JP6122538B2 - Oral composition - Google Patents

Description

  The present invention relates to an internal medicine composition containing a simple extract of Onji crude drug, in which deterioration over time such as alteration and discoloration is effectively prevented, and excellent medicinal effects are stably maintained over a long period of time.

  There are two types of preparations that contain herbal medicines: one that contains herbal medicine itself (raw drug substance) and one that contains herbal extract extracted by decocting herbal medicine with water. And since the bulky drug substance is bulky, many of them are blended with a crude drug extract. However, a preparation using a herbal extract has a problem that it is easily changed and discolored and is difficult to store and handle.

  Therefore, various proposals have been made to prevent such alteration, discoloration and the like in such a crude drug extract extract-containing preparation. For example, Patent Document 1 discloses a preparation in which an extract is extracted from an active pharmaceutical ingredient using water or the like, and a herbal extract extracted by mixing two kinds of adsorbents having specific adsorptive capacity into the extract and powdered. Proposed. When this herbal extract extract powder is used, caking (solidification) of the preparation and discoloration over time can be effectively suppressed.

  However, it is necessary to prepare a herbal medicine extract by a special and large-scale method in which two kinds of different adsorbents are mixed and powdered into an extract, and a simpler method is required. Yes.

JP 2013-32346 A

  The present invention has been made in view of such circumstances, and it is possible to effectively prevent deterioration over time such as alteration and discoloration, and it can be manufactured by a simple method, and an internal composition containing only Onji as a crude drug. The purpose is to provide goods.

In order to achieve the above object, the present invention is an internal composition containing onji extract (hereinafter referred to as “onji extract”) and stearic acid salt, and containing only onji as a crude drug, There is a stearic acid magnesium, the content of stearic acid salt, as its gist the oral composition is set within a range of 0.036 to 100 parts by mass with respect to Onjiekisu 1 part by weight.

That is, the present inventors repeated various studies in order to prevent deterioration of components derived from Onji extract over time when producing an oral composition containing only Onji as a crude drug. As a result, rather than Onji herbal itself (raw herbal), crude drugs and choose to use Onji extract from extract prepared decocted with water or the like, further, a and its Onji extract and specific salt stearate In combination, when the stearate content is set in the range of 0.036 to 100 parts by mass with respect to 1 part by mass of Onji extract, surprisingly, the color and shape change can be suppressed over a long period of time. Furthermore, the present inventors have found that the odor peculiar to Onji crude drug can be reduced immediately after production, and reached the present invention.

  In the present invention, "only Onji is blended as a crude drug" means that Onji is blended as a plain crude drug (a herbal medicine when used alone, not as a herbal medicine combining a plurality of herbal medicines). Means.

  As described above, the internal use composition of the present invention suppresses changes in color, shape, and odor even after long-term storage, thereby stabilizing the quality. In addition, since the unique odor derived from Onji crude drug is reduced immediately after production, this internal use composition can be easily taken even by a person who is not good at the unique odor of crude drug. Since the oral composition of the present invention contains Onji as a crude drug, it can be used as a brain function improving agent or a memory improving agent for the elderly.

  Next, an embodiment for carrying out the present invention will be described.

The internal use composition of the present invention contains Onji extract together with a specific stearate, but does not contain other herbal extracts. For this reason, it has excellent long-term storage stability while containing ingredients derived from Onji crude drugs, and the unique odor derived from Onji crude drugs is reduced. Play.

In the present invention, the Onji extract means water from Onji native agent (increments or powder), and extracted with an organic solvent or a mixture of ethanol, the whole thing from Onji extract, Onji extract, It is intended to include any form such as a soft extract obtained by concentrating it, an extract extract or an extract powder obtained by drying the soft extract. For the Onji extract of the present invention, it is preferable to use an extract powder from the viewpoint of miniaturization of the formulation and handling.

  In the internal use composition of the present invention, the content of the onji extract is not particularly limited. However, although depending on the yield, from the viewpoint of achieving the effect of the present invention, it is usually 1% by mass or more, preferably 5 to 99% by mass, and more preferably, based on the whole internal use composition. Is 8 to 95% by mass, particularly preferably 15 to 90% by mass, further preferably 20 to 75% by mass, more preferably 25 to 50% by mass, particularly preferably 25 to 40% by mass, and most preferably 30 to 40% by mass. % Content. Moreover, it is preferable to contain 200-2000 mg as a daily dose, More preferably, it is 300-1000 mg, More preferably, it is 400-1000 mg, Most preferably, it is 500-600 mg. That is, when there is too little Onji extract, the tendency which cannot fully mix | blend the medicinal component derived from Onji crude drug is seen, and the subject in this invention may not generate | occur | produce. On the other hand, when there are too many ONI extracts, the said medicinal component is mix | blended excessively and there exists a possibility that there may be no effect of this invention, such as solidification and coloring not being suppressed.

  Furthermore, the Onji extract is used as a daily dose of 1 to 10 g, preferably 3 to 10 g, more preferably 3 to 5 g, particularly preferably 3 g, and 200 to 120 times, preferably 10 to 120 times. It is preferable that the extract is obtained from an extract obtained by boiling with at least one of water and ethanol in an amount of 120 times. Moreover, as an on-distillate used for the internal use composition of this invention, the yield from a raw drug is 3-50 mass%, Preferably 5-30 mass%, Especially preferably, the thing of 10-20 mass% is used. It is preferable. If this yield is too low, there is a tendency that many impurities can not be sufficiently blended with medicinal ingredients derived from Onji crude drugs, and if it is too high, the above medicinal ingredients are excessively blended, and further, suppression of solidification and coloring, etc. This is because the effects of the present invention may not be achieved.

In general, stearates used in oral compositions are used as lubricants in the manufacture of compressed tablets. In the present invention, specific stearates are used. It is also used when the internal composition is not in the form of a compressed tablet. Examples of the stearate include magnesium stearate, calcium stearate, potassium stearate, sodium stearate, and zinc stearate. All of these are white powders with a slight difference, which may cause a slight odor and have common physical properties such as being hardly soluble in water and ethanol. Among such stearates, for use in the oral compositions of the present invention are magnesium stearate beam.

  In the internal use composition of the present invention, the content of stearate is not particularly limited, but from the viewpoint of achieving the effects of the present invention, it is preferable to contain 0.1 to 90% by mass with respect to the total internal composition. Preferably it is 0.3-50 mass%, More preferably, it is 0.5-10 mass%, Most preferably, it is 1-5 mass%.

Moreover, content of a stearate is set to the range of 0.036-100 mass parts with respect to 1 mass part of Onji extract . Preferably, it is set to the range of 1-10 mass parts. If the ratio of stearate to onji extract is too small, the effect of suppressing changes in the shape, odor, and color of the preparation tends to be weakened. This is because the above effect cannot be obtained. When it is set within the above range, the size of the preparation can be balanced with the effect of suppressing changes in the color, shape, and odor of the preparation in a well-balanced manner.

  Furthermore, the internal use composition of the present invention is characterized in that only Onji is blended as a crude drug, and does not contain any crude drug other than Onji extract and an extract obtained from the crude drug. In other words, the internal composition of the present invention does not correspond to an internal composition in which a plurality of herbal medicines such as traditional Chinese medicines containing an onji extract are combined as one of the constituent crude drugs. This is because when a drug substance other than Onji extract and a drug substance extract are contained, property changes such as coloring, solidification, or offensive odor are likely to occur, and the effect of the present invention tends not to be exhibited. However, a substance extracted from licorice, which is a crude drug, and purified as a single compound, such as dipotassium glycyrrhizinate, does not correspond to an extract obtained from a crude drug, and is contained in the oral composition of the present invention. be able to.

  And the internal use composition of this invention may contain other materials other than an onji extract and a stearate. That is, the internal use composition of the present invention is generally a pharmaceutical additive that can be used pharmaceutically, for example, a stabilizer, a stabilizer, a surfactant, a lubricant, a lubricant, a solubilizing agent. , Buffer, sweetener, base, adsorbent, taste-masking agent, binder, suspending agent, curing agent, antioxidant, brightener, fragrance, coating agent, skin, wetting agent, wetting adjustment Agent, filler, antifoaming agent, refreshing agent, chewing agent, antistatic agent, flavoring agent / fragrance, coloring agent, sugar-coating agent, tonicity agent, softening agent, emulsifier, adhesive, adhesion enhancement Agent, viscosity adjusting agent, foaming agent, pH adjusting agent, pH adjusting agent, excipient, dispersing agent, disintegrating agent, disintegrating aid, fragrance, moisture-proofing agent, preservative, preservative, solubilizer, dissolving An adjuvant, a solvent, and a fluidizing agent can be contained as needed.

  Specific examples of such formulation additives include purified sucrose, glucose, trehalose, lactose, maltose, mannitol, sorbitol, xylitol, erythritol, sodium saccharin, aspartame, acesulfame potassium, sucralose, licorice extract, stevia extract, lacanca extract Corn starch, potato starch, wheat starch, sodium bicarbonate, sodium chloride, crystalline cellulose, methylcellulose, ethylcellulose, hypromellose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, carmellose calcium, hypromellose phthalate Acid ester, cellulose acetate phthalate, dextri , Pregelatinized starch, gum arabic, gelatin, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, casein, sodium caseinate, carboxyvinyl polymer, talc, hydrogenated vegetable oil, macrogol, silicone oil, agar, sodium bicarbonate, sodium alginate, shellac , Glycerin, aromatic essential oils, water-soluble food dyes, yellow iron oxide, yellow iron sesquioxide, iron sesquioxide, brown iron oxide, black iron oxide, titanium dioxide, lake dye, benzoic acid, sodium benzoate, paraoxybenzoic acid , Polysorbate 80, glycerin fatty acid ester, honey beeswax, medium chain triglyceride, ascorbic acid, tocopherol, sodium thiosulfate, sodium edetate, orange and lemon citrus flavors, coffee flavors, chocolate And vegetable essential oils such as lemon flavor, peppermint oil, spearmint oil, and spice oil. In addition, the formulation additive which can be used for the internal use composition of this invention is not limited to what was enumerated above, and if it can utilize in pharmaceutics, it will not specifically limit.

  Among these, it is preferable to add a binder to the internal use composition of the present invention from the viewpoint of suppressing coloring and smell of the onji extract. Examples of the binder include purified sucrose, glucose, trehalose, lactose, maltose, saccharin sodium, aspartame, acesulfame potassium and other polysaccharides, corn starch, potato starch, wheat starch and their pregelatinized starch, mannitol, sorbitol, xylitol, erythritol. Cellulose alcohols such as sugar alcohols such as sucralose, crystalline cellulose, methylcellulose, ethylcellulose, hypromellose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, carmellose calcium, hypromellose phthalate, cellulose acetate phthalate Molecule. Particularly preferred binders include crystalline cellulose, potato starch, mannitol, and lactose.

  In the internal use composition of the present invention, the content of the binder is not particularly limited. However, from the viewpoint of achieving the effects of the present invention, it is usually contained in an amount of 5 to 95% by mass with respect to the entire internal use composition. More preferably, it is 20-90 mass%, Most preferably, it is 30-85 mass%, More preferably, it is 40-80 mass%.

  And the internal use composition of this invention can be obtained by mixing an on-di extract, a stearate salt, and other materials if needed by a conventional method. That is, first, the Onji extract and stearate may be mixed, and other ingredients may be mixed with the mixture, or all ingredients including Onji extract and magnesium stearate may be mixed at once. It may be. However, from the viewpoint that the odor derived from the Onji crude drug is further suppressed and the shape stability is enhanced, it is preferable to first mix the Onji extract and the stearate, and then mix other materials with this mixture. In many cases, the obtained internal use composition is dried and sized to become a solid composition.

  It is generally used when the internal use composition of the present invention is made into tablets, granules, fine granules, powders, pills, dry syrups, etc., that is, when it is necessary to adjust the shape of the internal use composition. Granulation methods, for example, spray granulation method, stirring granulation method, fluidized granulation method, rolling granulation method, wet granulation method such as rolling fluidization granulation method, dry granulation method such as compaction granulation method Can be used. Moreover, the internal use composition shape | molded in the tablet, the granule etc. can be divided | segmented and filled and it can also be set as a sachet. Tablets can be produced by mixing an internal composition, powder, fine granules, granules, pills, and the like with formulation additives and compression molding. Coating preparations such as sugar-coated tablets, film-coated tablets, and coated granules can be produced by conventional methods such as a pan coating method, a fluid coating method, a rolling coating method, and combinations thereof.

  And the internal use composition of the present invention is a tablet, powder, granule, pill, capsule, chewable tablet, sugar coating, film coating agent, foaming preparation, orally disintegrating preparation, matrix preparation, drink preparation, jelly preparation, Any shape such as a syrup may be used, but a solid composition such as a tablet, powder, granule, pill, chewable tablet or the like is preferable from the viewpoint that the effects of the present invention are remarkably achieved. From the viewpoint of easy administration, tablets or granules are more preferably used.

  Moreover, the internal use composition of this invention can prevent deterioration with time, such as a change and discoloration, and can keep the outstanding medicinal effect stably over a long period of time. For this reason, it is useful when the number of tablets and the number of packages to be taken per day is large or small. The number of tablets and the number of capsules to be taken per day of a solid composition containing an extract powder as a plain crude drug is usually 1 to 30, preferably 2 to 25 tablets, powders and granules. If it is an agent, it is about 2-5 packages. In that case, the mass per tablet (pack) is usually about 50 to 1000 mg, preferably about 200 to 600 mg.

  Furthermore, in the internal use composition of the present invention, functions such as stabilization, sustained release, sustained release, rapid disintegration, rapid dissolution, improved solubility, improvement in taking sensation of medicinal ingredients using formulation additives, etc. May be added. Addition of these functions can be performed by a commonly used method. For example, the medicinal ingredients are compounded into separate granules, formed into multilayer granules, formed into multilayer tablets or dry tablets, and formed into separate granules. Tablet, microcapsule, sugar-coated tablet, film-coated tablet, coated preparation such as coated granule, foamed preparation, chewable preparation, orally disintegrating preparation, Matrix preparation, co-grinding, Can be mentioned as a solid solution, adding sweeteners and cooling agents, adding antioxidants and stabilizers, adjusting to a specific pH, viscosity, osmotic pressure, salt concentration, You may combine these methods.

  Next, examples will be described together with comparative examples. However, the present invention is not limited to this. In addition, unless otherwise indicated, the component composition shown below is all shown with the mass reference | standard (mass part).

[Examples 1 to 9, Comparative Examples 1 to 17 ]
As shown in Tables 1 to 8 below, internal compositions (Examples 1 to 9, Comparative Examples 1 to 17 ) were prepared. That is, each material was prepared, these were mixed at once, and the powdery internal use composition was prepared. In addition, about the extract of each herbal medicine, the following were used, and the other materials used the Japanese pharmacopoeia collection.

Onji extract: The engraved Onji crude drug was boiled in 10 times the amount of water (about 100 ° C.) and extracted for 30 minutes. The obtained extract was filtered through a 100-mesh sieve, and the filtrate was concentrated at 70 ° C. or lower. The concentrated liquid was sterilized by heating and spray-dried to obtain a powdery Onji extract. In this method, about 0.55 g of Onji extract was obtained from 5 g of Onji crude drug substance (yield 11 mass%).
Licorice extract: Licorice extract powder (Nippon Flour Pharmaceutical Co., Ltd.)
Carrot extract: Ginseng dry extract (Nippon Flour Pharmaceutical Co., Ltd.)

  About the internal use composition of each Example and each comparative example, (1) Color difference suppression rate 1, (2) Mass change suppression rate, (3) Presence of solidification, (4) Odor suppression, (5) Odor change, (6) Evaluation was made for six items of a color difference suppression rate of 2. The evaluation method for each item is as follows. In addition, each evaluation of the said 6 item in each Example and each comparative example will become the same if the thing of a yield of 11 mass% is used as an Onji extract. That is, in place of about 0.55 g of Onji extract obtained from 5 g of Onji drug substance, about 0.33 g of Onji extract obtained from 3 g of Onji drug substance was used in the same amount. Each evaluation of the above six items in the examples and the comparative examples is not changed.

(1) Color difference suppression rate 1
The internal composition 0.5g prepared according to the composition shown in Table 1 and Table 2 was put into a plastic petri dish, and the color change of the internal composition after storage at 40 ° C. and humidity 75% RH for 10 minutes was measured with a color difference meter ( Using Konica Minolta, product number: CR-400), the color difference (ΔE * ab) before and after storage was determined using the following formula 1 using the color of the internal composition immediately after preparation as a standard. Furthermore, based on the color change over time (ΔE * ab) of the oral composition containing only Onji extract (Comparative Example 1), how much the color change over time could be suppressed (color difference suppression rate%). Calculated according to Equation 2. A higher color difference suppression rate means that discoloration under high temperature and high humidity storage was suppressed. The results are shown in Table 1 and Table 2.
Formula 1: Color difference (ΔE * ab) = [(Δa ^* ) ² + (Δb ^* ) ² + (ΔL ^* ) ² ] ^1/2
Δa ^* : a value of the tablet after storage−a value of the tablet before storage Δb ^* : b value of the tablet after storage−b value of the tablet before storage ΔL ^* : L value of the tablet after storage−before storage L value formula 2 of tablet: Color difference suppression rate (%) = ((color difference of Comparative Example 1−color difference of each composition) / color difference of Comparative Example 1) × 100

As shown in Table 1 and Table 2 above, in all of Examples 1 to 4 that contain Onji extract and magnesium stearate in a specific ratio, and only Onji is blended as a crude drug, under high temperature and high humidity It was confirmed that discoloration over time was dramatically suppressed and the quality was stable. On the other hand, discoloration was hardly suppressed in Comparative Example 2 that did not contain the ondi extract and magnesium stearate in a specific ratio. Moreover, in Comparative Examples 3 and 4 containing licorice extract or carrot extract as herbal medicines other than Onji extract, discoloration was not suppressed, but rather discoloration. Further, in Comparative Examples 5 to 7 using crystalline cellulose, potato starch, or mannitol instead of magnesium stearate, the color change was not suppressed, but rather the color was further changed.

(2) Mass change inhibition rate By internal absorption composition 0.5 g prepared according to the composition shown in the following Table 3 in a plastic petri dish and stored for 10 minutes at 40 ° C. and humidity 75% RH, due to moisture absorption of the internal composition The change in mass was calculated as a mass change rate (%) as shown in the following formula 3 using the mass of the internal composition immediately after preparation as a standard. Furthermore, based on the mass change rate (%) of the oral composition (Comparative Example 1) containing only Onji extract, how much the change in mass over time could be suppressed (mass change inhibition rate (%)). It calculated using the following formula 4. The higher the mass change inhibition rate, the more the mass change due to moisture absorption under high temperature and high humidity storage is suppressed. The results are shown in Table 3.
Formula 3: Mass change rate (%) = [(mass after storage−mass before storage) / mass before storage] × 100
Formula 4: Mass change inhibition rate (%) = [(Mass change rate of Comparative Example 1−Mass change rate of each composition) / Mass change rate of Comparative Example 1] × 100

As shown in Table 3 above, the mass under high temperature and high humidity in all of Examples 1 to 4 containing Onji extract and magnesium stearate in a specific ratio and containing only Onji as a crude drug. It was confirmed that the change was suppressed and the quality was stable.

(3) Presence / absence of solidification 10 g of an internal composition prepared according to the composition shown in Tables 4 and 5 below was put in a plastic petri dish, and the appearance after storage for 1 hour at 40 ° C. and humidity 75% RH was visually observed. The presence or absence of solidification of the internal use composition was evaluated based on the following criteria. The results are shown in Table 4 and Table 5.
A: Solidification did not occur.
○: Solidification was observed only slightly, but it was not problematic.
Δ: Partial solidification occurred.
X: The whole solidified.

As shown in Table 4 and Table 5, Comparative Comparative Example 8 containing only Onji extract solidified under high temperature and high _humidity, does not contain a Onji extract and magnesium stearate in a specific ratio While Example 9 slightly solidified , all of Examples 5 to 7 containing Onji extract and magnesium stearate in specific proportions and containing only Onji as a herbal medicine, solidified over time. It was confirmed that the quality was stable. On the other hand, solidification was not suppressed in Comparative Examples 10 to 12 containing licorice extract, carrot extract, or ginger extract as herbal medicines other than Onji extract. Further, in Comparative Examples 13 to 15 using crystalline cellulose, potato starch, or mannitol instead of magnesium stearate, solidification was not suppressed.

(4) Smell Suppression Immediately after the preparation of the internal preparation composition prepared according to the composition ratio shown in Table 6 below, the odor was sniffed from a distance of 10 cm and evaluated based on the following criteria. The evaluation is also shown in Table 6.
O: It felt that the smell derived from Onji crude drug was suppressed.
X: Suppression of odor derived from Onji crude drug was not felt.

(5) Change in odor 10 g of an oral composition prepared according to the composition ratio shown in Table 6 below was placed in a plastic petri dish and stored at 40 ° C. and humidity 75% RH for 1 hour. The odor of the internal composition immediately after preparation was compared with the odor of the internal composition after storage, and the change in odor of the internal composition was evaluated based on the following criteria. The evaluation is also shown in Table 6.
○: No change in odor was felt.
X: Odor deteriorated (unpleasant odor increased).

As shown in Table 6 above, Comparative Example 8 containing only Onji extract gave a herbal medicine-specific odor and the odor deteriorated under high temperature and high humidity. Onji Extract and magnesium stearate was contained at a specific ratio, the embodiment only Onji as crude drug is blended 6, 7 are both improved odor immediately after preparation, also have been suppressed deterioration with time in odor, quality stable It was confirmed that On the other hand, in Comparative Examples 13 to 15 using crystalline cellulose, potato starch, or mannitol instead of magnesium stearate, the odor was not improved and the deterioration of the odor was not suppressed.

(6) Color difference suppression rate 2
The color difference before and after storage after storage for 10 minutes at 40 ° C. and humidity 75% RH in the internal preparation prepared according to the composition shown in Tables 7 and 8 below was determined. The color difference and the color difference suppression rate were measured and calculated in the same manner as in the “color difference suppression rate 1” test. Incidentally, Comparative Example 16 in place of the Comparative Example 1 for Example 8, for example 9 had use of Comparative Example 17 in place of the Comparative Example 1. The results are shown in Tables 7 and 8 .

As shown in Table 7, 8, the comparative example 16, 17 containing no magnesium stearate, Examples 8 and 9 where the magnesium stearate Onji extract is blended in a specific ratio is In all cases, discoloration over time under high temperature and high humidity was suppressed, and it was confirmed that the quality was stable.

[Formulation example]
Using the materials shown in Tables 9 to 13 below, internal compositions (formulation examples 1 to 8, 11 to 20, 23 to 25) of the present invention were prepared. In addition, as a material of formulation examples 1-25, about Onji extract, what was used by the method used in Examples 1-9 and its equivalent was used, and other materials are listed in the Japanese Pharmacopoeia. Was used. In the table, a tablet (plain tablet) means an uncoated tablet, and a tablet (film) means a film-coated tablet.

For Formulation Example 1 to 25 shown in Table 9-13, the method similar to Example, the presence or absence of solidification, suppression of odor, the evaluation of three items smell change was carried out. As a result, solidification with time was suppressed in all of Formulation Examples 1 to 25 containing Onji extract and stearate in a specific ratio and containing only Onji as a crude drug, and the odor immediately after preparation Has been improved. Moreover, the deterioration of the odor over time was suppressed, and it was confirmed that the quality was stable.

  INDUSTRIAL APPLICATION This invention is an internal-combination composition containing the Onji plain crude drug extract excellent in long-term preservation | save property, and the improvement effect of memory ability of elderly people can be anticipated by taking.

Claims (6)

Containing the Onjiekisu and stearate, a oral composition only Onji as crude drug is formulated, the stearic acid salt is magnesium stearate arm, the content of stearic acid salt, the Onjiekisu 1 part by weight On the other hand, it is set in the range of 0.036 to 100 parts by mass.   The internal composition of Claim 1 which contains an onzi extract 1 mass% or more with respect to the whole internal composition.   The internal use composition of Claim 1 or 2 which contains the Onji extract extracted from 1-10 g of bulk drugs as a daily dose.   The internal use composition as described in any one of Claims 1-3 which uses a 3-50 mass% yield from a raw drug as an on-di extract.   The internal use composition as described in any one of Claims 1-4 shape | molded as a solid composition.   Furthermore, the internal use composition as described in any one of Claims 1-5 containing a binder.