JP6982290B2 - Solid pharmaceutical formulation for internal use containing Onji extract - Google Patents

Description

The present invention relates to an ondi-extract-containing solid pharmaceutical preparation for internal use in which discoloration (particularly browning) is effectively suppressed.

Onji extract is an extract of the root of Polygala tenuifolia, and has been reported to have various medicinal effects including its effect on psychiatric and neurological disorders.
As the preparation containing onji, a preparation containing the bulk powder of onji as it is can be used, but a preparation containing onji extract is preferred from the viewpoint of the bulkiness of the preparation due to the blending amount. However, the pharmaceutical product containing the ondi extract is prone to discoloration and the like over time, and has a problem in terms of quality control.

Various techniques have been proposed to address this problem. For example, Patent Document 1 proposes an ondi simple oral composition containing only ondi as a crude drug and containing an ondi extract and stearate (magnesium stearate). It is reported that the product was effectively prevented from deteriorating over time such as deterioration and discoloration.

JP-A-2017-75141

There is still a need for another simple technique to solve the above problems.
Therefore, an object of the present invention is to provide a solid pharmaceutical preparation for internal use containing ondi extract, which suppresses discoloration over time.

As a result of diligent studies to solve the above problems, the present inventors have obtained sodium fumarate stearyl, sucrose fatty acid ester and titanium oxide in each or in any combination over time as shown in the following examples. It has been found that it has an effect of suppressing target discoloration.

Therefore, the present invention provides a solid pharmaceutical preparation for internal use, which comprises ondi extract as a simple crude drug and at least one of stearyl fumarate, sucrose fatty acid ester and titanium oxide.
The present invention also provides an internal solid pharmaceutical preparation comprising ondi extract as a simple crude drug, stearyl fumarate or sucrose fatty acid ester, and titanium oxide.

According to the present invention, there is provided a solid pharmaceutical preparation for internal use containing an ondi extract, which suppresses discoloration over a long period of time.

The solid pharmaceutical preparation for internal use of the present invention is characterized by containing ondi extract as a simple crude drug and at least one of stearyl fumarate, sucrose fatty acid ester and titanium oxide.
With the above configuration, the solid pharmaceutical preparation for internal use of the present invention effectively suppresses discoloration over time.

<Onji extract>
Onji extract is included as a simple crude drug in the solid pharmaceutical preparation for internal use of the present invention.
Onji extract is an aqueous solvent (water, an organic solvent miscible with water (for example, lower [especially C1 to C4] alcohol) or a mixed solvent thereof (for example, [especially [especially 30% by volume or less] ethanol aqueous solution)) from Onji as a raw material raw medicine. ) Is not particularly limited as long as it is extracted using), but a dry form such as an extract powder is preferable.
As a specific extraction method, for example, an aqueous solvent (preferably water) in an amount (preferably water) about 1 to about 200 times the amount (mass) of the raw material crude drug is added, and the mixture is stirred or non-stirred at room temperature (room temperature) to about 100 ° C. Extraction (for example, about 0.5 to about 3 hours under stirring, about 5 to about 24 hours under non-stirring) for about 0.5 to about 24 hours (one or more extraction treatments), as needed. The method includes, but is not limited to, natural filtration or centrifugal filtration.

The dried onji extract (onji extract powder) can be obtained by using any method known in the art, for example, the extract obtained as described above or a concentrate (soft extract) thereof (for example). , And / or those obtained under heating) can be produced by, for example, spray-drying, freeze-drying, vacuum-concentrating drying, natural drying, or the like, and optionally pulverizing.
In the present invention, a commercially available product may be used as the ondi extract. Onji extract can be obtained from, for example, Alps Pharmaceutical Industry, Matsuura Pharmaceutical Industry, Nippon Powder Chemicals, Tokiwa Plant Chemistry Research Institute and the like.

The content of the ondi extract in the formulation is not particularly limited and can be selected from a wide range. For example, the content of ondi extract (dry mass) in the pharmaceutical product is 1 to 95% by mass, for example, 10 to 90% by mass, for example, 20 to 80% by mass, for example, 30 to 70% by mass, based on the total mass of the pharmaceutical product. For example, it can be 40 to 60% by mass. In the solid pharmaceutical preparation for internal use of the present invention, the coloration of Ondi over time is effectively suppressed, so that the content (blending amount) of Ondi extract can be increased. Therefore, the solid pharmaceutical preparation for internal use of the present invention can be provided as an antitussive expectorant, a sedative or a nourishing tonic, or a brain function improving agent or a memory (forgetfulness) improving agent for middle-aged and elderly people.
The content of the ondi extract in the oral solid pharmaceutical preparation of the present invention is, for example, 200 to 2000 mg, preferably 300 to 1500 mg, more preferably 400 to 1000 mg, and particularly preferably 500 to 700 mg in terms of crude drug as a daily dose. Is.

<Sodium stearyl fumarate, sucrose fatty acid ester and titanium oxide>
Sodium stearyl fumarate is not particularly limited as long as it conforms to the pharmaceutical additive standard.
A sucrose fatty acid ester is a monoester or polyester of sucrose having a fatty acid (eg, a diester and / or a tri-ester) or a mixture thereof. In the present invention, the sucrose fatty acid ester is also not particularly limited as long as it conforms to the pharmaceutical additive standard, but the fatty acid may be, for example, a saturated or unsaturated fatty acid having 12 to 22 carbon atoms (preferably 16 to 22). Specific examples thereof may be stearic acid, palmitic acid, myristic acid, oleic acid, lauric acid, behenic acid, and erucic acid. Those having an HLB value of 1 to 11 are preferable, and those having an HLB value of 1 to 8 are more preferable.
The titanium oxide is not particularly limited as long as it conforms to the 17th revised Japanese Pharmacopoeia or the pharmaceutical additive standard, and any crystal structure of anatase type, rutile type and brookite type can be used.

In the solid pharmaceutical preparation for internal use of the present invention, stearyl fumarate, sucrose fatty acid ester and titanium oxide may be used alone, or may be used in combination of two or three.
When the two are combined, the combination may be any of stearyl fumarate and sucrose fatty acid ester, stearyl fumarate and titanium oxide, sucrose fatty acid ester and titanium oxide, but with stearyl fumarate or sucrose fatty acid ester. The combination with titanium oxide is preferable. That is, in one preferred embodiment, the solid pharmaceutical preparation for internal use of the present invention is characterized by containing ondi extract as a simple crude drug, sodium stearyl fumarate or sucrose fatty acid ester, and titanium oxide. do.

In the solid pharmaceutical preparation for internal use of the present invention, the content ratio (mass ratio) of stearyl sodium fumarate and / or sucrose fatty acid ester and / or titanium oxide to ondi extract (dry mass) is not particularly limited, but is, for example, 0.01. It is in the range of ~ 50, preferably in the range of 0.01 to 20, more preferably in the range of 0.01 to 10, more preferably in the range of 0.015 to 5, and more preferably in the range of 0.02 to 1. The content ratio (mass ratio) of titanium oxide is more preferably in the range of 0.05 to 10, more preferably in the range of 0.1 to 5, and more preferably in the range of 0.15 to 1.

Alternatively, in the oral solid pharmaceutical preparation of the present invention, the content (% by mass) of sodium fumarate and / or sucrose fatty acid ester and / or titanium oxide with respect to the entire preparation is not particularly limited, but is, for example, 0.1. It is in the range of ~ 50%, preferably in the range of 0.2 to 20%, and more preferably in the range of 0.5 to 10%. The content (% by mass) of titanium oxide is more preferably in the range of 0.5 to 50%, more preferably in the range of 1 to 20%, and more preferably in the range of 5 to 10%.
The content ratio (mass ratio) or content rate (mass%) of the solid pharmaceutical preparation for internal use of the present invention may be appropriately determined so that the preparation exerts a discoloration suppressing effect based on the description of the following Examples. can.

In the oral solid pharmaceutical preparation containing titanium oxide according to the present invention, the titanium oxide is in a state of being mixed with the ondi extract which is an active ingredient. However, this does not mean that the oral solid pharmaceutical preparation of the present invention does not further contain titanium oxide that is not in a mixed state with the ondi extract.

<Other ingredients>
In the solid pharmaceutical preparation for internal use of the present invention, other components generally blended in the solid preparation can be appropriately blended.
Other components that can be commonly incorporated into solid formulations include, for example, excipients, binders, sluices, sluice agents, disintegrants, disintegrant aids, stabilizers, soluble (solubilized) agents. , Buffering agent, base, adsorbent, curing agent, antioxidant, brightener, surfactant, dispersant, suspending agent, coating agent, filler, cooling agent, sweetening agent, Examples thereof include a chewing agent, an antioxidant, a coloring agent, a sugar coating agent, a foaming agent, a pH adjuster, a moisture-proofing agent, a preservative, a preservative, a fluidizing agent, a flavoring agent, and a odorant.
Specific examples of each are not particularly limited as long as they are pharmaceutically usable (for example, those conforming to the 17th revised Japanese Pharmacopoeia or the pharmaceutical additive standard), but the following can be exemplified.

Excipients include, for example, crystalline cellulose, powdered cellulose, sugar alcohols (eg, erythritol, martitol, mannitol, sorbitol, xylitol, lactitol), starch (eg, derived from corn, potato or wheat), polysaccharides (eg, [eg, [ Purification] Sucrose, trehalose, lactose, glucose, malt sugar, fructose, maltose, [powder] reduced maltose water candy), dextrin, magnesium aluminometasilicate, calcium monohydrogen phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, Examples thereof include calcium lactate, precipitated calcium carbonate, talc, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide and kaolin.

Examples of the binder include gum arabic powder, cellulose and cellulose derivatives (eg, crystalline cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hypromellose, carmellose, etc. These salts), polysaccharides, sugar alcohols, gelatin, povidone, copolyvidone, polyvinyl alcohol, acrylic acid-based polymers, purulan, dextrin, pregelatinized starch, hydroxypropyl starch, tragant powder, sodium alginate and the like.

Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose, carmellose sodium, croscarmellose sodium, carmellose calcium, crospovidone, starch, carboxymethyl starch sodium, hydroxypropyl starch, partially pregelatinized starch, and hydrogen carbonate. Examples include sodium and starch powder.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, glycerin fatty acid ester, hydrogenated oil, macrogol and the like.
Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, kaolin and the like.

Examples of the antioxidant include ascorbic acid and its salt, tocopherol, dibutylhydroxytoluene, propyl gallate, butylhydroxyanisole, citric acid and the like.
Examples of the preservative include benzoic acid, paraoxybenzoic acid ester and the like.
Examples of the pH adjuster include potassium carbonate and sodium hydrogen carbonate.
Examples of the coating agent include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, povidone, enteric base, gastrosoluble base, polysaccharide and the like.
The blending amount of the above-mentioned other components in the oral solid pharmaceutical preparation of the present invention may be appropriately selected from the range generally adopted in pharmaceutics so as not to impair the effect of the present invention.

<Dosage form and manufacturing method>
The dosage form of the solid pharmaceutical preparation for internal use of the present invention is not limited as long as it is a solid preparation, and oral administration of tablets, pills, powders, granules, fine granules, chewable tablets, sugar coating agents, orally disintegrating tablets and the like. It can be a pharmaceutical product. Tablets, powders, fine granules, granules, chewable tablets or orally disintegrating tablets are preferred.

In one embodiment, the oral solid pharmaceutical preparation of the present invention does not have a coating layer.
In another embodiment, the oral solid pharmaceutical preparation of the present invention comprises a drug nucleus and a coating layer, wherein the drug nucleus comprises the titanium oxide. In this case, the coating layer may or may not contain titanium oxide. Here, the "drug nucleus" means a nucleus particle containing an active ingredient (ondi extract in the present invention), and when the dosage form is a tablet, "tablet nucleus", "uncoated tablet" or "naked tablet". In the case of granules, it is also called "elementary granules" or "bare granules". That is, in this embodiment, the solid pharmaceutical preparation for internal use of the present invention contains an ondi extract as a simple crude drug, a drug nucleus containing at least one of stearyl fumarate, a sucrose fatty acid ester and titanium oxide, and Includes a coating layer.

The solid pharmaceutical preparation for internal use of the present invention can be produced by a general method in the pharmaceutical field. That is, in the solid pharmaceutical preparation for internal use of the present invention, after mixing the ondi extract, at least one of stearyl fumarate, sucrose fatty acid ester and titanium oxide, and optionally other additives, by a conventional method. , Can be manufactured by conventional molding into a desired dosage form. The mixing may be carried out by mixing all the materials used for the said preparation (in the case of a preparation having a coating layer, its drug nucleus) at once, or ondi extract, stearyl fumarate sodium and sucrose fatty acid ester. And at least one of titanium oxide may be mixed in advance and then mixed with the remaining material.

For example, the granules can be produced by a wet or dry granulation method, for example, a spray granulation method, a stirring granulation method, a fluidized bed granulation method, a rolling granulation method, a rolling flow granulation method, etc. It can be manufactured by using an extrusion granulation method or a compaction granulation method. The preferred granulation method is the fluidized bed granulation method. If necessary, sizing may be performed.
Tablets can be produced by compression molding using a tableting machine after granulating the obtained mixture as it is or (by the method described above) in advance.
Granules and tablets may be produced as a coated preparation (for example, sugar-coated tablets, film-coated tablets, coated granules, etc.). The coating layer can be obtained by applying a coating agent to a drug nucleus (elementary granules, uncoated tablets, etc.) by a conventional method such as a pan coating method, a fluidized coating method, or a rolling coating method.

Hereinafter, the present invention will be described with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

1. 1. Production of solid pharmaceuticals The solid pharmaceuticals (Formulation Examples 1 to 10) according to the component composition (content (mass) unit is "mg"; dry mass for ondi extract) shown in Tables 1 and 2 below were produced.
Each of the materials shown in the table was mixed and compression-molded using a rotary tableting machine (Collect 24; manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a tablet having a weight of 200 mg per tablet.
"Onji dry extract" ([water extract] extract: protozoan = 1: 5.6; Alps Pharmaceutical Industry) as onji extract, and "Ryoto (registered trademark) sugar ester S-370" (sucrose stearic acid) as sucrose fatty acid ester. An acid ester, HLB value 3; Mitsubishi Chemical Foods) was used, and "titanium oxide NA61" (crystal structure: rutile type; manufactured by Toho Titanium Co., Ltd.) was used as titanium oxide. For other materials, the products listed in the Japanese Pharmacopoeia were used.
The obtained tablets were subjected to the following tests.

2. 2. Test 1
The tablets of Formulation Examples 1 to 5 were examined for tablet physical characteristics (thickness, hardness and disintegration time). The disintegration time was evaluated using "water" according to the evaluation method described in "(1) Tablets" of the 17th revised Japanese Pharmacopoeia "Disintegration Test Method". The tablet hardness was measured using a tablet hardness tester (SCHLEUNIGER 6D type; manufactured by Freund Sangyo Co., Ltd.), and the tablet thickness was measured using a thickness meter (model number C1012BS; manufactured by Mitutoyo Co., Ltd.).
In addition, another tablet of the same formulation is placed in a glass bottle (PS-4K; manufactured by Daiichi Glass Co., Ltd.) and placed in a high-temperature and high-humidity environment with a temperature of 40 ° C and a relative humidity of 75% for 15 minutes and 24 without closing the lid. After time exposure, the degree of discoloration (especially browning) of each tablet before and after exposure was confirmed. The evaluation was performed by using the tablets immediately after production as initials and measuring the color difference between the tablets after exposure for each time. The color difference was measured using a spectrocolor difference meter (SE6000; manufactured by Nippon Denshoku Kogyo Co., Ltd.).

ΔＥの値が５を超えると、目視で感知可能な色調差が生じていることを示す。よって、ΔＥ値が小さくなれば、錠剤の経時的色変化が抑制されたことを意味する。 The color difference ΔE is calculated by the following formula using the difference (ΔL, Δa and Δb, respectively) between two samples of the color tone parameters (L value indicating lightness, a value and b value indicating hue and saturation).

When the value of ΔE exceeds 5, it indicates that a visually perceptible color difference has occurred. Therefore, when the ΔE value becomes small, it means that the color change of the tablet with time is suppressed.

The results are shown in Table 1.

As is clear from the results shown in Table 1, a remarkable discoloration is observed over time in the solid preparation containing the ondi extract (Prescription Example 1 [Comparative Example 1]).
On the other hand, the preparation containing stearyl sodium fumarate (Prescription Example 4 [Example 1]) and the preparation containing sucrose fatty acid ester (Prescription Example 5 [Example 2]) are the preparations containing calcium stearate (Prescription Example 3 [Comparison]). It showed a higher effect of suppressing discoloration over time than Example 3]), and suppressed discoloration over time to the same extent as or more than the pharmaceutical product containing magnesium stearate (Prescription Example 2 [Comparative Example 2]).
The obtained tablets (Prescription Examples 1 to 5) all showed good tablet physical properties, but the preparations containing sodium fumarate or sucrose fatty acid ester (Prescription Examples 4 and 5) contained magnesium stearate. The hardness was superior to that of the formulation containing (Prescription Example 2) and the formulation containing calcium stearate (Prescription Example 3).

3. 3. Test 2
The tablets of Formulation Examples 1 to 2, 4 and 6 to 10 were examined for their physical characteristics in the same manner as in Test 1.
Further, for another tablet of the same prescription example, the color difference was measured and evaluated in the same manner as in Test 1.
The results are shown in Table 2.

As is clear from Table 2, a remarkable discoloration is observed again with time in the solid preparation containing the ondi extract (Prescription Example 1 [Comparative Example 1]).
On the other hand, a preparation containing stearyl sodium fumarate (Prescription Example 4 [Example 1]), a preparation containing titanium oxide (Prescription Example 6 [Example 3]), and a preparation containing sodium stearyl fumarate and titanium oxide (Prescription Example). 7 [Example 4]), a preparation containing titanium oxide and magnesium stearate (Formulation Example 10 [Example 7]), a preparation containing sucrose fatty acid ester and titanium oxide (Formation Example 8 [Example 5]). The preparation containing stearyl sodium fumarate, the sucrose fatty acid ester and titanium oxide (Formulation Example 9 [Example 6]) is more effective than the preparation containing magnesium stearate (Prescription Example 2 [Comparative Example 2]) over time. The target discoloration was suppressed.

The obtained tablets (Prescription Examples 1, 2, 4 and 6 to 10) all showed good tablet physical characteristics, but the preparation containing stearyl sodium fumarate was again the preparation containing magnesium stearate. The hardness was superior in comparison (prescription example 4 vs. prescription example 2).
In addition, the hardness of the pharmaceutical product was significantly reduced by blending titanium oxide (Prescription Example 1 vs. Formulation Example 6), but by blending sodium stearyl fumarate and / or sucrose fatty acid ester together with titanium oxide, this hardness The decrease was suppressed (Prescription Example 6 vs. Prescription Examples 7, 8 and 9). On the other hand, the same suppression was not observed even when magnesium stearate was blended with titanium oxide (Prescription Example 6 vs. Prescription Example 10).
Further, the tablets containing titanium oxide (Prescription Examples 6 to 10) had improved disintegration property as compared with the tablets containing no titanium oxide (Prescription Examples 1, 2 and 4).

As can be understood from the above test results, the solid pharmaceutical preparation for internal use of the present invention suppresses discoloration over time under high temperature and high humidity to the same extent as or more than that of the conventional preparation containing magnesium stearate. Was confirmed.
In addition, it was confirmed that the oral solid pharmaceutical preparation of the present invention has a higher hardness (without affecting the disintegration property) than the preparation containing magnesium stearate.
Furthermore, it was confirmed that the solid pharmaceutical preparation for internal use of the present invention has improved disintegration property when titanium oxide is blended. Then, it was confirmed that when stearyl fumarate and / or sucrose fatty acid ester was blended together with titanium oxide, the decrease in hardness of the pharmaceutical product could be suppressed at the same time.

Claims (6)

It is characterized by containing ondi extract as a simple crude drug and at least one of stearyl fumarate, sucrose fatty acid ester and titanium oxide, and the ondi extract is extracted from ondi using an aqueous solvent. A solid pharmaceutical product for internal use. It is characterized by containing ondi extract as a simple crude drug, stearyl fumarate or sucrose fatty acid ester, and titanium oxide, and the ondi extract is an extract extracted from ondi using an aqueous solvent. Solid pharmaceutical preparation for internal use. Claim 1 or 2 characterized in that the content ratio (mass ratio) of sodium fumarate and / or sucrose fatty acid ester and / or titanium oxide to the ondi extract (dry mass) is in the range of 0.015-1. The solid pharmaceutical preparation for internal use described in. The solid pharmaceutical preparation for internal use according to any one of claims 1 to 3, wherein the sucrose fatty acid ester is composed of saturated fatty acids having 16 to 22 carbon atoms and exhibits HLB of 1 to 11. The solid pharmaceutical preparation for internal use according to claim 2, which has no coating layer or contains a drug nucleus and a coating layer, and the drug nucleus contains the titanium oxide. The solid pharmaceutical preparation for internal use according to any one of claims 1 to 5, which is a tablet, a powder, a fine granule, a granule, a chewable tablet or an orally disintegrating tablet.