referred to as "component (A)") and (B) light anhydrous silicic acid and / or cellulose compound (hereinafter collectively referred to as "component (B)"). The solid pharmaceutical composition of the present invention will be described in detail below.

[0011] (A) Saikatsukaito extract The solid pharmaceutical composition of the present invention contains a Saikatsukaijito extract as component (A). Examples of crude drugs that make up Saikatsukaijito include the prescriptions of Rokusho, Unyo, or Asada, and in the present invention, any of these prescriptions may be used.

[0012] The amount of each crude drug in the crude drug formulation used to produce the Saikatsukaijito extract used in the present invention is not particularly limited, but in any formulation, the amount of ginger, for example, is 1 to 5 parts by weight per 100 parts by weight of the total crude drug formulation. To further enhance the discoloration suppression, the amount of ginger per 100 parts by weight of the total crude drug formulation is preferably 3 to 5 parts by weight, more preferably 3.5 to 5 parts by weight, and even more preferably 4 to 5 parts by weight.

[0013] As a preferred example of the crude drug formulation used in the production of the Saikatsukaito extract used in the present invention, from the viewpoint of further enhancing discoloration suppression, the formulation of Asada is preferred. The crude drug formulation used in the production of the Saikatsukaito extract according to Asada's formulation consists of Bupleurum root, Pueraria lobata, Ephedra herb, Cinnamon bark, Scutellaria baicalensis, Peony root, Pinellia tuber, Ginger, Licorice root, and Gypsum. Preferred amounts of these crude drugs include 1.5 to 5 parts by weight of Bupleurum root, 1.25 to 4 parts by weight of Pueraria lobata, 1 to 3 parts by weight of Ephedra herb, 1 to 3 parts by weight of Cinnamon bark, 1 to 3 parts by weight of Scutellaria baicalensis, 1 to 3 parts by weight of Peony root, 1 to 4 parts by weight of Pinellia tuber, 0.5 to 1 part by weight of Zingiber officinale (preferably 0.8 to 1 part by weight, more preferably 0.9 to 1 part by weight), 0.5 to 2 parts by weight of Licorice root, and 2 to 8 parts by weight of Gypsum. Particularly preferred examples include 4 parts by weight of Bupleurum root, 4 parts by weight of Pueraria lobata, 2.5 parts by weight of Ephedra herb, 2 parts by weight of Cinnamon bark, 2 parts by weight of Scutellaria baicalensis, 2 parts by weight of Peony root, 3 parts by weight of Pinellia tuber, 1 part by weight of Zingiber officinale, 1 part by weight of Licorice root, and 6 parts by weight of Gypsum.

[0014] The Saikatsu Kaijito extract used in the present invention can be obtained by extracting the aforementioned crude drug formulation using a known method. The method for extracting the crude drug formulation can be the same as the conventional method for extracting Saikatsu Kaijito extract. For example, the crude drug formulation can be extracted by adding about 10 to 20 times, preferably 10 to 15 times, amount of water, and stirring at about 80 to 100°C, preferably 95 to 100°C, for about 0.5 to 3 hours, preferably 0.5 to 1 hour. After extraction, the solids can be removed by solid-liquid separation such as centrifugation or filtration, and if necessary, the Saikatsu Kaijito extract can be obtained by concentration treatment or drying treatment.

[0015] To obtain the extract of Saikatsukaito as an extract powder, the extract from which the solid components have been removed can be concentrated as needed, and then subjected to drying treatments such as spray drying, vacuum concentration drying, or freeze drying. Furthermore, when subjecting the extract to drying treatment (especially spray drying), excipients may be added as needed.

[0016] The content of component (A) in the solid pharmaceutical composition of the present invention is not particularly limited, and examples thereof include 45 to 98% by weight, 50 to 95% by weight, 52 to 80% by weight, 54 to 70% by weight, or 56 to 60% by weight.

[0017] (B) Light anhydrous silicic acid and / or cellulose compounds The solid pharmaceutical composition of the present invention contains light anhydrous silicic acid (hereinafter also referred to as “component (B1)”) and / or a cellulose compound (hereinafter also referred to as “component (B2)”) as component (B). Component (B) suppresses discoloration during storage in the solid pharmaceutical composition containing component (A). In the present invention, as component (B), component (B1) or component (B2) may be used alone, or component (B1) and component (B2) may be used in combination.

[0018] A cellulose compound is a compound having a cellulose skeleton, which is obtained by subjecting cellulose as a raw material to treatments such as biologically or chemically introducing functional groups and / or depolymerizing. Specific examples of the cellulose compound used in the present invention 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, crystalline cellulose, and the like. These cellulose compounds may be used alone or in combination of multiple types. Among these cellulose compounds, from the viewpoint of further improving the discoloration inhibitory property, preferably carmellose salts, croscarmellose salts, hydroxypropyl cellulose, and crystalline cellulose are mentioned, more preferably carmellose salts, hydroxypropyl cellulose is mentioned, still more preferably carmellose salts are mentioned, even more preferably alkaline earth metal salts of carmellose are mentioned, and particularly preferably carmellose calcium is mentioned.

[0019] 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, and examples thereof include 0.5 to 50% by weight in total.

[0020] When component (B) contains component (B1), the content of component (B1) is preferably 3 to 50% by weight, more preferably 8 to 50% by weight, still more preferably 15 to 50% by weight, even more preferably 20 to 50% by weight, still even more preferably 25 to 50% by weight, 25 to 40% by weight, or 25 to 30% by weight, from the viewpoint of further improving the discoloration inhibitory property.

[0021] When component (B) contains component (B2), the content of component (B2) is preferably 1 to 50% by weight, 2 to 50% by weight, 4 to 50% by weight, 10 to 50% by weight, 20 to 50% by weight, 30 to 50% by weight, or 35 to 50% by weight, from the viewpoint of further improving the discoloration inhibitory property. Since component (B2) exhibits preferable discoloration inhibitory property even with a small content, the upper limit of the content range of component (B2) may be 40% by weight or less, 30% by weight or less, 20% by weight or less, 10% by weight or less, 7% by weight or less, 5% by weight or less, or 3% by weight or less.

[0022] In the solid pharmaceutical composition of the present invention, the content (total amount) of component (B) per 100 parts by weight of component (A) is determined by the content of each of the above components, and examples thereof include 1 to 70 parts by weight.

[0023] When component (B) contains component (B1), the content of component (B1) per 100 parts by weight of component (A) is preferably 5 to 70 parts by weight, more preferably 15 to 70 parts by weight, still more preferably 25 to 70 parts by weight, even more preferably 30 to 70 parts by weight, still even more preferably 40 to 70 parts by weight, 40 to 60 parts by weight, or 40 to 50 parts by weight, from the viewpoint of further improving the discoloration inhibitory property.

[0024] When component (B) contains component (B2), the content of component (B2) per 100 parts by weight of component (A) is preferably 1.5 to 70 parts by weight, 5 to 70 parts by weight, 8 to 70 parts by weight, 15 to 70 parts by weight, 30 to 70 parts by weight, 50 to 70 parts by weight, or 60 to 70 parts by weight, from the viewpoint of further improving discoloration suppression. Since component (B2) exhibits desirable discoloration suppression even in a small ratio to component (A), the upper limit of the content range of component (B2) may be 55 parts by weight or less, 35% by weight or less, 20 parts by weight or less, 15 parts by weight or less, 10 parts by weight or less, or 3 parts by weight or less.

[0025] (C) Starch, lactose and / or dextrin From the viewpoint of further improving discoloration suppression, the solid pharmaceutical composition of the present invention may further contain starch, lactose and / or dextrin (hereinafter also referred to as "component (C)") as component (C).

[0026] The starch is not particularly limited, but examples include corn starch and potato starch.

[0027] Among these (C) components, starch and lactose are preferred, starch is preferred, and corn starch is even more preferred, from the viewpoint of further improving discoloration suppression.

[0028] The content of component (C) in the solid pharmaceutical composition of the present invention can be, for example, 4 to 50% by weight in total, preferably 20 to 45% by weight, and more preferably 30 to 40% by weight.

[0029] 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.

[0030] The additives and bases are not particularly limited to the extent that they are pharmaceutically acceptable, but examples include binders (e.g., sodium alginate, polyvinylpyrrolidone, etc.), disintegrants (e.g., agar, etc.), lubricants (e.g., magnesium stearate, calcium stearate, sucrose fatty acid esters, talc, etc.), colorants (e.g., caramel, gardenia pigment, titanium dioxide, iron oxide, etc.), preservatives (e.g., L-ascorbic acid, etc.), antiseptics (e.g., benzoates, parahydroxybenzoic acid esters, etc.), pH adjusters (e.g., potassium carbonate, sodium bicarbonate, etc.), surfactants (e.g., saponins, lecithin, sucrose fatty acid esters, etc.), and coating agents (e.g., shellac, macrogol, carnauba wax, etc.). 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.

[0031] Furthermore, the solid pharmaceutical composition of the present invention may contain other nutritional components and pharmacological components in addition to the Saikatsukaito 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.

[0032] 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), among which tablets are particularly preferred.

[0033] When the solid pharmaceutical composition of the present invention is in the form of a tablet, the shape and size of the tablet are not particularly limited. Examples of tablet shapes include round, oval, triangular, and square. In the case of a round tablet, the diameter is 6 to 12 mm, preferably 8 to 10 mm. The weight per tablet is 200 to 600 mg, preferably 300 to 400 mg.

[0034] The tablets produced from the solid pharmaceutical composition of the present invention may be uncoated tablets (unwrapped tablets) or coated tablets with a coating applied to 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.

[0035] Manufacturing method The solid pharmaceutical composition of the present invention can be manufactured using the above-mentioned components (A) and (B), and optionally component (C) and / or other components, according to conventional formulation methods used in the pharmaceutical field. Preferably, the method for manufacturing the solid pharmaceutical composition of the present invention includes a granulation step of granulating a mixture of the above-mentioned components (A) and (B), and optionally component (C) and / or other components, and a tableting step of tableting the granules. The tableting pressure in the tableting step is, for example, 4 to 20 kN, preferably 8 to 15 kN.

[0036] 2. Discoloration inhibitor for solid pharmaceutical compositions containing Saikatsukaito extract. As described above, light anhydrous silicic acid and / or cellulose compounds can suppress discoloration of solid pharmaceutical compositions containing Saikatsukaito extract. Accordingly, the present invention also provides a discoloration inhibitor for solid pharmaceutical compositions containing Saikatsukaito extract, which includes light anhydrous silicic acid and / or cellulose compounds.

[0037] Regarding the discoloration inhibitor for solid pharmaceutical compositions containing Saikatsukaito extract, the types and amounts of ingredients used are as described in the "1. Solid Pharmaceutical Composition" section above. [Examples]

[0038] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0039] Test example 1. Manufacturing of Saikatsukaito extract powder As raw materials, Bupleurum root 4.0 (parts by weight, the same applies hereafter), Pueraria root 4.0, Ephedra herb 2.5, Cinnamon bark 2.0, Scutellaria root 2.0, Peony root 2.0, Pinellia tuber 3.0, Ginger rhizome 1.0, Licorice root 1.0, and Gypsum 6.0 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 Saikatsukaijito 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.

[0040] 2. Manufacturing of solid pharmaceutical compositions The Saikatsukaito extract powder obtained in step 1 above was mixed with the components shown in Tables 1 and 2 in the composition shown in the table. The mixture was then compressed and molded at a pressure of 12 kN using a tabletop standard press (manufactured by NPC Systems Co., Ltd.) and its corresponding mortar and pestle to obtain tablets (plain tablets) with a diameter of 9.5 mm and a weight of 350 mg.

[0041] 3. Discoloration Inhibition Test The obtained tablets (uncoated tablets) were stored for 90 minutes under conditions of 40°C and 75% RH. For each stored tablet, the relative L value (%) was measured using a Konica Minolta CM-700d spectrophotometer, with the L value of the immediately manufactured product set to 100%. The "discoloration suppression rate" (%) was calculated by subtracting the obtained relative L value (%) from 100%. The closer the discoloration suppression rate is to 100%, the higher the discoloration suppression effect. The results are shown in Tables 1 and 2.

[0042] [Table 1]

[0043] [Table 2]

[0044] As is clear from Tables 1 and 2, it was found that solid pharmaceuticals containing Saikatsukaito extract could significantly improve their discoloration inhibition by incorporating light anhydrous silicic acid or cellulose compounds (Examples 1-20). Furthermore, when talc, which is a silicic acid compound, and hydrated silicon dioxide, which is a silicon dioxide compound, were incorporated, the desired discoloration inhibition could not be obtained in either case (Comparative Examples 2-5). This indicates that the remarkable discoloration inhibition achieved by incorporating light anhydrous silicic acid is an effect unique to light anhydrous silicic acid. In addition, among cellulose compounds, carmellose salt (carmellose calcium) in particular exhibited exceptionally remarkable discoloration inhibition even in small amounts (Examples 4-6, 16, 18, 20).

Claims

1. A solid pharmaceutical composition comprising (A) Saikatsukaito extract and (B) carmellose salt.

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

3. The solid pharmaceutical composition according to claim 1, wherein the herbal medicine preparation used to extract component (A) contains 3 to 5 parts by weight of ginger per 100 parts by weight of the herbal medicine preparation.

4. The solid pharmaceutical composition according to claim 1, wherein the content of component (B) is 0.5 to 50% by weight in total.

5. The solid pharmaceutical composition according to claim 1, wherein the content of component (B) per 100 parts by weight of component (A) is 1 to 70 parts by weight in total.

6. The solid pharmaceutical composition according to claim 1, further comprising (C) starch, lactose and / or dextrin.

7. A discoloration inhibitor for a solid pharmaceutical composition containing carmellose salt and Saikatsukaito extract.

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