JP2016183138A - Solid pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solid pharmaceutical composition containing Polygala tenuifolia Wilfenow root extract that inhibits the discoloration of Polygala tenuifolia Wilfenow root extract with time during preservation and has excellent storage stability.SOLUTION: A solid pharmaceutical composition comprises (A) extract of Polygala tenuifolia Wilfenow roots, and (B) at least one silicate compound selected from the group consisting of hydrous silicon dioxide and light anhydrous silicic acid.SELECTED DRAWING: None

Description

The present invention relates to a solid pharmaceutical composition containing an ondi extract.

Onji is a root of Polygala tenuifolia Wilenow, and is a perennial plant belonging to the family Vespaceae distributed in northern China, Siberia, and the northern part of the Korean Peninsula. It is said that “distant” is “becoming distant” and is also used for mental and neurological diseases such as insomnia and amnesia. Various pharmacological effects of Onji have been reported, focusing on the effects of Onji on mental and neurological diseases. Specifically, an improvement effect on memory learning disorders, a possibility of improving dementia symptoms such as Alzheimer's disease (Non-patent Document 1), a sedative action, an anti-dementia action, an anti-ulcer action, an expectorant action, an anti-allergic action, an anti-allergic action, Various medicinal effects such as virus action have been reported.

When using Onji as a raw material for pharmaceuticals or the like, Onji extract, which is an extract of Onji, can be used. Usually, as a form of Onji extract, Onji extract powder obtained by concentrating, drying and pulverizing Onji can be used. However, the onji extract is easily hygroscopic or oxidized, and the composition containing the onji extract has a problem that discoloration occurs due to moisture absorption or oxidation during storage.

As a method for suppressing the discoloration of such an extract, for example, Patent Document 1 introduces a solid preparation in which polyvinyl acetate is blended with a Kampo extract. However, in order to obtain a discoloration suppressing effect by this method, a step of spraying and mixing (coating) polyvinyl acetate on a Chinese medicine extract is required. In addition, as a method of suppressing discoloration in a packaging form, a method of storing together with a desiccant has been introduced (Non-patent Document 3). However, in such a method, there is a problem that the packaging form is limited and an extra packaging material cost such as a desiccant is required. For this reason, there has been a demand for a simpler method that does not require a new manufacturing process as described above and does not require extra packaging material costs.

JP 2014-166994 A

JIM Vol.14, No.5, p443-445 "Distance and nerves" (2004) Monthly Kampo Research, September 2005, p35-42 "Medicine efficacy and pharmacology series 86 Onji" Clinical and pharmacotherapy No. 69, p278-282 “Special feature: How to use Chinese medicine using extract <General remarks> About storage of extract preparations” (1992)

An object of the present invention is to provide a solid pharmaceutical composition containing an ondi extract which suppresses discoloration in the preparation process or storage and is excellent in stability. Moreover, the subject of this invention is providing the solid pharmaceutical composition which has the said characteristic, without increasing a new manufacturing process and packaging material cost.

The present inventor has intensively studied to solve the above-mentioned problems, and at least one silicate compound selected from the group consisting of hydrous silicon dioxide and light anhydrous silicic acid is blended into an on-distillate to prepare a solid form. As a result, it was found that the stability of the onge extract was increased and discoloration could be effectively suppressed, and the present invention was completed.

The present invention provides the following solid pharmaceutical compositions and the like.
Item 1: A solid pharmaceutical composition comprising (A) ondi extract, and (B) at least one silicic acid compound selected from the group consisting of hydrous silicon dioxide and light anhydrous silicic acid.
Item 2: The solid pharmaceutical composition according to Item 1, further comprising (C) a cellulose compound.
Item 3: The solid pharmaceutical composition according to Item 2, wherein the component (C) is carmellose calcium. Item 4: The component (A) is 40 to 80% by weight, the component (B) is 1 to 20% by weight, Item 4. The solid pharmaceutical composition according to Item 2 or 3, wherein the component is 1 to 20% by weight.
Item 5: The solid pharmaceutical composition according to any one of Items 1 to 4, which is a tablet.
Item 6: The solid pharmaceutical composition according to any one of Items 1 to 5, wherein the component (B) is 1 to 40 parts by weight with respect to 100 parts by weight of the component (A).
Item 7. (A) Onji extract is characterized by blending at least one silicic acid compound selected from the group consisting of (B) hydrous silicon dioxide and light anhydrous silicic acid into (A) Onji extract, A method for suppressing discoloration of a contained pharmaceutical composition.
Item 8: The method for inhibiting discoloration according to Item 7, further comprising (C) a cellulose compound.
Item 9: The method for suppressing discoloration according to Item 8, wherein the component (C) is carmellose calcium.
Item 10: The proportion in 100% by weight of the final pharmaceutical composition is such that (A) component is 40 to 80% by weight, (B) component is 1 to 20% by weight, and (C) component is 1 to 20% by weight. Item 10. The method for suppressing discoloration according to Item 8 or 9.
Item 11: The method for suppressing discoloration according to any one of Items 7 to 10, wherein the solid form is a tablet.
Item 12: The method for suppressing discoloration according to any one of Items 7 to 11, wherein the component (B) is 1 to 40 parts by weight with respect to 100 parts by weight of the component (A).

According to the solid pharmaceutical composition of the present invention, stability is improved by containing at least one of ondi extract, hydrous silicon dioxide, and light anhydrous silicic acid, and significantly suppresses discoloration that may occur over time. be able to. Since the effect of the present invention can be obtained only by containing ondi extract and at least one of hydrous silicon dioxide and light anhydrous silicic acid, the number of steps for newly coating the extract as in the conventional method, There is no need for extra packaging costs.

The solid pharmaceutical composition of the present invention may be referred to as an ondiextract ((A) component), and at least one of hydrous silicon dioxide and light anhydrous silicic acid (may be referred to as (B) component) It is characterized by containing. Furthermore, the discoloration inhibitory effect improves further by containing a cellulose compound (it may describe with (C) component). Hereinafter, the solid pharmaceutical composition of the present invention will be described.

(A) Onji extract The solid pharmaceutical composition of the present invention contains an onji extract (component (A)).
The form of the component (A) used in the present invention is not particularly limited as long as it is an onji extract (extract), and may be in the form of a concentrate (concentrated extract form such as soft extract or flow extract) of the onji extract. Also, it may be in the form of a dried product (dried extract form such as extract powder). Usually, a dry powder form such as extract powder is preferably used.

Such onji extract can be prepared by extracting from onji, which is a crude drug raw material, and processing (concentrating and drying). The extraction and processing methods are not particularly limited, and methods generally employed in the technical field can be used. The extraction method is preferably a heat extraction method using a solvent as described below, and the processing method includes a concentration and drying method described below.

The method for extracting Onji extract from Onji, which is a crude drug raw material, is not limited. Specifically, 1 to 25 times the weight of Onji, preferably 5 to 15 times the amount of extraction solvent is added, and 70 to 100 ° C. For example, a method of extracting for 0.5 to 2 hours at a degree and obtaining an extract by centrifugation and / or filtration as necessary can be mentioned. The extraction solvent is not particularly limited, and examples thereof include water, ethanol, acetic acid, and a mixture thereof.

Moreover, the concentrate of Onji extract can be manufactured by concentrating the extract obtained above, for example under reduced pressure. At this time, it is good also as a form of adsorption extract by adding adsorption agent to the concentrate of the obtained onji extract. The adsorbent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include dextrin, starch, gelatin, and calcium silicate. These adsorbents may be used alone or in combination of two or more. The amount of the adsorbent is not limited, and is 20 to 50 parts by weight, preferably 30 to 40 parts by weight, per 100 parts by weight of the finally obtained ondi extract (dry product).

In addition, a dried product of Onji extract can be produced by drying Onji extract or a concentrate of Onji extract. The drying method is not particularly limited, and examples include spray drying, vacuum concentration drying, freeze drying, and the like, and preferably spray drying. An adsorbent may be added when the onzi extract or the concentrate of the onji extract is subjected to a drying treatment. By adding the adsorbent, it is possible to shorten the drying time, reduce the hygroscopicity of the dried product of the extract obtained, and improve the final yield of the dried product. As described above, examples of the additive include dextrin, starch, gelatin, calcium silicate and the like, and these may be used alone or in combination of two or more. . The amount of the adsorbent is not limited, and 20 to 50 parts by weight, preferably 30 to 40 parts by weight, are exemplified per 100 parts by weight of the dry product of the onzi extract finally obtained.

Although content in particular of (A) component in the solid pharmaceutical composition of this invention is not restrict | limited, For example, 40 to 80 weight%, Preferably 50 to 70 weight% is mentioned.

(B) Hydrous silicon dioxide and light anhydrous silicic acid The solid pharmaceutical composition of the present invention contains at least one of hydrous silicon dioxide and light anhydrous silicic acid. As shown in the Example mentioned later, discoloration of an on-di extract can be suppressed by containing at least 1 type of a hydrous silicon dioxide and a light silicic acid anhydride.

The hydrous silicon dioxide and light anhydrous silicic acid used in the present invention are a kind of silicic acid compound. Examples of other silicate compounds include heavy anhydrous silicic acid, anhydrous silicic acid hydrate, synthetic aluminum silicate, calcium silicate, aluminum silicate, magnesium silicate, magnesium aluminate silicate, and metasilicate aluminate. Examples thereof include magnesium and magnesium aluminum silicate. Surprisingly, however, water-containing silicon dioxide and light anhydrous silicic acid among silicic acid compounds were confirmed to have a discoloration-inhibiting effect of ondi extract, but other silicic acid compounds were not able to confirm the same discoloration-inhibiting effect. .

Hydrous silicon dioxide and light anhydrous silicic acid can be used alone or in combination with the above component (A), or both can be used in combination with component (A). In addition, as long as the effect of the present invention is not hindered, both the hydrous silicon dioxide and the light anhydrous silicic acid can be used in combination with the other silicic acid compounds described above, and are not limited thereto. .

Although it does not restrict | limit especially about content of (B) component in the solid pharmaceutical composition of this invention, For example, 1-20 weight%, Preferably 1-15 weight% is mentioned. Moreover, when preparing a solid pharmaceutical composition as a tablet, it is especially preferable that the content rate of (B) component is 1-40 weight part when (A) component is 100 weight part.

(C) Cellulose compound The solid pharmaceutical composition of the present invention contains (C) a cellulose compound in addition to (A) ondi extract, (B) hydrous silicon dioxide and light anhydrous silicic acid. You may do it. By containing (C) component, it becomes possible to suppress discoloration of (A) component further than the case where only (B) component is contained.

About the kind of (C) component used by this invention, for example, carmellose (carboxymethylcellulose), croscarmellose sodium (crosslinked carmellose sodium), carmellose calcium (carboxymethylcellulose calcium), and carmellose potassium (carboxymethylcellulose potassium) ) And the like. These may be used alone or in combination with the component (A) and the component (B), or may be used in combination with the component (A) and the component (B) by arbitrarily combining two or more kinds. Carmellose calcium is particularly preferable from the viewpoint of suppressing discoloration.

Although it does not restrict | limit especially about content of (C) component in the solid pharmaceutical composition of this invention, For example, 1-20 weight%, Preferably 5-15 weight% is mentioned.

Other ingredients The solid pharmaceutical composition of the present invention may be prepared by using conventionally known excipients (e.g., crystalline cellulose, corn starch, potato starch, lactose, etc.), binders (e.g., hydroxypropyl cellulose, Sodium alginate, povidone, etc.), disintegrating agents (eg, agar, low substituted hydroxypropyl cellulose, etc.), lubricants (eg, magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, etc.), colorants (eg, Caramel, gardenia pigment, titanium oxide, iron oxide, etc.), preservatives (eg, L-ascorbic acid, etc.), preservatives (eg, benzoic acid, etc.), pH adjusters (eg, potassium carbonate, sodium bicarbonate, etc.), Surfactants (eg saponins, lecithins, sucrose fatty acid esters, etc.), Computing agent (e.g., shellac, hypromellose, macrogol, carnauba wax, hydroxypropyl cellulose, etc.) can also be prepared containing the components such.

The solid pharmaceutical composition of the present invention is not limited as long as it is a solid preparation, and may be any of solid preparations such as tablets, pills, powders, fine granules, granules, capsules and the like.

The solid pharmaceutical composition of the present invention is preferably prepared as a tablet. Tablets can be prepared by a method well known in the technical field to which the present invention belongs, for example, a compression molding method using a tableting machine. For tableting, the mixed components may be compressed as they are, or the mixed components may be subjected to a granulation step and the resulting granules may be compressed. In one embodiment, the tablet of the present invention can be prepared by adding each component according to the formulation, mixing, granulating, drying, granulating and mixing, and tableting the resulting preparation mixture. Moreover, you may make a coated tablet using a coating agent after shaping | molding of a tablet. The solid pharmaceutical composition of the present invention is particularly characterized in that it can exhibit a discoloration inhibiting effect even in an uncoated tablet (bare tablet).

The solid pharmaceutical composition of the present invention may be prepared as granules. Granules can be prepared by methods well known in the technical field to which the present invention belongs, for example, rolling granulation method, fluidized bed granulation method, compression granulation method, extrusion granulation method, stirring granulation method and the like. . The granule may be produced, for example, by wet granulation using bound water or dry granulation. Capsules can be prepared by filling the granules into capsules.

The daily intake of the solid pharmaceutical composition of the present invention can be appropriately adjusted according to the body shape, age, physical condition, etc. of the subject. For example, the daily dose taken by an adult (over 15 years old) is usually about 500 mg to 2500 mg as a dried product of Onji extract. The pharmaceutical composition of the present invention is usually taken in the form of oral administration divided into 1 to 3 times a day before or between meals.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not restrict | limited to these Examples.

1. Method for producing dry product of onji extract In this test example, a dry product of onji extract obtained as follows was used.
30 kg of water at 95 ° C. was added to 2 kg of dried Onji roots cut to about 5 to 10 mm, and the mixture was extracted with stirring for 60 minutes. Subsequently, the extract obtained by solid-liquid separation was concentrated under reduced pressure at 60 ° C. or lower using a rotary evaporator, and the concentrated liquid was spray-dried to obtain 500 (g) of dried Onji extract.

2. Method for producing solid pharmaceutical composition Dry product of onji extract obtained as described above, silicic acid compound (hydrous silicon dioxide: “Carplex # 80” (manufactured by DSL Japan), light anhydrous silicic acid: “ADSOLIDER 101” (Freund Sangyo Co., Ltd.), magnesium metasilicate aluminate: “Neusilin” (Fuji Chemical Industry Co., Ltd.), cellulose compound (carmellose calcium: “ECG505” (Nichirin Chemical Co., Ltd.)), crystal Cellulose: “Theorus PH-101” (manufactured by Asahi Kasei Co., Ltd.) and magnesium stearate: “magnesium stearate botanical” (manufactured by Taihei Chemical Sangyo Co., Ltd.) were weighed in accordance with Table 1 described later, and mixed together. Using a press machine (manufactured by NPC Corporation) and a corresponding mortar and pestle, 5 kN The tablet was compression-molded under pressure to obtain tablets having a diameter of 9 mm and a weight of 300 mg (Comparative Examples 1 to 3, Examples 1 to 5). The tablet-shaped composition obtained as described above was subjected to the following test. The unit of content of each component in the table is weight (mg).

3. Test method Tablet-shaped composition (6 tablets for each preparation, 1 tablet 300 mg) prepared as described above, and screw tube ("borosilicate glass (brown NO. 6)" manufactured by Nippon Electric Glass) And stored for 1 week in an environment of temperature 50 ° C. and humidity 60%, and the discoloration of the tablet was confirmed before and after storage. The evaluation of the color change was performed by measuring the color difference between the tablet immediately after production (before storage) and the tablet after storage. The color difference (ΔE * ab) was measured using a spectrocolorimeter CM-700d manufactured by Konica Minolta. The smaller the color difference value, the smaller the color difference between the tablet after storage and the tablet before storage, which means that the effect of suppressing discoloration is high. The evaluation results are shown in Table 1.

As shown in Table 1, in the tablets containing ONDI EXTRACT, the color was remarkably changed when water-containing silicon dioxide or light anhydrous silicic acid was not included (Comparative Examples 1 to 3), but when water-containing silicon dioxide was included. Discoloration was remarkably suppressed (Examples 1 to 3). Furthermore, when carmellose calcium was contained in addition to hydrous silicon dioxide (Example 4), discoloration was further suppressed as compared with the case where carmellose calcium was not contained (Example 1). Moreover, even when the hydrous silicon dioxide of Example 2 was replaced with light anhydrous silicic acid, discoloration of the ondi extract was significantly suppressed (Example 5). On the other hand, surprisingly, even when the same silicate compound was used, when magnesium metasilicate aluminate was used instead of hydrous silicon dioxide, the effect of inhibiting the discoloration of Onji extract was not confirmed (Comparative Example 3). .

Formulation Examples 1-9
Using the dried onji extract obtained as described above, the following components were mixed according to the formulation shown in Table 2, and a desktop standard press machine (manufactured by NPC System Co., Ltd.) and the corresponding mortar and pestle The resulting product was compression-molded at a pressure of 5 kN to obtain tablets (Prescription Examples 1 to 9) having a diameter of 9 mm and a weight of 300 mg. Hydrous silicon dioxide: “Carplex # 80” (manufactured by DSL Japan Co., Ltd.), light anhydrous silicic acid: “Adsolider 101” (manufactured by Freund Sangyo Co., Ltd.), carmellose calcium: “ECG505” (manufactured by Nichirin Chemical Industries, Ltd.) ), Croscarmellose sodium: “Kickolate ND-200” (manufactured by Nichirin Chemical Industry Co., Ltd.), crystalline cellulose: “Theoras PH-101” (manufactured by Asahi Kasei Co., Ltd.), corn starch: “corn starch ST-C” (Japan) Starch Chemical Co., Ltd.), magnesium stearate: “magnesium stearate vegetable” (produced by Taihei Chemical Sangyo Co., Ltd.), talc: “talc raw powder“ Maruishi ”(manufactured by Maruishi Pharmaceutical Co., Ltd.). Each of the obtained pharmaceutical compositions was excellent in the effect of suppressing discoloration as in the above-described Examples. The unit of content of each component in the table is weight (mg).

Claims (8)

A solid pharmaceutical composition comprising (A) ondi extract, and (B) at least one silicic acid compound selected from the group consisting of hydrous silicon dioxide and light anhydrous silicic acid. The solid pharmaceutical composition according to claim 1, further comprising (C) a cellulose compound. The solid pharmaceutical composition according to claim 2, wherein the component (C) is carmellose calcium. The solid pharmaceutical composition according to claim 2 or 3, wherein the component (A) is 40 to 80% by weight, the component (B) is 1 to 20% by weight, and the component (C) is 1 to 20% by weight. The solid pharmaceutical composition according to any one of claims 1 to 4, which is a tablet. The solid pharmaceutical composition according to any one of claims 1 to 5, wherein the component (B) is 1 to 40 parts by weight relative to 100 parts by weight of the component (A). (A) Onji extract is characterized by blending (B) water-containing silicon dioxide and light anhydrous silicic acid together with at least a silicic acid compound selected from the group consisting of (B) hydrous silicon dioxide and molding into a solid form. A method for suppressing discoloration of a contained pharmaceutical composition. Furthermore, the discoloration suppression method of Claim 7 which mix | blends (C) a cellulose compound.