JP2015086171A - Coated powder comprising pyrroloquinoline quinones, and production method thereof, as well as composition thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a coated powder comprising a protein or peptide component, or pyrroloquinoline quinones which are hard to cause discoloration even if they contact the tongue or tissue in a mouth physically for a long time, and are excellent in storage stability and tableting properties, and to provide a production method thereof, as well as to provide a composition comprising the coated powder.SOLUTION: The invention provides a coated powder containing a nucleus containing pyrroloquinoline quinones, a first coating layer which coats at least a part of the surface of the nucleus and contains a water-insoluble substance, and a second coating layer which coats at least one part of the surface of the first coating layer and contains oil and fat.

Description

  The present invention relates to a coating powder containing pyrroloquinoline quinones, a method for producing the same, and a composition containing the coating powder.

This pyrroloquinoline quinone (hereinafter also referred to as “PQQ”) is a compound represented by the following formula (1).

  Pyrroloquinoline quinone and its derivatives (hereinafter also referred to as “PQQs”) are attracting attention as useful compounds in the fields of food such as health supplements, cosmetics and the like. PQQs are also expected to be used in the pharmaceutical field. PQQ exists in bacteria, eukaryotic fungi, and yeast, and plays an important role as a coenzyme. Specifically, cell proliferation promoting action, anti-cataract action, liver disease prevention and treatment action, wound healing action, anti-allergic action, reverse transcriptase inhibitory action, and glyoxalase I inhibitory action of PQQs until recently Many physiological activities such as anticancer effects have been clarified.

  In order to use such PQQs in the pharmaceutical field, food field, cosmetic field, etc., several problems arise. For example, PQQ and PQQs such as PQQ alkali metal salts containing 1 to 3 alkali metal ions are water-soluble compounds, and these compounds do not dissolve in oil. Therefore, Patent Document 1 discloses an adjustment liquid composition for soft capsule filling in which PQQs are dispersed in the range of 1 to 50% by mass in the edible fat for the purpose of stably dispersing in the edible fat. ing.

  In addition, color is an important factor in foods, cosmetics, etc., and it is required that foods, cosmetics, etc. do not change color. However, PQQs are known to be red-colored substances (Non-Patent Document 1), and may react with ingredients in foods, cosmetics and the like to discolor foods and cosmetics. A method for suppressing discoloration due to PQQs is not well known. For example, as in the case of PQQs, the discoloration of vitamins used in the fields of pharmaceuticals, foods, cosmetics, etc. In order to suppress the deterioration of vitamins in the presence of (metal salt) and discoloration to black-brown, etc., water-insoluble polyvalent metal salt is coated with enzymatically decomposed lecithin and polyglycerin fatty acid ester, A method for suppressing the reaction is disclosed (for example, see Patent Document 2).

JP 2012-36094 A JP 2007-22928 A

Chem. Central. J, 2012. 6, 57

  However, the adjustment liquid composition described in Patent Document 1 is merely a mixture of PQQs added to oil and fat and stirred with a mixer. Even if PQQs are stably dispersed in edible oils and fats, In the coexisting environment, PQQs may be immediately dissolved in water. Therefore, discoloration derived from PQQs cannot be suppressed in an aqueous environment or an environment in which water and fats and oils coexist.

  In addition, discoloration derived from PQQs is caused by contact of PQQs with proteins and hydrolysates thereof, and substances used for discoloration suppression must have low reactivity with PQQs, but are derived from PQQs. A compound that suppresses discoloration and has low reactivity is not known. Furthermore, as in Patent Document 2, even if PQQs are coated, discoloration due to contact with a protein or a decomposition product thereof is not sufficient.

  Furthermore, in recent years, many functional foods and pharmaceuticals have been used that break up tablets in the mouth called chewable tablets. Such chewable tablets, candies and gums stay in the mouth for a long time. In this way, functional foods and medicines that stay in the mouth for a long time come into contact with saliva and meal residues, the tongue, and tissues in the mouth for a long time. PQQs tend to change color from red to green, blue, and black when present in the mouth for a long time. The cause of this is amino acids and proteins caused by diet and physical condition, and colors tissues such as saliva and tongue. Therefore, in such applications, there is a need for PQQ-containing substances that are unlikely to discolor even when left in contact with saliva and meal residues or tissues in the tongue or mouth for a long time.

  In addition, when PQQs are used by being added to food materials, they are often consumed at the same time as PQQs and protein or peptide components having many amino groups. Therefore, even in such applications, there is a demand for PQQ-containing materials that do not easily cause discoloration even when the PQQ-containing materials and these components come into contact with each other.

  In view of the above problems, the present invention is less likely to cause discoloration even when physically contacted with a protein or peptide component, or tissue in the tongue or mouth for a long time, and is excellent in storage stability and tableting property. It is an object of the present invention to provide a coating powder containing pyrroloquinoline quinones, a method for producing the same, and a composition containing the coating powder.

  Furthermore, the manufacturing method of the substance which has this effect was also made into the subject.

  The present inventors have intensively studied to solve the above problems. As a result, by covering the PQQs with a hydrophobic membrane and an oily membrane, the elution rate of the PQQs from the inside of the membrane to the outside of the membrane is suppressed, and the PQQs existing in the nucleus and the proteins and peptides It has been found that the above-mentioned problems can be solved by suppressing contact with sex components and tissues in the tongue and mouth, and the present invention has been completed.

That is, the present invention is as follows.
[1]
A nucleus containing pyrroloquinoline quinones,
A first coating layer covering at least a part of the surface of the core and containing a poorly water-soluble substance;
A coating powder comprising: a second coating layer which covers at least a part of the surface of the first coating layer and contains fats and oils.
[2]
The coated powder according to [1] above, comprising at least one selected from the group consisting of ascorbate and calcium phosphate compounds.
[3]
The coated powder according to [1] or [2] above, wherein the core contains at least one selected from the group consisting of an ascorbate and a calcium phosphate compound.
[4]
The coating powder according to any one of [1] to [3], wherein at least one of the core, the first coating layer, and the second coating layer contains a fatty acid salt having 10 or more carbon atoms.
[5]
A composition comprising the coating powder according to any one of [1] to [4] above.
[6]
A step (A) of forming a first coating layer by coating at least part of the surface of the nucleus containing pyrroloquinoline quinones with a poorly water-soluble substance;
And (B) a step of coating at least a part of the surface of the first coating layer covering the core with fats and oils.
[7]
In the said process (A), the said core contains at least 1 sort (s) chosen from the group which consists of an ascorbate and a calcium phosphate type compound, The manufacturing method of the coating powder of the preceding clause [6].

  According to the present invention, when used in foods, cosmetics, and medicines, discoloration hardly occurs even after prolonged contact with protein or peptide components and tissues in the tongue or mouth (hereinafter referred to as “discoloration suppression”). It is also an object of the present invention to provide a coating powder containing pyrroloquinoline quinones, a method for producing the same, and a composition containing the coating powder, which are excellent in storage stability.

It is a figure which shows the result of the elution test in an Example.

  DESCRIPTION OF EMBODIMENTS Hereinafter, a mode for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described in detail. However, the present invention is not limited to this, and various modifications can be made without departing from the gist thereof. Is possible.

[Coating powder]
The coating powder according to this embodiment is
A nucleus containing pyrroloquinoline quinones (hereinafter also referred to as “PQQs”);
A first coating layer covering at least a part of the surface of the core and containing a poorly water-soluble substance;
A second coating layer that covers at least a part of the surface of the first coating layer and contains fats and oils.

[Nuclear]
The nucleus is not particularly limited as long as it contains pyrroloquinoline quinones, and may contain other additives. Other additives include, but are not particularly limited to, for example, excipients, ascorbates, calcium phosphate compounds, and active ingredients such as various vitamins within a range that does not cause a decrease in content by contact with PQQ. May be included.

(Pyrroloquinoline quinones)
PQQs are not particularly limited. For example, oxidized pyrroloquinoline quinone represented by formula (2), reduced pyrroloquinoline quinone represented by formula (3), oxidized or reduced pyrroloquinoline Examples include quinone salts, pyrroloquinoline quinone esters, and hydrates and solvates of the above compounds. The PQQs include any combination of PQQ, an ester of PQQ, and a salt of PQQ. That is, monoalkyl ester dicarboxylate, dialkyl ester monocarboxylate, and the like are also included.

(In formulas (2) and (3), each R ¹ is independently an alkali metal such as sodium or potassium; an alkaline earth metal such as magnesium or calcium; an organic amine such as ammonium, triethanolamine or trimethylamine; And a basic amino acid such as arginine; a monovalent organic group such as an alkyl group, an aralkyl group, an alkylaryl group, an alkenyl group, or an alkynyl group.)

  Among the pyrroloquinoline quinones represented by the formulas (2) and (3), the free form, sodium salt, and potassium salt of pyrroloquinoline quinone are easy to use because of easy production, and more preferably disodium salt. is there.

  Although it does not specifically limit as said salt of PQQ, For example, the alkali salt of three carboxylic acids which exist in PQQ may be sufficient, and the acid salt of pyridine or a pyrrole may be sufficient. Further, the salt of PQQ may be, for example, a monocarboxylate, a dicarboxylate, or a tricarboxylate, and the monocarboxylate may be any carboxylic acid salt. May be any combination of salts as long as they are salts of two carboxylic acids.

  Examples of the method for producing a salt of PQQ include a method of producing a salt by adding an appropriate amount of a corresponding acid or base to PQQ by a conventionally known method, and is not particularly limited.

  A method for producing a PQQ triester is not particularly limited. For example, PQQ or a salt thereof is reacted with an alcohol under acidic conditions (JP-A-3-123781 and JP-A-3-145492). And a method of reacting PQQ or a salt thereof with an alkyl halide, halogenated aralkyl, halogenated alkylaryl, halogenated alkenyl, halogenated alkynyl or the like in the presence of a base.

  Moreover, a monoester body and a diester body can be obtained by partially hydrolyzing the triester body of PQQ obtained by the above method under acidic or basic conditions. In the ester formation reaction, partial esterification can be performed to obtain a monoester form or a diester form.

  PQQs may be used alone or in appropriate combination of two or more.

  The content of PQQs is preferably 0.1 to 99.8% by mass, more preferably 0.5 to 90.0% by mass, and still more preferably 1. It is 0-80.0 mass%. When the content of PQQs is 0.1% by mass or more, the amount of the coating powder becomes appropriate when the desired amount of PQQs is ingested, and the effects of PQQs tend to be exhibited better. Moreover, when content is 99.8 mass% or less, it exists in the tendency for the content of the poorly water-soluble substance and fats and oils which are a film agent to become suitable amount, and to show | coat covering performance favorably.

(Manufacturing method of PQQs)
Although it does not specifically limit as a manufacturing method of PQQs, For example, the method of organic-chemical synthesis | combination, or a fermentation method is mentioned. Among them, the fermentation method is, for example, a method for producing PQQ by culturing bacteria having methanol-assimilating ability and ability to produce PQQ using methanol as a carbon source.

  The ester of PQQ or the salt of PQQ can be synthesized according to a conventional method using PQQ thus obtained as a starting material. PQQs or salts thereof can be separated and purified from the reaction solution by a conventional method such as column chromatography, recrystallization method, or solvent extraction method. In addition, various means such as elemental analysis, NMR spectrum, IR spectrum, and mass spectrometry are used for identification.

(Excipient)
An excipient | filler means what has a pharmacologically inactive function which forms coating powder. The excipient is not particularly limited, and examples thereof include reducing sugar, dextrin, crystalline cellulose, powdered cellulose, maltitol, reduced palatinose, sorbitol, xylitol, erythritol, and starch. The excipient may be used alone or in combination of two or more.

(Ascorbate and calcium phosphate compounds)
The core preferably contains at least one selected from the group consisting of ascorbate and calcium phosphate compounds. By containing these compounds, the discoloration suppressing effect tends to be further improved.

  The ascorbate is not particularly limited, and examples thereof include alkali metal salts or alkaline earth metal salts of ascorbic acid such as sodium ascorbate and calcium ascorbate, and L, D, and racemates thereof. Among these, sodium ascorbate and calcium ascorbate are preferable. Ascorbate may be used alone or in combination of two or more.

  The calcium phosphate compound is not particularly limited as long as it is a compound in which phosphoric acid and calcium are chemically bound, and may be a hydrate. Examples of such calcium phosphate compounds include apatites such as calcium triphosphate (hydroxyapatite) and fluoroapatite (fluorapatite); calcium dihydrogen phosphate (primary calcium phosphate), calcium monohydrogen phosphate (dibasic calcium phosphate) ), Tricalcium phosphate (tricalcium phosphate), tetracalcium phosphate, or hydrates thereof. Among these, calcium triphosphate, calcium dihydrogen phosphate, and tricalcium phosphate are preferable, and tricalcium phosphate and tricalcium phosphate are more preferable. A calcium phosphate type compound may be used individually by 1 type, or may be used in combination of 2 or more types as appropriate.

  The Ca / P molar ratio of the calcium phosphate compound is preferably 0.2 to 4.0, more preferably 1.0 to 2.0. In addition, when the calcium phosphate compound used in the present embodiment is a hydrate, examples of the hydrate include 0.5 to 10 hydrate, and preferably a dihydrate. .

[First coating layer]
The first coating layer covers at least a part of the surface of the nucleus. Two or more first coating layers may be formed. The first coating layer is not particularly limited as long as it contains a poorly water-soluble substance, and may contain other additives. Although it does not specifically limit as another additive, For example, ascorbate, a calcium phosphate type compound, a fatty acid salt, etc. are mentioned. Hereinafter, each component will be described.

(Poorly water-soluble substance)
The first coating layer includes a poorly water-soluble substance. Here, the “poorly water-soluble substance” means a substance that requires 30 mL or more of water to dissolve 1 g of the substance at 25 ° C., or a substance that cannot dissolve 1 g in 30 mL of water at any temperature range. . As a method for determining whether or not it is a poorly water-soluble substance, the method described in Examples can be used.

  Further, the poorly water-soluble substance is not particularly limited, and examples thereof include zein, gum arabic, hydroxypropyl cellulose, polyvinyl pyrrolidone, and shellac. Among these, zein which is a poorly water-soluble protein is preferable. A poorly water-soluble substance may be used alone or in combination of two or more.

  The content of the hardly water-soluble substance is preferably 0.1 to 99.8% by mass, more preferably 5.0 to 94.5% by mass, and still more preferably 10% with respect to 100% by mass of the coating powder. 0.0 to 89.0% by mass. When the hardly water-soluble substance content is 0.1% by mass or more, the effect of the coating performance tends to be exhibited well. Moreover, when it is 99.8 mass% or less, the content of PQQs is appropriate, and the coating performance tends to be satisfactorily exhibited without taking in too much as the coating powder.

(Ascorbate and calcium phosphate compounds)
From the viewpoint of further improving the discoloration suppressing effect, the first coating layer preferably contains at least one selected from the group consisting of ascorbate and calcium phosphate compounds. Examples of ascorbate and calcium phosphate compounds include those similar to those described above.

(Fatty acid salt)
It is preferable that a 1st coating layer contains a fatty acid salt. By including the fatty acid salt, the film thickness uniformity of the coating layer can be further improved, and the outflow of the core component from the thin film thickness tends to be suppressed. The fatty acid salt is not particularly limited, and examples thereof include an alkali metal salt or an alkaline earth metal salt of a saturated or unsaturated fatty acid having 10 or more carbon atoms having a linear structure, a branched structure, or a ring structure. It is done. Specific examples thereof include calcium stearate and magnesium stearate.

[Second coating layer]
The second coating layer covers at least a part of the surface of the first coating layer. Note that two or more second coating layers may be formed. The second coating layer is not particularly limited as long as it contains fats and oils, and may contain other additives. Although it does not specifically limit as another additive, For example, ascorbate, a calcium phosphate type compound, a fatty acid salt, etc. are mentioned. Hereinafter, each component will be described.

(Oil and fat)
Oils and fats are preferably used in the pharmaceutical field, food field, cosmetic field, and the like. Such fats and oils are not particularly limited, and examples thereof include animal fats and oils, vegetable fats and oils, hydrocarbon oils, ester oils, and silicone oils. The oil may be liquid at normal temperature, semi-solid, or solid. Moreover, the refined deodorized oil which performed fats and oils processing, such as hardening, fractionation, and transesterification, may be sufficient as these fats. Fats and oils may be used alone or in combination of two or more.

  Although it does not specifically limit as said animal oil and fat, For example, beef tallow, lard, fish oil, squalene, mink oil, turtle oil, egg yolk oil, these hardened oils, etc. are mentioned. Although these fats and oils are not specifically limited, For example, they are often used especially in the field of food and cosmetics, and are used suitably in the said field | area.

  The vegetable oils and fats are not particularly limited. Examples include almond oil, avocado oil, cocoon oil, and hardened oils thereof. Although these fats and oils are not specifically limited, For example, they are often used especially in the foodstuff field, and are used suitably in the said field | area.

  The hydrocarbon oil is not particularly limited, and examples thereof include liquid paraffin, squalane, squalene, and petroleum jelly. Although these fats and oils are not specifically limited, For example, they are often used especially in the pharmaceutical field and the cosmetics field, and are used suitably in the said field | area.

  The ester oil is not particularly limited, and examples thereof include octyl decyl myristate, isopropyl palmitate, butyl stearate, cetyl isooctanoate, neopentyl glycol diisooctylate, and glyceryl triisooctylate. Although these fats and oils are not specifically limited, For example, they are often used especially in the cosmetics field, and are used suitably in the said field | area.

  Although it does not specifically limit as said silicone oil, For example, dimethyl polysiloxane, methylphenyl polysiloxane, methyl hydrogen polysiloxane, etc. are mentioned. Although these fats and oils are not specifically limited, For example, they are often used especially in the cosmetics field, and are used suitably in the said field | area.

  Although melting | fusing point of fats and oils is not specifically limited, Preferably it is 35 degreeC or more, More preferably, it is 40 degreeC or more, More preferably, it is 55 degreeC or more. Moreover, although the upper limit of melting | fusing point of fats and oils is not specifically limited, Preferably it is 80 degrees C or less. When the melting point is within the above range, the fluidity of the resulting coating powder is further improved, and secondary particles tend not to be formed during the production process. The fluidity of the coating powder can be evaluated by measuring the angle of repose.

  The content of fats and oils is preferably 0.1 to 99.8% by mass, more preferably 5.0 to 94.5% by mass, and still more preferably 10.0 to 100% by mass of the coating powder. It is -89.0 mass%. When the fat content is 0.1% by mass or more, the effect of the coating performance tends to be exhibited well. Moreover, when it is 99.8 mass% or less, the content of PQQs is appropriate, and the coating performance tends to be satisfactorily exhibited without taking in too much as the coating powder.

(Ascorbate and calcium phosphate compounds)
From the viewpoint of further improving the discoloration suppressing effect, the first coating layer preferably contains at least one selected from the group consisting of ascorbate and calcium phosphate compounds. Examples of ascorbate and calcium phosphate compounds include those similar to those described above.

(Fatty acid salt)
It is preferable that a 1st coating layer contains a fatty acid salt. By including the fatty acid salt, the film thickness uniformity of the coating layer can be further improved, and the outflow of nuclei from the thin film thickness tends to be suppressed. Examples of the fatty acid salt include those similar to the above.

〔Composition〕
The composition according to the present embodiment includes the above-described coating powder, and may include water, an organic solvent, and other additives that can be used in the following applications as necessary.

[Method for producing coating powder]
The manufacturing method of the coating powder according to the present embodiment,
A step (A) of forming a first coating layer by coating at least part of the surface of the nucleus containing pyrroloquinoline quinones with a poorly water-soluble substance;
A step (B) of coating at least a part of the surface of the first coating layer covering the core with fats and oils.

(Process (A))
Step (A) is a step of forming a first coating layer by coating at least part of the surface of the nucleus containing pyrroloquinoline quinones with a poorly water-soluble substance. Specifically, a method of forming a nucleus containing pyrroloquinoline quinones and, if necessary, optional components such as excipients, and coating the formed nucleus with a poorly water-soluble substance; The method of coating with a water-insoluble substance is not particularly limited. The raw material used for forming the nucleus is not particularly limited as long as it includes PQQs, and for example, a mixture of PQQs, excipients, binders and other optional components can be used. Hereinafter, the nucleus having the first coating layer obtained in the step (A) is also referred to as a granulated product.

  In the step (A), it is preferable that the nucleus includes at least one selected from the group consisting of ascorbate and a calcium phosphate compound. Specifically, it is preferable to use a mixture of at least one selected from the group consisting of PQQs, ascorbates and calcium phosphate compounds, and other optional components, as a raw material used for forming nuclei.

  Core formation and coating with poorly water-soluble substances are usually used in the pharmaceutical field, food field, cosmetics field, etc., fluidized bed granulator, stirred fluidized bed granulator with agitated blades attached to fluidized bed granulator , Fluidized-type granulators such as rolling-fluidized bed granulator equipped with rolling plates, Wurster-type fluidized-bed coating machine, stirring type granulation by stirring powder and adding binder into it A granulator, an extrusion granulator or the like that extrudes powder at a high pressure together with a binder can be used. The coating conditions are not particularly limited. For example, when performing using a fluidized bed granulator, it can be performed under known conditions.

  The average particle diameter of the particles after the first coating layer is formed by coating at least a part of the surface of the nucleus containing PQQ with a poorly water-soluble substance is preferably 1 to 1000 μm, more preferably 50 to It is 900 micrometers, More preferably, it is 100-800 micrometers. When the average particle size of the particles after forming the first coating layer is within the above range, the handling property tends to be excellent in the subsequent process for producing the final product. The average particle diameter of the particles after forming the first coating layer can be measured by a dry particle size distribution meter. In addition, the average particle diameter of the particles after forming the first coating layer can be appropriately adjusted according to the size of the nucleus and the thickness of the first coating layer.

(Process (B))
Step (B) is a step of coating at least part of the surface of the first coating layer covering the core obtained in the step (A) with oils and fats. Although it does not specifically limit as a coating method in a process (B), An oil-fat powder is made to contact and / or collide with the granulated material obtained at the process (A), and it is applied to at least one part of the surface of a 1st coating layer. Method 1 for fixing oils and fats for coating 1; Method for spraying oils and fats in a fluidized bed to the granulated product obtained in step (A) and coating at least part of the surface of the first coating layer with oils and fats 2 etc. are mentioned. Among these, Method 1 is preferable from the viewpoint that a uniform coating layer can be obtained.

  The fat powder used in Method 1 is preferably a hardened oil powder, and the average particle diameter of the fat powder is preferably 0.1 to 50 μm, more preferably 1 to 10 μm. The average particle size of the oil and fat powder can be measured by a dry particle size distribution meter.

  In Method 1, when the fat and oil powder is brought into contact with and / or collided with the first coating obtained in step (A), the weight mixing ratio of the fat and oil powder to the first coating (fat and fat powder / first coating) The product) is not particularly limited, and can be appropriately determined in consideration of the particle size ratio between the particle size of the first coating and the particle size of the hardened oil powder. For example, preferably 95: 5 to 60: 40, more preferably 70:30 to 90:10. The contact and / or collision between the first coating and the hardened oil powder in Method 1 can be performed using a known powder contacting device such as a high efficiency powder mixing device. The contact and / or collision conditions in Method 1 are not particularly limited. For example, when the oil powder is not completely melted but the surface of the oil powder is melted and contacted and / or collided, the first coating layer is used. The condition that oils and fats adhere to at least a part of the surface of the resin is mentioned.

  The liquid spraying of fats and oils on the first coating in the method 2 can be performed using a device that sprays on a known powder such as a fluidized bed granulator. In Method 2, the conditions for spraying the oil and fat in the fluidized bed are not particularly limited as long as they do not form a lump.

  The coating powder of the present invention is a coating obtained by the above production method, and the coating is formed on at least a part of the surface of the core containing PQQs, on the hardly water-soluble substance layer and at least a part of the outer surface thereof. The oil and fat layer is provided. The average particle size of the obtained coating powder is preferably 1 to 1000 μm, more preferably 50 to 900 μm, and still more preferably 100 to 800 μm in order to have excellent coating performance. When the average particle diameter of the coating powder is within the above range, the handling property tends to be excellent in the subsequent process for producing the final product. The average particle diameter of the coating powder can be measured with a dry particle size distribution meter.

  In the step (A) and / or the step (B), it is preferable to use a fatty acid salt from the viewpoint of preventing coalescence of particles in the step and improving the film thickness uniformity of the coating layer. A specific operation for adding the fatty acid salt includes a method of adding the powder as it is. Among these, it is preferable to use a fatty acid salt in the step (A). The upper limit of the number of carbon atoms of the fatty acid salt is not particularly limited, but is preferably 40 or less.

  In the step (B), it is preferable to further add at least one selected from the group consisting of an ascorbate and a calcium phosphate compound. A specific operation includes a method of adding the powder as it is.

  The coating powder according to this embodiment and the composition containing the coating powder are not easily discolored and are stable. Moreover, the improvement of the moldability at the time of tableting as a secondary effect and the improvement of bioabsorbability can be expected. The coated powder and composition according to this embodiment can actually be used as a compression-molded tablet, powder, or suspension. Necessary excipients, flavors, surfactants, and sweeteners can be used as necessary.

[Use]
The coated powder obtained in the present embodiment and the composition containing the coated powder can be used as foods, functional foods, pharmaceuticals or quasi drugs for humans or animals. The functional food here means foods taken for the purpose of maintaining health or supplementing nutrition instead of dietary foods such as health foods, nutritional supplements, functional nutritional foods, and nutrition insurance foods. Specific forms include, but are not limited to, capsules, tablets, chewable tablets, drinks and the like.

  When commercialized as a functional food, additives used in food, such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, coloring agents, bleaching agents, antibacterial and antifungal agents, gum bases Bitterings, enzymes, brighteners, acidulants, seasonings, emulsifiers, fortifiers, manufacturing agents, fragrances, spice extracts and the like can be used. In general, it can also be added to ordinary foods such as miso, soy sauce, instant miso soup, ramen, fried noodles, curry, corn soup, merbaudofu, marvo eggplant, pasta sauce, pudding, cake, bread and the like.

  The mode of administration when used as a pharmaceutical or quasi drug is not particularly limited, and examples thereof include oral administration and parenteral administration such as intravenous, intraperitoneal, subcutaneous, or transdermal. The dosage form is not particularly limited. For example, tablets, powders, granules, pills, suspensions, emulsions, soaking / decoction, capsules, syrups, solutions, elixirs, extracts, tinctures, flow Extracts, injections, drops, creams, suppositories and the like can be mentioned.

  In particular, when used as a tablet, the coating powder of the present invention may be molded alone or various additives may be added. Preferably, various excipients, lubricants and the like are added to the coated powder of the present invention for tableting. As a manufacturing method of a tableting molded object, the method of carrying out direct compression molding can be used, for example. Specifically, there is a method in which powders of respective components are mixed as uniformly as possible and directly fed to a tableting machine for tableting. Although it does not specifically limit as this tableting machine, Tableting machines, such as rotary tableting machine collect 12HU (made by Kikusui Seisakusho), are mentioned, It can shape | mold by a low pressure. As the pressure, for example, it is possible to mold at a pressure of about 1 to 3 t.

  The tablet hardness of the tableting product obtained in this way is 3 to 20 kgf, preferably 5 to 15 kgf. When the tablet hardness is higher than 3 kgf, it is preferable that the obtained molded product is not easily broken on the production line or in the distribution process. In addition, when the tablet hardness is lower than 20 kgf, the texture is preferable without being too hard, and the content does not easily dissolve, so that the absorption rate tends to be suitable, which is preferable.

  The size of the molded body thus obtained is not particularly limited, but is preferably selected as appropriate depending on the amount of PQQ ingested, the amount of other compounds, and the number of times of ingestion. For example, from the point of taking, the size of one tablet is usually preferably 5 to 20 mm in diameter, and the weight is preferably 200 to 2000 mg. The shape of the molded body is not particularly limited, although there are various shapes such as a round shape, a square shape, a hexagon shape, a cylindrical shape, and a meteorite shape.

  When formulated as an oral preparation, it is not particularly limited. For example, excipients, binders, disintegrants, lubricants, dispersants, suspension agents, emulsifiers, diluents, buffers, antioxidants, bacteria Additives such as inhibitors can be used.

  When the coated powder obtained in this embodiment and the composition containing the coated powder are used as a liquid preparation suitable for oral administration, for example, a syrup, sugars such as water, sucrose, sorbitol, and fructose; Glycols such as polyethylene glycol and propylene glycol; oils such as sesame oil, olive oil and soybean oil; preservatives such as p-hydroxybenzoic acid esters; paraoxybenzoic acid derivatives such as methyl paraoxybenzoate; preservatives such as sodium benzoate; It can be formulated by adding flavors such as strawberry flavor and peppermint.

  In addition, when the coated powder obtained in this embodiment and the composition containing the coated powder are suitable for oral administration, for example, as tablets, powders, granules, etc., there are no particular limitations, but for example, lactose, glucose Sugars such as sucrose, mannitol and sorbitol; starches such as potato, wheat and corn; inorganic substances such as calcium carbonate, calcium sulfate, sodium hydrogen carbonate and sodium chloride; plant powders such as crystalline cellulose, licorice powder and gentian powder Forming agents: starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, sodium hydrogen carbonate, sodium alginate, etc .; magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil Lubricants such as polyvinyl alcohol It may be formulated with the addition of glycerin plasticizers such like; surfactants such as fatty acid esters; hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carmellose, gelatin, binding agents of the starch glue solution and the like.

  Moreover, when using the coating powder obtained by this embodiment and the composition containing this coating powder as a formulation for oral administration, the additive generally used for food-drinks, for example, a food sweetener, a coloring agent, a preservative , Thickeners, antioxidants, color formers, bleaches, fungicides, gum bases, bitters, enzymes, brighteners, acidulants, seasonings, emulsifiers, fortifiers, manufacturing agents, fragrances, spice extracts Etc. may be added. Formulations suitable for oral administration may be as they are or in the form of, for example, powdered foods, sheet foods, bottled foods, canned foods, retort foods, capsule foods, tablet foods, liquid foods, drinks, etc. It may also be used as a food or drink such as health food, functional food, nutritional supplement.

  EXAMPLES Hereinafter, although an Example and a comparative example demonstrate this invention further in detail, this invention is not limited to these.

[Method for determining poorly water-soluble substances]
After the substance was solid or powdered, it was placed in a predetermined amount of water, and when it was vigorously shaken at 25 ° C. every 5 minutes for 30 seconds, a substance that did not dissolve within 30 minutes was determined as a poorly water-soluble substance. In this judgment test, the fact that a substance is soluble in a solvent means that the substance is clearly mixed.

[Dissolution test]
The dissolution property of the components contained in the core of the coated powder in water was evaluated according to the method defined by “Japanese Pharmacopoeia 6.10 Dissolution Test Method”. 900 mL purified water was used as the test solution, the detection wavelength was 259 nm, and the amount of powder sample was 20 mg based on PQQ disodium. As a powder sample, the powder obtained by Example 1, Example 7, and the comparative example 1, and PQQ disodium powder (Mitsubishi Gas Chemical Co., Ltd. make, brand name: BioPQQ, and the same below) were used. The results are shown in FIG.

[Contact test 1]
Inhibition of discoloration due to contact of the powders obtained in Examples and Comparative Examples and PQQ disodium powder with amino acids or proteins was evaluated by a discoloration test using amino acids (contact test 1). A 2 mg powder sample was placed in a container and mixed with 2 mL of a 10% by weight aqueous solution of bactotryptone as an amino acid source. After mixing, the mixture was allowed to stand for 30 minutes in an environment of 30 ° C. Thereafter, 100 μL was sampled, and the absorbance at 450 nm was measured with a plate reader (manufactured by PerkinElmer, product name ARVO X3). Moreover, the change of the color visually was described. The results are shown in Table 1.

[Contact test 2]
Suppression of discoloration due to contact of the powders obtained in Examples and Comparative Examples and PQQ disodium powder with amino acids or proteins was evaluated by a discoloration test (contact test 2) when placed on the tongue. Meat pork tongue was cut to a length of 3 cm and used as a source of amino acids and protein. 10 mg of the powder obtained in Examples and Comparative Examples was placed on the tongue and wrapped. In this state, it was left at 37 ° C. for 1 hour. Thereafter, the tongue was washed with tap water and the degree of discoloration was observed. The results are shown in Table 1.

[Example 1 Preparation of coated powder]
360 g PQQ disodium powder and 150 g crystalline cellulose (Asahi Kasei Chemicals Co., Ltd., trade name: Theolas UF-F702, the same shall apply hereinafter) Fluidized bed granulator (Freund Sangyo Co., Ltd., trade name: Flow Coater Mini, hereinafter) In the same manner), a coating solution in which 90 g of zein (manufactured by Kobayashi Fragrance Co., Ltd., trade name: Kobayashi Zein DP) is dissolved in 360 g of hydrous ethanol (purified water / ethanol = 30/70 (v / v)) is sprayed. 565 g of zein-coated powder was obtained. The operating conditions were an air supply temperature: 75 ° C., an air supply amount: 1 m ³ / min, a rotor rotation speed: 300 rpm, and a spray liquid speed: 15 g / min.

  Next, 450 g of the obtained zein-coated powder is again charged into the fluidized bed granulator, 90 g of rapeseed oil (melting point: 36 ° C., manufactured by NOF Corporation) is added, and the oil and fat is sprayed in the fluidized bed in a liquid state. A coated powder was obtained. Table 1 shows the results of the dissolution test and the contact test using the obtained coating powder.

[Example 2]
360 g of PQQ disodium powder and 210 g of crystalline cellulose were charged into a fluidized bed granulator, and 30 g of hydroxypropylcellulose (hereinafter also referred to as “HPC”, manufactured by Nippon Soda Co., Ltd., trade name: Celny L) was added to hydrous ethanol (purified water). / Ethanol = 30/70 (v / v)) The coating solution dissolved in 600 g was sprayed to obtain 574 g of HPC-coated powder. The operating conditions were the same as in Example 1.

  Subsequently, 450 g of the obtained HPC-coated powder was charged into a stirring granulator (trade name: OMD-3 type, manufactured by Nara Machinery Co., Ltd.), and rape extremely hardened oil (melting point 68 ° C., manufactured by NOF Corporation) 90 g Part of the surface of the oil / fat powder was melted, and the oil / fat powder and the zein-coated powder were brought into contact with and / or collided to obtain a coated powder. The operating conditions were an in-machine temperature of 20 ° C., a spindle speed of 500 rpm, a countershaft speed of 1000 rpm, and a stirring time of 10 minutes. The results of contact tests using the obtained coating powder are shown in Table 1.

Example 3
A coated powder was obtained in the same manner as in Example 2 except that a coating solution obtained by dissolving 30 g of gum arabic (Sanei Pharmaceutical Trading Co., Ltd., trade name: Arabic Coal SS) in 600 g of purified water was used. The results of contact tests using the obtained coating powder are shown in Table 1.

Example 4
Charge 513 g of reduced palatinose (Mitsui Sugar Co., Ltd., trade name: Palatinit) to a fluidized bed granulator (Freund Sangyo Co., Ltd., trade name: Spiraflow), and dissolve 48 g of PQQ disodium powder in 408 g of purified water. The solution thus obtained was sprayed to obtain 510 g of PQQ-containing powder.

  500 g of the obtained PQQ-containing powder was again charged into a fluidized bed granulator, 26.7 g of zein and 8.1 g of calcium stearate (trade name: calcium stearate (vegetable) manufactured by Taihei Chemical Sangyo Co., Ltd.) with water-containing ethanol ( The coating solution dissolved in 170 g of purified water / ethanol = 30/70 (v / v) was sprayed to obtain 510 g of zein-coated powder.

  Next, 450 g of the obtained zein-coated powder was charged into an agitation granulator (trade name: OMD-3 type, manufactured by Nara Machinery Co., Ltd.), and rapeseed extremely hardened oil (melting point 68 ° C., manufactured by NOF Corporation) 64 .3 g was added and stirred to obtain a coated powder. The operating conditions were the same as in Example 1. The results of contact tests using the obtained coating powder are shown in Table 1.

Example 5
A coated powder was obtained in the same manner as in Example 1 except that 150 g of sodium ascorbate (DSM Nutrition Japan Co., Ltd., sodium ascorbate crystal) was used instead of crystalline cellulose. The results of contact tests using the obtained coating powder are shown in Table 1.

Example 6
In Example 1, a coated powder was obtained by the same operation as in Example 1 except that 15 g of 150 g of crystalline cellulose was replaced with tricalcium phosphate (manufactured by Taihei Chemical Industrial Co., Ltd., tricalcium phosphate). . The results of contact tests using the obtained coating powder are shown in Table 1.

Example 7
In Example 2, a coated powder was obtained in the same manner as in Example 2 except that 15 g of 210 g of crystalline cellulose was replaced with tricalcium phosphate. Table 1 shows the results of the dissolution test and the contact test using the obtained coating powder.

[Comparative Example 1]
405 g of PQQ disodium powder and 45 g of zein were mixed. Next, 400 g of the obtained zein mixed powder was charged into an agitation granulator (trade name: OMD-3 type, manufactured by Nara Machinery Co., Ltd.), and rapeseed extremely hardened oil (melting point: 68 ° C., manufactured by NOF Corporation) 50 g Was added and stirred to obtain a powder. The operating conditions were the same as in Example 2. Table 1 shows the results of the dissolution test and the contact test using the obtained powder.

[Comparative Example 2]
PQQ disodium powder 450 g and crystalline cellulose 210 g were charged into a fluidized bed granulator (Freund Sangyo Co., Ltd., trade name: Flow Coater Mini), and zein 90 g was mixed with hydrous ethanol (purified water / ethanol = 30/70 (v / v)) A coating solution dissolved in 360 g was sprayed to obtain 565 g of zein-coated powder. The operating conditions were the same as in Example 1. The results of contact tests using the obtained zein-coated powder are shown in Table 1.

(Evaluation criteria for degree of discoloration)
+: Not discolored ++: Almost discolored +++: Slightly discolored +++++: Discolored slightly +++++: Discolored (evaluation criteria for comprehensive evaluation)
A: Absorbance is less than 1 in contact test 1, and discoloration degree is + in contact test 2.
A: Absorbance is less than 1 in contact test 1, and color change degree is ++ to +++++ in contact test 2.
X: Absorbance is 1 or more in the contact test 1, and the degree of color change is ++ to +++++ in the contact test 2.

  From the above results, it was found that the coating powders of Examples 1 to 7 were difficult to dissolve the core component in the aqueous solution containing amino acids and hardly changed the color of the aqueous solution. Moreover, it turned out that the coating powder of Examples 1-7 is hard to discolor a tongue also when it physically contacts on a tongue. Among these, it was found that Example 4 using calcium stearate, Example 5 using sodium ascorbate, and Examples 6 and 7 using tricalcium phosphate were particularly excellent in discoloration suppressing effect. That is, it was shown that the coating powder of the present invention has a slow elution rate of the core component and a high effect of suppressing coloring.

  Comparative Example 1 is an example in which only the fats and oils are coated on PQQs, but they are inferior in terms of elution in an aqueous solution containing amino acids. Comparative Example 2 is an example in which only a poorly water-soluble substance is coated on PQQs, but it is inferior in terms of the degree of discoloration when placed on the tongue.

[Tablet testing]
(Examples 8 to 14)
20% by mass of the coating powder obtained in each of Examples 1 to 7, 15% by mass of crystalline cellulose (made by Asahi Kasei) as an excipient, 63% by mass of lactose monohydrate (manufactured by Wako Pure Chemical Industries), and lubricant 2% by mass of sucrose fatty acid ester (Mitsubishi Chemical Foods) was mixed for 10 minutes with a mixer (V-2, manufactured by Tokuju Kosakusho).

  The obtained mixture was obtained with a rotary tableting machine (Correct 12HU (manufactured by Kikusui Seisakusho)), and a tablet of 300 mg was obtained at a setting of 30 rpm with a turntable rotation speed of 碁 φ 9 mm and a meteorite type (15R). The molded product obtained from the coated powder of Example 1 was obtained in Example 8, the molded product obtained from the coated powder in Example 2 was used in Example 9, and the molded product obtained from the coated powder in Example 3 was used in Example 10. The molded body obtained from the coating powder of Example 4 is the Example 11, the molded body obtained from the coating powder of Example 5 is the Example 12, and the molded body obtained from the coating powder of Example 6 is the Example. 13. A molded product obtained from the coating powder of Example 7 is referred to as Example 14. In tableting, tableting troubles such as capping, lamination and sticking did not occur, and a good molded article could be obtained.

(Examples 15 to 19)
20 mg of the coating powder obtained in Examples 1, 4, 5, 6, and 7 was packed in each mold, and Ichihashi Seiki Co., Ltd. HANDTAB-100 (R) 8 mm tablet mold was used and a pressure of 10 kN was applied. Thereafter, the pressure was immediately reduced and the molded body was taken out from the molding machine. The molded body obtained from the coated powder of Example 1 was applied to the molded body obtained from the coated powder of Example 15 and Example 4, the molded body obtained from the coated powder of Example 16 and Example 5. The molded bodies obtained from the coated powders of Example 17 and Example 6 are referred to as Example 18 and the molded bodies obtained from the coated powder of Example 7 are referred to as Example 19. As a result, it was possible to form tablets with the coating powder alone.

(Comparative Examples 3 and 4)
Using the powders of Comparative Examples 1 and 2, the same operations as in Examples 8 to 14 were performed to obtain molded bodies. The molded body obtained from the coated powder of Comparative Example 1 is referred to as Comparative Example 3 and the molded body obtained from the coated powder of Comparative Example 2 is referred to as Comparative Example 4.

(Comparative Example 5)
Using the uncoated PQQ disodium powder, the same operation as in Examples 8 to 14 was performed to obtain a molded body (Comparative Example 5). In addition, although PQQ disodium powder alone could be formed into a tablet, it was found that corners were missing at room temperature immediately after molding, and it was easily broken.

  As in Table 1, the molded bodies of Examples 8 to 19 obtained were light green, the molded bodies of Comparative Examples 3 to 4 were green, and the molded body of Comparative Example 5 was dark green.

[Storage stability test]
Using the coating powder obtained in Example 4, an accelerated test (stored in an aluminum bag under an environment of 40 ° C. and 75% Rh) was performed, and then the PQQ content of the coating powder was measured under the following conditions using HPLC. did. As a result, the PQQ content in accelerated 3 months (equivalent to normal temperature 1 year and a half) was 101.4% with respect to the initial value. Thereby, it was shown that the coating powder which concerns on this invention is excellent in storage stability.
HPLC conditions:
Shimadzu LC-2010
Column: YMC-Pack ODS-A
Detection wavelength: 259 nm
Mobile phase: 30 mM acetic acid-70 mM ammonium acetate Column temperature 40 ° C.

  The coated powder according to the present invention has industrial applicability in the pharmaceutical field, food field, cosmetic field and the like.

Claims (7)

A nucleus containing pyrroloquinoline quinones,
A first coating layer covering at least a part of the surface of the core and containing a poorly water-soluble substance;
A coating powder comprising: a second coating layer which covers at least a part of the surface of the first coating layer and contains fats and oils.   The coating powder according to claim 1, comprising at least one selected from the group consisting of ascorbate and a calcium phosphate compound.   The coated powder according to claim 1 or 2, wherein the core contains at least one selected from the group consisting of an ascorbate and a calcium phosphate compound.   The coating powder according to any one of claims 1 to 3, wherein at least one of the core, the first coating layer, and the second coating layer contains a fatty acid salt having 10 or more carbon atoms.   The composition containing the coating powder of any one of Claims 1-4. A step (A) of forming a first coating layer by coating at least part of the surface of the nucleus containing pyrroloquinoline quinones with a poorly water-soluble substance;
And (B) a step of coating at least a part of the surface of the first coating layer covering the core with fats and oils.   The manufacturing method of the coating powder of Claim 6 in which the said nucleus contains at least 1 sort (s) chosen from the group which consists of an ascorbate and a calcium phosphate type compound in the said process (A).