WO2017061627A1 - ポリフェノール含有固体組成物 - Google Patents
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- WO2017061627A1 WO2017061627A1 PCT/JP2016/080036 JP2016080036W WO2017061627A1 WO 2017061627 A1 WO2017061627 A1 WO 2017061627A1 JP 2016080036 W JP2016080036 W JP 2016080036W WO 2017061627 A1 WO2017061627 A1 WO 2017061627A1
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- polyphenol
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- curcumin
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Definitions
- the present invention relates to a polyphenol-containing solid composition and the like.
- Polyphenols typified by curcumin are said to have physiological effects such as cholesterol elevation inhibitory action, blood pressure elevation inhibitory action, blood glucose elevation inhibitory action, antiallergic action, and body fat inhibitory action.
- physiological effects such as cholesterol elevation inhibitory action, blood pressure elevation inhibitory action, blood glucose elevation inhibitory action, antiallergic action, and body fat inhibitory action.
- Polyphenols are components contained in edible plants and the like, and can be ingested even in ordinary meals. However, it is convenient and efficient to ingest in the form of a solid composition such as a tablet containing the same. .
- Patent Document 1 proposes an oral composition containing a curcuminoid and a turmeric essential oil.
- further development of new technology is required from the viewpoint of efficient intake of polyphenols.
- An object of the present invention is to provide a polyphenol-containing solid composition that enables efficient intake of polyphenol.
- the present inventors aim to solve the above problems by a polyphenol-containing solid composition with improved elution of polyphenols into the intestinal fluid.
- Amorphous poorly water-soluble polyphenol By the solid composition containing (2) hydrophilic polymer, and (3) one or more nonionic surfactants selected from the group consisting of polyglycerin fatty acid ester, sucrose fatty acid ester, and lecithin
- the present invention has been completed.
- the present invention includes the following aspects.
- Item 1 (1) Amorphous poorly water-soluble polyphenol, (2) A solid composition containing a hydrophilic polymer, and (3) one or more nonionic surfactants selected from the group consisting of polyglycerin fatty acid esters, sucrose fatty acid esters, and lecithin.
- Item 2. The solid composition according to Item 1, wherein the amorphous poorly water-soluble polyphenol is one or more selected from curcumin, silymarin, and luteolin.
- Item 3. Item 3.
- the solid composition according to Item 1 or 2 wherein the hydrophilic polymer is one or more selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose.
- Item 4. Item 4.
- Item 5. The solid composition according to any one of Items 1 to 4, which is an oral preparation.
- Item 6. (1) crystalline polyphenol, Item 1 to Step including a step of kneading (2) a hydrophilic polymer and (3) one or more nonionic surfactants selected from the group consisting of polyglycerin fatty acid ester, sucrose fatty acid ester, and lecithin. 6. The method for producing a solid composition according to any one of 5 above.
- the solid composition of the present invention When the solid composition of the present invention is orally administered or ingested, it exhibits a high solubility of polyphenols in body fluids (preferably intestinal fluid) and is maintained for a long time, thereby enabling efficient ingestion of polyphenols. To. That is, according to the present invention, it is possible to provide a polyphenol-containing solid composition that enables efficient intake of polyphenol.
- Example 1 in comparison with a solid composition containing no nonionic surfactant (Comparative Example 1), a solubilized formulation (Comparative Example 2), and a solid composition prepared without heating (Comparative Example 3) It is a graph which shows the time-dependent change of the elution property to the artificial intestinal fluid of curcumin from a curcumin containing formulation. Time course of dissolution of silymarin from the silymarin-containing preparation of Example 10 into the artificial intestinal fluid in comparison with the solid composition containing no nonionic surfactant (Comparative Example 8) and the solubilized preparation (Comparative Example 9) It is a graph which shows a change.
- Time course of dissolution of luteolin from the luteolin-containing preparation of Example 11 into the artificial intestinal fluid in comparison with the solid composition containing no nonionic surfactant (Comparative Example 10) and the solubilized preparation (Comparative Example 11) It is a graph which shows a change.
- Time course of dissolution properties of curcumin from the preparation of Example 1 into artificial intestinal fluid in comparison with various nonionic surfactants (Comparative Examples 4 to 7) other than the nonionic surfactant used in the present invention It is a graph which shows a change.
- 6 is a graph showing changes with time of the dissolution properties of curcumin into artificial intestinal juice from curcumin-containing preparations (Examples 1 to 3) using various types of polyglycerol fatty acid esters.
- FIG. 6 is a graph showing changes over time in the dissolution properties of curcumin into artificial intestinal fluid from curcumin-containing preparations (Examples 1 and 6 to 9) using various nonionic surfactants. It is a graph which shows the time-dependent change of the blood curcumin density
- room temperature means a temperature within the range of 10 to 40 ° C.
- Solid composition The solid composition of the present invention comprises: (1) Amorphous poorly water-soluble polyphenol, (2) a hydrophilic polymer, and (3) one or more nonionic surfactants selected from the group consisting of polyglycerin fatty acid ester, sucrose fatty acid ester, and lecithin.
- the polyphenol contained in the solid composition of the present invention is “amorphous hardly water-soluble polyphenol”.
- the “slightly water-soluble polyphenol compound” in the present invention has a solubility in pure water at 25 ° C. of 0.1% by mass or less.
- the “slightly water-soluble polyphenol compound” in the present invention has an octanol / water partition coefficient (log P) in the range of ⁇ 1.0 to 4.0.
- the logP value can be determined by high performance liquid chromatography in accordance with JIS Z 7260-117 (2006).
- the logP value is defined by the following equation.
- polyphenol means a compound having two or more phenolic hydroxy groups in the same molecule.
- polyphenol of “amorphous poorly water-soluble polyphenol” contained in the solid composition of the present invention examples include the following.
- the following examples can be compounds or compositions. 1.
- Phenolic acid eg, hydroxycinnamic acid (eg, p-coumaric acid, caffeic acid, ferulic acid), hydroxybenzoic acid: (eg, p-hydroxybenzoic acid, gallic acid, ellagic acid), rosmarinic acid]
- Phenolic acid eg, hydroxycinnamic acid (eg, p-coumaric acid, caffeic acid, ferulic acid), hydroxybenzoic acid: (eg, p-hydroxybenzoic acid, gallic acid, ellagic acid), rosmarinic acid]
- Flavonoids eg, flavones (eg, luteolin, apigenin, flavoxate, diosmine, nobiletin), flavanones (eg, hesperetin, naringenin, hesperidin, hesperetin), flavanols (eg, quercetin, myricetin, simiralin, silymarin, silybinine, rutin, isoquercitol) , Flavan-3-ol, catechin (E), epicatechin (EC), theaflavin, epicatechin gallate (ECg), epigallocatechin (EGC), epigallocatechin gallate (EGCg), isoflavone (eg, genistein, daidzein) Anthocyanidins (eg, cyanidin, delphinidin, malvidin, pelargonidin, peonidin, proanthocyanidins, oligomeric proanthocyanidins
- Stilbenoids eg, resveratrol
- Tannins eg, condensed tannins (proanthocyanidins) and hydrolyzable tannins
- Monophenol eg, hydroxytyrosol, p-tyrosol
- Capsaicinoids eg, capsaicin, dihydrocapsaicin] 7
- Curcuminoids eg, curcumin (keto and enol), dimethoxycurcumin, bisdimethoxycurcumin], and tetrahydrocurcumin, 8).
- Preferred examples thereof include curcumin, silymarin, and luteolin.
- the solid composition of the present invention can contain one kind or two or more kinds of polyphenols.
- the polyphenol contained in the solid composition of the present invention may be, for example, a natural product-derived extract.
- a natural product-derived extract examples thereof are turmeric extract, milk thistle extract, coffee extract, licorice extract, cucumber extract, quette extract, gentian (or gentian) extract, ginger pepper extract, cholesterol and its derivatives, hawthorn extract, Peonies extract, Ginkgo biloba extract, Koganebana (or Ogon) extract, Carrot extract, Maikaika (or Maikai, Hermanus) extract, Sunpens (or Kawaraketsumei) extract, Tormentilla extract, Parsley extract, Button (Or buttonpi) extract, mokka (or bokeh) extract, Melissa extract, Yashajitsu (or Yasha) extract, Yukinoshita extract, rosemary (or Mannenrou) extract, lettuce extract, tea extract Products (eg, oolong tea extract, black tea extract, green tea) Kiss) include microbial fermentation metabolites, and Lo Han Guo
- the amorphous poorly water-soluble polyphenol includes curcumin.
- the content of the amorphous poorly water-soluble polyphenol in the solid composition of the present invention is preferably in the range of 1 to 50% by mass, more preferably in the range of 5 to 40% by mass, and still more preferably 10 to 30%. It is in the range of mass%.
- the solid composition of the present invention may contain crystalline polyphenol, but it is preferable that the amount or the ratio thereof relative to the whole solid composition or the total polyphenol is small.
- the amorphous state of the polyphenol contained in the solid composition of the present invention can be confirmed by a method such as powder X-ray diffraction or differential scanning calorimetry.
- the amount of amorphous polyphenol can be calculated from the peak area in differential scanning calorimetry.
- the polyphenol is the same as the polyphenol of “amorphous poorly water-soluble polyphenol” contained as an essential component in the solid composition of the present invention. Or some of them may be the same or different.
- the solid composition of the present invention is substantially or completely free of crystalline polyphenols.
- the content of all polyphenols (the “total polyphenols” include amorphous poorly water-soluble polyphenols and crystalline polyphenols) contained in the solid composition of the present invention is preferably 1 to 50% by mass More preferably, it is in the range of 5 to 40% by mass, and more preferably in the range of 10 to 30% by mass.
- the hydrophilic polymer used in the present invention does not need to be hydrophilic or water-soluble under any conditions, and preferably is hydrophilic or water-soluble at least at the pH in the intestinal tract. Good.
- the hydrophilic polymer used in the present invention is preferably solid at room temperature.
- the hydrophilic polymer used in the present invention preferably has a glass transition temperature (Tg) of about 50 ° C. or higher, more preferably in the range of about 80 ° C. to about 180 ° C.
- the glass transition temperature (Tg) can be determined according to JIS K 7121: 2012.
- the solid composition of the present invention can contain one kind or two or more kinds of hydrophilic polymers.
- hydrophilic polymers used herein include the following: (1) N-vinyl lactam (preferably N-vinyl pyrrolidone) homopolymer [eg, polyvinyl pyrrolidone (ie, PVP, or povidone) (eg, Kollidon TM 12PF, Kollidon TM 17PF, Kollidon TM 25, Kollidon TM 30 , Kollidon TM 90F, or equivalents thereof], and copolymers thereof (eg, N-vinyl pyrrolidone, and those containing vinyl acetate monomers (ie, copovidone), or N-vinyl pyrrolidone, and vinyl propionate) Including monomers)]; (2) Cellulose esters, and cellulose ethers, especially methylcellulose, ethylcellulose, (hydroxyalkyl) cellulose [eg, hydroxypropylcellulose (ie, HPC)], (hydroxyalkyl) alkyl-cellulose [eg, hydroxypropylmethylcellulose
- the solid composition of the present invention contains at least one hydrophilic polymer selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Further, other hydrophilic polymer may be contained. In a particularly preferred embodiment of the present invention, the solid composition of the present invention contains at least polyvinylpyrrolidone as the hydrophilic polymer, and may further contain other hydrophilic polymer.
- the hydrophilic polymer is at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose. In another particularly preferred embodiment of the present invention, the hydrophilic polymer is polyvinylpyrrolidone.
- the content of the hydrophilic polymer in the solid composition of the present invention is preferably within the range of 5 to 90% by mass, more preferably within the range of 20 to 90% by mass, and even more preferably within the range of 40 to 90% by mass. It is.
- the nonionic surfactant contained in the solid composition of the present invention is at least one nonionic surfactant selected from the group consisting of polyglycerin fatty acid ester, sucrose fatty acid ester, and lecithin.
- polyglycerin fatty acid ester used in the present invention examples include (a) polyglycerin having an average degree of polymerization of 2 or more (preferably 3 to 15, more preferably 3 to 10), and (b) having 8 to 18 carbon atoms.
- esters with fatty acids eg, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid).
- polyglycerol fatty acid esters used in the present invention include diglycerol monolaurate, diglycerol monostearate, diglycerol monooleate, decaglycerol monolaurate, decaglycerol monostearate, and decaglycerol monooleate.
- the polyglycerin fatty acid ester used in the present invention can be a single type or a combination of two or more types.
- the HLB value of the sucrose fatty acid ester used in the present invention is preferably 10 or more, and more preferably 12 or more.
- the carbon number of the fatty acid in the sucrose fatty acid ester used in the present invention is preferably 12 or more, and more preferably in the range of 12-20.
- Preferable specific examples of the sucrose fatty acid ester used in the present invention include sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose stearate, sucrose oleate, and sucrose behenate. And sucrose erucic acid ester.
- the sucrose fatty acid ester used in the present invention can be a single type or a combination of two or more types.
- Lecithin used in the present invention is a phosphoric acid derivative adduct of glycerin difatty acid ester (diglyceride) and is widely distributed in animals and plants.
- lecithin used in the present invention include egg yolk lecithin contained in egg yolk, soybean lecithin contained in soybean, and sunflower lecithin contained in sunflower.
- lecithin used in the present invention also include fractionated lecithin obtained by extracting an active ingredient from these lecithins, enzyme-treated lecithin obtained by treating lecithin with an enzyme, and enzyme-degraded lecithin.
- lecithin used in the present invention examples include lecithin, enzymatically decomposed lecithin (phosphatidic acid), lysolecithin, soybean lecithin (soybean phospholipid), and egg yolk lecithin.
- the lecithin used in the present invention is commercially available, and examples thereof include SLP-white (trade name, Sakai Oil Co., Ltd.).
- the lecithin used in the present invention can be a single type or a combination of two or more types.
- nonionic surfactant contained in the solid composition of the present invention include polyglycerol fatty acid esters.
- the solid composition of the present invention can contain one kind or two or more kinds of nonionic surfactants.
- the nonionic surfactant is a polyglycerol fatty acid ester.
- the content of the nonionic surfactant in the solid composition of the present invention is preferably in the range of 5 to 90% by mass, more preferably in the range of 5 to 60% by mass, and still more preferably 10 to 40% by mass. Is within the range.
- the solid composition of the present invention may optionally contain components other than the above components as long as the effects of the present invention are not significantly impaired.
- examples of such ingredients include excipients, fillers, bulking agents, binders, disintegrants, surfactants, seasonings, fragrances, and lubricants.
- the types and amounts of such components may be appropriately selected and designed based on common general knowledge as long as the effects of the present invention are not significantly impaired.
- the composition of the present invention can be used for foods, functional foods, dietary supplements (supplements), foods for specified health use, quasi drugs, and pharmaceuticals. .
- the solid composition of the present invention is preferably an oral preparation. Suitable examples of the form of the preparation include tablets, granules, powders, fine granules, granules, pills, and lozenges.
- the composition of the present invention may be a preparation material for these preparations.
- the administration or intake of the solid composition of the present invention may vary depending on the type of polyphenol, the age, weight, symptoms, dosage form, treatment period, etc. of the user.
- curcumin In the case of curcumin, according to the WHO Technical Report, ADI of curcumin is 0-3 mg / kg body weight / day, NOAEL: 250-320 mg / kg body weight / day (WHO Technical Report Series: 1237259778265_0.pdf, 33), within this range, it can be suitably administered or ingested once to several times a day (eg, twice, three times, four times, five times).
- the solid composition obtained by this invention can be added not only to uses, such as foodstuffs but to cosmetics etc., for example.
- cosmetics include skin care cosmetics such as lotions, creams, lotions, emulsions, and cosmetics, hair cosmetics such as shampoos, mouthwashes, and the like, and further restrict ingredients that are commonly used in the cosmetics field.
- surfactants include anions such as glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene fatty acid ester, carboxylate, and sulfonate.
- surfactants include anions such as glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene fatty acid ester, carboxylate,
- the solid composition of the present invention When the solid composition of the present invention is orally administered or ingested, it exhibits a high solubility of polyphenols in body fluids (preferably intestinal fluid) and is maintained for a long time, thereby enabling efficient ingestion of polyphenols.
- body fluids preferably intestinal fluid
- Method for producing a solid composition (1) crystalline polyphenol, (2) a hydrophilic polymer, and (3) one or more nonionic surfactants selected from the group consisting of polyglycerin fatty acid esters, sucrose fatty acid esters, and lecithins, and (4) other optionally used It is a manufacturing method including the process of mixing these components, Comprising: It can manufacture by the manufacturing method including the process of changing the said crystalline polyphenol into an amorphous
- the composition of this invention can be manufactured at low cost, without using a big container etc.
- the step of mixing the respective components and the step of changing the crystalline polyphenol into an amorphous state may be separate, a part of them may be common, or they may be completely common. Also good.
- the crystalline polyphenol is changed into an amorphous state at a higher ratio. It is particularly preferred that substantially all or all of the crystalline polyphenol changes to amorphous.
- the composition of the present invention can be produced by, for example, a solvent precipitation method, a spray drying method, a freeze drying method, a reduced pressure drying method, a kneading method, or a combination thereof.
- the composition of the present invention preferably has (1) crystalline polyphenol, (2) a hydrophilic polymer, and (3) one or more nonionic surfactants selected from the group consisting of polyglycerin fatty acid esters, sucrose fatty acid esters, and lecithins, and (4) other optionally used
- This component is produced by a production method including a step of kneading.
- the crystalline polyphenol, the hydrophilic polymer, and the nonionic surfactant are kneaded simultaneously.
- a part, preferably substantially all or all of the crystalline polyphenol is changed to amorphous.
- the kneading can be suitably performed by using, for example, a single screw extruder, a meshing screw extruder, or a multi-screw extruder (eg, a twin screw extruder), but using a spatula or the like on a hot plate. Kneading with a relatively weak force such as hand kneading can also be suitably performed.
- the components of the present invention are heated and kneaded to a temperature at which each component is melted, cooled to room temperature after each component is melted, and the resulting solid composition is pulverized into powder by a pulverizer You can get things.
- the primary particle size of the composition of the present invention is preferably in the range of 0.1 to 500 ⁇ m, for example.
- the composition of the present invention is preferably, for example, A step of preparing a slurry in which the polyphenol is dissolved by thoroughly mixing the crystalline polyphenol, the hydrophilic polymer, the nonionic surfactant, and an oil; and drying the slurry. It is manufactured by a method including steps. Examples of the drying method include a spray drying method, a freeze drying method, a vacuum drying method, a drum drying method, and a far-infrared drying method, and the spray drying method is particularly preferable.
- CUR Curcumin SIL: Silymarin LUT: Luteolin
- PVP Polyvinylpyrrolidone
- PGFE Polyglycerol fatty acid ester
- HPC Hydroxypropyl cellulose
- HPMC Hydroxypropyl methylcellulose
- Example preparation method Each composition was prepared by heating and kneading each composition having the composition described in Table 1-1, 1-2, or 1-3 described later to the melting temperature, and cooling to room temperature. The powder was used. However, in the preparation of the composition of Comparative Example 3, the components were mixed without being heated, and this was used as a test sample.
- the heat kneading was carried out by setting the hot plate at curcumin, silymarin at 240 ° C. and luteolin at 350 ° C., and then kneading by hand with a spatula until the composition was melted.
- PGFE (A) is a polyglyceryl myristate ester of HLB12.
- Curcumin raw material Purity: Curcumin 90% or more
- Koridon K30 (trade name, BASF): PVP (Polyvinylpyrrolidone) ⁇ Nonionic surfactant>
- Comparative Example 1 and Comparative Examples 4 to 7 it was confirmed that the crystalline curcumin peak was completely or partially disappeared by powder X-ray diffraction measurement, and amorphous curcumin was contained. confirmed.
- Comparative Example 2 it was confirmed by differential scanning calorimetry that the peak of crystalline curcumin decreased and amorphous curcumin was contained. Since the composition of Comparative Example 3 is simply a mixture, it is naturally assumed that this contains crystalline curcumin.
- Test Example 1-1 Using the samples shown in Table 2-1, the dissolution of curcumin into artificial intestinal fluid over time in comparison with solid compositions containing no surfactant, solubilized preparations, and solid compositions prepared without heating Changes were tested. The results are shown in Table 3-1 and FIG. 1-1. As will be understood from the above, the composition of the present invention exhibited a high dissolution property of polyphenols into body fluids (preferably intestinal fluid) and was maintained for a long time.
- Test Example 1-2 Using the samples shown in Table 2-2, changes over time in the dissolution properties of silymarin into artificial intestinal fluid in comparison with solid compositions containing no surfactant and solubilized preparations were tested. The results are shown in Table 3-2 and FIG. 1-2.
- the composition of the present invention exhibited a high dissolution property of polyphenols into body fluids (preferably intestinal fluid) and was maintained for a long time.
- Test Example 1-3 Using the samples shown in Table 2-3, changes over time in the dissolution properties of luteolin into artificial intestinal fluid in comparison with solid compositions containing no surfactant and solubilized preparations were tested. The results are shown in Table 3-3 and FIG. 1-3. As will be understood from the above, the composition of the present invention exhibited a high dissolution property of polyphenols into body fluids (preferably intestinal fluid) and was maintained for a long time.
- Test example 2 Using the samples shown in Table 4, the change with time of the dissolution properties of curcumin into artificial intestinal fluid in comparison with other nonionic surfactants was tested. The results are shown in Table 5 and FIG. As will be understood from this, only when a specific nonionic surfactant is used, the composition of the present invention exhibits a high solubility of polyphenols into body fluids (preferably intestinal fluids), and this is a long time. Maintained.
- Test example 3 The samples shown in Table 6 were tested for changes over time in the dissolution properties of curcumin into artificial intestinal fluid when various types of polyglycerol fatty acid esters were used. The results are shown in Table 7 and FIG. As will be understood from this, with various polyglycerin fatty acid esters, the composition of the present invention exhibited high elution of polyphenols into body fluids (preferably intestinal fluids) and was maintained for a long time.
- Test example 4 The samples shown in Table 8 were tested for changes over time in the dissolution properties of curcumin into artificial intestinal fluid when polyglycerol fatty acid esters were used in various amounts. The results are shown in Table 9 and FIG. As will be understood from this, even if the amount of polyglycerin fatty acid ester used is changed, the composition of the present invention exhibits a high solubility of polyphenols in body fluids (preferably intestinal fluid) and is maintained for a long time. It was.
- body fluids preferably intestinal fluid
- Test Example 5 The samples shown in Table 10 were tested for changes over time in the dissolution properties of curcumin into artificial intestinal fluid when sugar ester or lecithin was used in comparison with polyglycerin fatty acid esters. The results are shown in Table 11 and FIG. As understood from this, even when sugar ester or lecithin is used, the composition of the present invention is highly soluble in body fluid (preferably intestinal fluid) of polyphenol as in the case of using polyglycerol fatty acid ester. And was maintained for a long time.
- body fluid preferably intestinal fluid
- Test Example 6 A composition was prepared by the manufacturing method described above using HPC or HPMC instead of PVP, and a test similar to the above test was performed. As a result, compared to the case of using PVP, when HPC or HPMC was used, the elution of polyphenol into body fluids (preferably intestinal fluid) was low, but the same tendency as PVP was confirmed. Dissolution to body fluid (preferably intestinal fluid) was maintained for a long time.
- Test Example 7 By the following test method, the time-dependent change of the blood curcumin density
- curcumin bulk powder was administered.
- Animals 3 SD rats (male, 7 weeks old, fasted from 14 to 16 hours before administration) were used.
- Administration 100 mg / KG / single oral administration as curcumin (Sonte method)
- Blood collection Immediately before administration and 0.5, 1, 2, 4, 8, and 24 hours after administration, jugular vein blood collection Analysis: 25 ⁇ l of plasma was enzymatically treated with ⁇ -glucuronidase. Further, curcumin was extracted with acetonitrile, and then the solvent was dried. This was re-diluted with methanol and measured by UV detection (420 nm).
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Abstract
Description
ポリフェノールは、可食性植物等に含有する成分であり、通常の食事等でも摂取可能であるが、これを含有する錠剤等の固体組成物の形態で摂取することが、簡便、且つ効率的である。
しかし、ポリフェノールは難水溶性のものが多いので、これを含有する固体組成物を摂取しても、体液に溶出、および吸収される速度が遅い。
このような問題に関して、例えば、特許文献1では、クルクミノイドおよびターメリックの精油を含む経口用の組成物が提案されている。
しかし、ポリフェノールの効率的な摂取の観点からは、さらに新たな技術の開発が求められている。
(1)非晶質の難水溶性ポリフェノール、
(2)親水性ポリマー、および
(3)ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、およびレシチンからなる群より選択される1種以上の非イオン性界面活性剤
を含有する固体組成物
によって、前記課題が解決できることを見出し、本発明を完成するに至った。
(1)非晶質の難水溶性ポリフェノール、
(2)親水性ポリマー、および
(3)ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、およびレシチンからなる群より選択される1種以上の非イオン性界面活性剤
を含有する固体組成物。
項2.
前記非晶質の難水溶性ポリフェノールが、クルクミン、シリマリン、及びルテオリンからなるより選択される1種以上である項1に記載の固体組成物。
項3.
前記親水性ポリマーが、ポリビニルピロリドン、ヒドロキシプロピルセルロース、およびヒドロキシプロピルメチルセルロースからなる群より選択される1種以上である項1又は2に記載の固体組成物。
項4.
前記非イオン性界面活性剤が、ポリグリセリン脂肪酸エステルである項1~3のいずれか一項に記載の固体組成物。
項5.
経口用製剤である項1~4のいずれか一項に記載の固体組成物。
項6.
(1)結晶質のポリフェノール、
(2)親水性ポリマー、および
(3)ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、およびレシチンからなる群より選択される1種以上の非イオン性界面活性剤
を、混練する工程を含む
項1~5のいずれか一項に記載に記載の固体組成物の製造方法。
すなわち、本発明によれば、ポリフェノールの効率的な摂取を可能にするポリフェノール含有固体組成物を提供することが可能になる。
本明細書中の記号及び略号は、特に限定のない限り、本明細書の文脈に沿い、本発明が属する技術分野において通常用いられる意味に理解できる。
本明細書中、語句「含有する」は、語句「から本質的になる」、及び語句「からなる」を包含することを意図して用いられる。
特に限定されない限り、本明細書中に記載されている工程、処理、又は操作は、室温で実施され得る。
本明細書中、室温は、10~40℃の範囲内の温度を意味する。
本発明の固体組成物は、
(1)非晶質の難水溶性ポリフェノール、
(2)親水性ポリマー、および
(3)ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、およびレシチンからなる群より選択される1種以上の非イオン性界面活性剤
を含有する。
通常、ほとんどのポリフェノールは、結晶質であり、その結果、水に難溶性、または不溶性である。
または、本発明における「難水溶性ポリフェノール化合物」は、オクタノール/水分配係数(logP)が-1.0~4.0の範囲内である。当該logP値の決定は、JIS Z 7260-117(2006)に準拠して、高速液体クロマトグラフィー法により実施することができる。logP値は、次式により定義される。
logP=log(Coc/Cwa)
Coc:1-オクタノール層中の被験物質濃度
Cwa:水層中の被験物質濃度
本発明における「難水溶性ポリフェノール化合物」は、好適には、日本薬局方溶出試験に準拠した方法で測定した、第十六改正日本薬局方の第2液に対する溶解度が、0.2mg/100mL以下である。
1.フェノール酸[例、ヒドロキシ桂皮酸(例、p-クマル酸、コーヒー酸、フェルラ酸)、ヒドロキシ安息香酸:(例、p-ヒドロキシ安息香酸、没食子酸、エラグ酸)、ロスマリン酸]、
2.フラボノイド[フラボン(例、ルテオリン、アピゲニン、フラボキセート、ジオスミン、ノビレチン)、フラバノン(例、ヘスペレチン、ナリンゲニン、ヘスペリジン、ヘスペレチン)、フラバノール(例、ケルセチン、ミリセチン、シミラリン、シリマリン、シリビニン、ルチン、イソクエルシトリン)、フラバン-3-オール、カテキン(E)、エピカテキン(EC)、テアフラビン、エピカテキンガレート(ECg)、エピガロカテキン(EGC)、エピガロカテキンガレート(EGCg)、イソフラボン(例、ゲニステイン、ダイゼイン)、アントシアニジン(例、シアニジン、デルフィニジン、マルビジン、ペラルゴニジン、ペオニジン、プロアントシアニジン、オリゴメリックプロアントシアニジン(OPC)、プロシアニジン、ポリシアニジン、
3.スチルベノイド[例、レスベラトロール]、
4.タンニン[例、縮合型タンニン(プロアントシアニジン)、および加水分解性タンニン]
5.モノフェノール[例、ヒドロキシチロソール、p-チロソール]、
6.カプサイシノイド[例、カプサイシン、ジヒドロカプサイシン]、
7.クルクミノイド[例、クルクミン(ケト型、およびエノール型)、ジメトキシクルクミン、ビスジメトキシクルクミン]、ならびにテトラヒドロクルクミン、
8.これらのアグリコン、およびそれらの誘導体(例、アセチル化物、マロニル化物、メチル化物、配糖体)
その例は、ウコン抽出物、オオアザミ抽出物、コーヒー抽出物、カンゾウ抽出物、キュウリ抽出物、ケイケットウ抽出物、ゲンチアナ(または、リンドウ)抽出物、ゲンノショウコ抽出物、コレステロール及びその誘導体、サンザシ抽出物、シャクヤク抽出物、イチョウ抽出物、コガネバナ(または、オウゴン)抽出物、ニンジン抽出物、マイカイカ(または、マイカイ、ハマナス)抽出物、サンペンズ(または、カワラケツメイ)抽出物、トルメンチラ抽出物、パセリ抽出物、ボタン(または、ボタンピ)抽出物、モッカ(または、ボケ)抽出物、メリッサ抽出物、ヤシャジツ(または、ヤシャ)抽出物、ユキノシタ抽出物、ローズマリー(または、マンネンロウ)抽出物、レタス抽出物、茶抽出物(例、烏龍茶エキス、紅茶エキス、緑茶エキス)、微生物醗酵代謝産物、および羅漢果抽出物等を包含する。
本発明で用いられる親水性ポリマーは、あらゆる条件下で親水性もしくは水溶性である必要はなく、好ましくは、少なくとも腸管管中のpHで、親水性もしくは水溶性であればよい。
本発明で用いられる親水性ポリマーは、好ましくは室温で固体である。
本発明で用いられる親水性ポリマーは、好ましくは約50℃以上、より好ましくは約80℃~約180℃の範囲内のガラス転移温度(Tg)を有する。当該ガラス転移温度(Tg)の決定は、JIS K 7121:2012に準拠して実施できる。
(1)N-ビニルラクタム(好ましくは、N-ビニルピロリドン)のホモポリマー[例、ポリビニルピロリドン(すなわち、PVP、またはポビドン)(例、KollidonTM 12PF、KollidonTM 17PF、KollidonTM 25、KollidonTM 30、KollidonTM 90F、またはそれらの同等物)]、およびそのコポリマー[例、N-ビニルピロリドン、および酢酸ビニルのモノマーを含有するもの(すなわち、コポビドン)、またはN-ビニルピロリドン、およびプロピオン酸ビニルのモノマーを含有するものなど)];
(2)セルロースエステル、およびセルロースエーテル、特に、メチルセルロース、エチルセルロース、(ヒドロキシアルキル)セルロース[例、ヒドロキシプロピルセルロース(すなわち、HPC)]、(ヒドロキシアルキル)アルキル-セルロース[例、ヒドロキシプロピルメチルセルロース(すなわち、HPMC)]、またはヒプロメロース(例、MethocelTM E3、MethocelTM E5、MethocelTM E6、MethocelTM E15、またはそれらの同等物、MethocelTM K3、またはその同等物)、フタル酸セルロース、およびコハク酸セルロース[例、酢酸フタル酸セルロース、フタル酸ヒドロキシプロピルメチルセルロース、コハク酸ヒドロキシプロピルメチルセルロース、および酢酸コハク酸ヒドロキシプロピルメチルセルロース(すなわち、HPMC-AS)];
(3)高分子量ポリアルキレンオキシド[例、ポリエチレンオキシド、ポリプロピレンオキシド、ならびにエチレンオキシド、および酸化プロピレンのコポリマー(例、ポロクサマー)];
(4)ポリアクリレート、およびポリメタクリレート[例、メタクリル酸/アクリル酸エチルコポリマー、メタクリル酸/メタクリル酸メチルコポリマー、メタクリル酸ブチル/メタクリル酸2-ジメチルアミノエチルコポリマー、ポリ(ヒドロキシアルキルアクリレート)、およびポリ(ヒドロキシアルキルメタクリレート)];
(5)ポリアクリルアミド;
(6)酢酸ビニルポリマー、およびポリビニルアルコールのコポリマー;
オリゴ糖、および多糖(例、カラギーナン、ガラクトマンナン、およびキサンタンガム);
ならびにこれらの2つ以上の混合物。
本発明の特に好適な一態様においては、本発明の固体組成物が、前記親水性ポリマーとして、少なくとも、ポリビニルピロリドンを含有し、更に他の親水性ポリマーを含有してもよい。
本発明の別の特に好適な一態様においては、前記親水性ポリマーが、ポリビニルピロリドンである。
本発明に用いられるポリグリセリン脂肪酸エステルの具体例は、ジグリセリンモノラウレート、ジグリセリンモノステアレート、ジグリセリンモノオレート、デカグリセリンモノラウレート、デカグリセリンモノステアレート、およびデカグリセリンモノオレートを包含する。
本発明で用いられるポリグリセリン脂肪酸エステルは、1種単独、または2種以上の組み合わせであることができる。
本発明に用いられるショ糖脂肪酸エステルにおける脂肪酸の炭素数は、好ましくは12以上、およびより好ましくは12~20の範囲内である。
本発明に用いられるショ糖脂肪酸エステルの好ましい具体例は、ショ糖ラウリン酸エステル、ショ糖ミリスチン酸エステル、ショ糖パルミチン酸エステル、ショ糖ステアリン酸エステル、ショ糖オレイン酸エステル、ショ糖ベヘニン酸エステル、およびショ糖エルカ酸エステルを包含する。
本発明で用いられるショ糖脂肪酸エステルは、1種単独、または2種以上の組み合わせであることができる。
本発明で用いられるレシチンの例は、卵黄に含まれている卵黄レシチン、大豆に含まれている大豆レシチン、およびヒマワリに含まれているヒマワリレシチンを包含する。
本発明で用いられるレシチンの例は、また、これらのレシチンから有効成分を取りだしたものである分別レシチン、ならびにレシチンを酵素で処理したものである、酵素処理レシチン、および酵素分解レシチンを包含する。
すなわち、本発明に用いられるレシチンの具体例は、レシチン、酵素分解レシチン(フォスファチジン酸)、リゾレシチン、ダイズレシチン(ダイズリン脂質)、卵黄レシチンを包含する。
本発明で用いられるレシチンは、商業的に入手可能であり、例えば、SLP-ホワイト(商品名、辻製油社)を挙げることができる。
本発明で用いられるレシチンは、1種単独、または2種以上の組み合わせであることができる。
本発明の固体組成物は、所望により、本発明の効果が著しく損なわれない限りにおいて、前記成分以外の成分を含有してもよい。
このような成分の例は、賦形剤、充填剤、増量剤、結合剤、崩壊剤、界面活性剤、調味料、香料、および滑沢剤を包含する。
このような成分の種類、およびその量は、本発明の効果が著しく損なわれない限りにおいて、技術常識に基づき、適宜、選択、および設計すればよい。
本発明の組成物は、食品、機能性食品、栄養補助食品(サプリメント)、特定保健用食品、医薬部外品、および医薬品等の用途に用いることができる。
本発明の固体組成物は、好ましくは経口用製剤である。
当該製剤の形態の好適な例は、錠剤、顆粒剤、散剤、細粒剤、顆粒剤、丸剤、およびトローチ剤を包含する。本発明の組成物は、これらの製剤の製剤材料であってもよい。
この場合、本発明の固体組成物(経口ポリフェノール製剤)の投与または摂取量は、ポリフェノールの種類、使用者の年齢、体重、症状、投与形態、および処置期間などによって変わり得るが、例えば、ポリフェノールがクルクミンである場合、WHOのTechnical Reportによると、クルクミンのADI:0~3mg/kg体重/日、NOAEL:250~320mg/kg体重/日とされており(WHO Technical Report Series : 1237259778265_0.pdf,第33頁)、この範囲内で、1日に1回~複数回(例、2回、3回、4回、5回)に分けて、好適に投与または摂取できる。
例えば、界面活性剤としては、グリセリン脂肪酸エステル、プロピレングリコール脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレン脂肪酸エステル、カルボン酸塩、スルホン酸塩等のアニオン界面活性剤、アミン塩、アンモニウム塩等のカチオン界面活性剤等の一種以上を、本発明の固体組成物と組み合わせて使用することができる。
本発明の組成物は、例えば、
(1)結晶質のポリフェノール、
(2)親水性ポリマー、および
(3)ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、およびレシチンからなる群より選択される1種以上の非イオン性界面活性剤、ならびに
(4)所望により用いられるその他の成分
を混合する工程を含む製造方法であって、当該結晶質のポリフェノールを、非晶質に変化させる工程を含む製造方法により、製造できる。
当該混合においては、前記成分を、同時に混合してもよく、または逐次的に混合してもよい。
当該混合においては、好適に、有機溶媒等の溶媒を使用しないことができる。
当該溶媒を使用する場合であっても、ポリフェノール等の前記成分は、当該溶媒に完全に溶解されないことができる。
これにより、本発明の組成物は、大きな容器等を用いずに低コストで製造できる。
前記各成分を混合する工程と、前記結晶質のポリフェノールを、非晶質に変化させる工程とは、別々であってもよく、一部が共通していてもよく、または完全に共通していてもよい。
ここで、結晶質のポリフェノールが、より多い割合で非晶質に変化することが、より好ましい。結晶質のポリフェノールの実質的に全部、または全部が非晶質に変化することが特に好ましい。
本発明の組成物は、例えば、溶媒沈殿法、噴霧乾燥法、凍結乾燥法、減圧乾燥法、または混練法、あるいはこれらの組み合わせにより、製造できる。
(1)結晶質のポリフェノール、
(2)親水性ポリマー、および
(3)ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、およびレシチンからなる群より選択される1種以上の非イオン性界面活性剤、ならびに
(4)所望により用いられるその他の成分
を、混練する工程を含む製造方法により、製造される。
当該混練においては、前記結晶質のポリフェノール、前記親水性ポリマー、および前記非イオン性界面活性剤が、同時に混練されることが好ましい。
当該混練により、結晶質のポリフェノールの一部、好ましくは実質的に全部、または全部が、非晶質に変化する。
当該混練では、例えば、各成分が融解する温度まで加熱混練し、各成分の融解後、室温まで冷却して、得られた固体組成物を粉砕機で粉末状に粉砕して、本発明の組成物を得ることができる。
前記結晶質のポリフェノール、前記親水性ポリマー、および前記非イオン性界面活性剤、ならびに油脂を、十分に混合することにより、前記ポリフェノールが溶解しているスラリーを調製する工程;および
当該スラリーを乾燥する工程
を含む方法により、製造される。
当該乾燥の方法としては、例えば、噴霧乾燥法、凍結乾燥法、真空乾燥法、ドラム乾燥法、および遠赤外線乾燥法などが挙げられ、なかでも噴霧乾燥法が好ましい。
CUR: クルクミン
SIL: シリマリン
LUT: ルテオリン
PVP: ポリビニルピロリドン
PGFE: ポリグリセリン脂肪酸エステル
HPC: ヒドロキシプロピルセルロース
HPMC: ヒドロキシプロピルメチルセルロース
各組成物は、後記の記載の表1-1、1-2、又は1-3に記載の組成を有する各組成物を融解温度まで加熱混練し、融解後、室温まで冷却して、粉砕機で粉末状にしたものを用いた。
但し、比較例3の組成物の調製においては、加熱せず、成分を混合したのみで、これを試験試料とした。
[成分]
<クルクミン>
クルクミン原料(純度:クルクミン 90%以上)(原末)
<親水性ポリマー>
Koridon K30(商品名、BASF社):
PVP(ポリビニルピロリドン)
<非イオン性界面活性剤>
PGFE(A):
PGFE(ポリグリセリン脂肪酸エステル)
リョートーポリグリエステル1-50SV(商品名、三菱化学フーズ社):
PGFE(デカグリセリンステアリン酸エステル)
リョートーポリグリエステルM-10D(商品名、三菱化学フーズ社):
PGFE(デカグリセリンミリスチン酸エステル)
NIKKOL HCO-60(商品名、日光ケミカルズ社):
ポリオキシエチレン硬化ヒマ油
NIKKOL TS-10V(商品名、日光ケミカルズ社):
ポリオキシエチレンソルビタン高級脂肪酸エステル(ポリソルベート60)
NIKKOL TO-10V(商品名、日光ケミカルズ社):
ポリオキシエチレンソルビタン高級脂肪酸エステル(ポリソルベート80)
NIKKOL TMGS-15V(商品名、日光ケミカルズ社):
モノステアリン酸ポリオキシエチレングリセリル
溶出試験は、以下の材料、および条件を採用して、第十六改正日本薬局方に記載の試験方法に準じて、実施した。分析は、各時間で、試験液の少量を採取して、行った。
(溶出試験の材料、および条件)
[1]クルクミン溶出試験
溶出試験機:PJ-32S(製品名、宮本理研工業社)
試験液:日本薬局方第二液(人工腸液、pH6.8)
試料量:クルクミンとして10mg/100ml
温度:37℃
採取:0.2μmメンブランフィルターにてろ過後、ろ液を分析した。
分析:HPLC法
[2]シリマリン溶出試験
溶出試験機:PJ-32S(製品名、宮本理研工業社)
試験液:日本薬局方第二液(人工腸液、pH6.8)
試料量:シリマリンとして10mg/100ml
温度:37℃
採取:0.2μmメンブランフィルターにてろ過後、ろ液を分析した。
分析:HPLC法
[3]ルテオリン溶出試験
溶出試験機:PJ-32S(製品名、宮本理研工業社)
試験液:日本薬局方第二液(人工腸液、pH6.8)
試料量:ルテオリンとして10mg/100ml
温度:37℃
採取:0.2μmメンブランフィルターにてろ過後、ろ液を分析した。
分析:HPLC法
表2-1に示す試料を用いて、界面活性剤を含有しない固体組成物、可溶化製剤、及び加熱せずに調製した固体組成物との比較における、クルクミンの人工腸液への溶出性の経時変化を試験した。結果を、表3-1、及び図1-1に示す。これから理解されるように、本発明の組成物は、ポリフェノールの体液(好ましくは腸液)への高い溶出性を発揮し、且つこれが長時間維持された。
試験例1-2
表2-2に示す試料を用いて、界面活性剤を含有しない固体組成物、及び可溶化製剤、との比較における、シリマリンの人工腸液への溶出性の経時変化を試験した。結果を、表3-2、及び図1-2に示す。これから理解されるように、本発明の組成物は、ポリフェノールの体液(好ましくは腸液)への高い溶出性を発揮し、且つこれが長時間維持された。
試験例1-3
表2-3に示す試料を用いて、界面活性剤を含有しない固体組成物、及び可溶化製剤、との比較における、ルテオリンの人工腸液への溶出性の経時変化を試験した。結果を、表3-3、及び図1-3に示す。これから理解されるように、本発明の組成物は、ポリフェノールの体液(好ましくは腸液)への高い溶出性を発揮し、且つこれが長時間維持された。
表4に示す試料を用いて、他の非イオン性界面活性剤との比較における、クルクミンの人工腸液への溶出性の経時変化を試験した。結果を、表5、及び図2に示す。これから理解されるように、特定の非イオン性界面活性剤を用いた場合にのみ、本発明の組成物は、ポリフェノールの体液(好ましくは腸液)への高い溶出性を発揮し、且つこれが長時間維持された。
表6に示す試料について、様々な種類のポリグリセリン脂肪酸エステルを用いた場合の、クルクミンの人工腸液への溶出性の経時変化を試験した。結果を、表7、及び図3に示す。これから理解されるように、様々なポリグリセリン脂肪酸エステルで、本発明の組成物は、ポリフェノールの体液(好ましくは腸液)への高い溶出性を発揮し、且つこれが長時間維持された。
表8に示す試料について、様々な量でポリグリセリン脂肪酸エステルを用いた場合の、クルクミンの人工腸液への溶出性の経時変化を試験した。結果を、表9、及び図4に示す。これから理解されるように、ポリグリセリン脂肪酸エステルの使用量を変化させても、本発明の組成物は、ポリフェノールの体液(好ましくは腸液)への高い溶出性を発揮し、且つこれが長時間維持された。
表10に示す試料について、ポリグリセリン脂肪酸エステルとの比較において、シュガーエステル、またはレシチンを用いた場合の、クルクミンの人工腸液への溶出性の経時変化を試験した。結果を、表11、及び図5に示す。これから理解されるように、シュガーエステル、またはレシチンを用いた場合でも、ポリグリセリン脂肪酸エステルを用いた場合と同様に、本発明の組成物は、ポリフェノールの体液(好ましくは腸液)への高い溶出性を発揮し、且つこれが長時間維持された。
PVPに変えて、HPC、またはHPMCを用いて、前記で記載した製造方法で、組成物を調製し、および前記試験と同様の試験を行った。その結果、PVPを用いた場合に比べると、HPC、またはHPMCを用いた場合は、ポリフェノールの体液(好ましくは腸液)への溶出性は低かったが、PVPと同様の傾向が確認され、ポリフェノールの体液(好ましくは腸液)への溶出性が長時間維持された。
以下の試験方法により、実施例1の非晶質製剤を投与したラットの血中クルクミン濃度の経時変化を調べた。比較例としては、クルクミン原末を投与した。
(試験方法)
動物:SDラット(雄、7週齢、投与の14~16時間前から絶食)を各3匹使用
投与:クルクミンとして100mg/KG / 単回経口投与(ゾンテ法)
採血:投与直前、並びに投与の0.5、1、2、4、8、及び24時間後にそれぞれ頸静脈採血
分析:血漿25μlをβ-グルクロニダーゼにて酵素処理した。さらにクルクミンをアセトニトリルで抽出した後、溶媒を乾固した。これをメタノールにて再希釈し、UV検出(420nm)にて測定した。
Claims (6)
- (1)非晶質の難水溶性ポリフェノール、
(2)親水性ポリマー、および
(3)ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、およびレシチンからなる群より選択される1種以上の非イオン性界面活性剤
を含有する固体組成物。 - 前記非晶質の難水溶性ポリフェノールが、クルクミン、シリマリン、及びルテオリンからなるより選択される1種以上である請求項1に記載の固体組成物。
- 前記親水性ポリマーが、ポリビニルピロリドン、ヒドロキシプロピルセルロース、およびヒドロキシプロピルメチルセルロースからなる群より選択される1種以上である請求項1又は2に記載の固体組成物。
- 前記非イオン性界面活性剤が、ポリグリセリン脂肪酸エステルである請求項1~3のいずれか一項に記載の固体組成物。
- 経口用製剤である請求項1~4のいずれか一項に記載の固体組成物。
- (1)結晶質のポリフェノール、
(2)親水性ポリマー、および
(3)ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、およびレシチンからなる群より選択される1種以上の非イオン性界面活性剤
を、混練する工程を含む
請求項1~5のいずれか一項に記載に記載の固体組成物の製造方法。
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US15/767,044 US10709672B2 (en) | 2015-10-09 | 2016-10-07 | Polyphenol-containing solid composition |
KR1020187011939A KR102662912B1 (ko) | 2015-10-09 | 2016-10-07 | 폴리페놀 함유 고체 조성물 |
JP2017544254A JP6971006B2 (ja) | 2015-10-09 | 2016-10-07 | ポリフェノール含有固体組成物 |
EP16853778.5A EP3360546B1 (en) | 2015-10-09 | 2016-10-07 | Polyphenol-containing solid composition |
CN201680071648.5A CN108366978B (zh) | 2015-10-09 | 2016-10-07 | 含有多酚的固体组合物 |
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EP (1) | EP3360546B1 (ja) |
JP (1) | JP6971006B2 (ja) |
KR (1) | KR102662912B1 (ja) |
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Cited By (5)
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WO2019018774A1 (en) * | 2017-07-20 | 2019-01-24 | Amri Ssci, Llc | AMORPHOUS DISPERSIONS OF EPIGALLOCATECHE GALLATE |
WO2019070056A1 (ja) | 2017-10-05 | 2019-04-11 | ペトロユーロアジア株式会社 | ルテオリン含有組成物およびその製造方法 |
JP2019112355A (ja) * | 2017-12-25 | 2019-07-11 | 花王株式会社 | 難水溶性芳香族化合物含有組成物の製造方法 |
WO2019160146A1 (ja) | 2018-02-19 | 2019-08-22 | 株式会社セラバリューズ | 経口摂取用組成物 |
JP6821863B1 (ja) * | 2019-08-30 | 2021-01-27 | 三栄源エフ・エフ・アイ株式会社 | 非晶質の難水溶性素材を含有する固体組成物、及びその製造方法 |
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CN114557965B (zh) * | 2022-02-09 | 2023-06-09 | 汕头大学 | 一种提高姜黄素稳定性和生物可及性的磷脂复合物纳米粒及制备方法 |
FR3134973A1 (fr) * | 2022-04-28 | 2023-11-03 | L'oreal | Composition de maquillage comprenant un polyphénol, un composé polyoxyalkyléné ou polyglycérolé, un monoalcool et un acide carboxylique hydroxylé, et procédé la mettant en œuvre |
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WO2019018774A1 (en) * | 2017-07-20 | 2019-01-24 | Amri Ssci, Llc | AMORPHOUS DISPERSIONS OF EPIGALLOCATECHE GALLATE |
JP7246386B2 (ja) | 2017-07-20 | 2023-03-27 | エイエムアールアイ エスエスシーアイ, リミテッド ライアビリティ カンパニー | エピガロカテキンガレートの非晶質分散体 |
JP2020527610A (ja) * | 2017-07-20 | 2020-09-10 | エイエムアールアイ エスエスシーアイ, リミテッド ライアビリティ カンパニー | エピガロカテキンガレートの非晶質分散体 |
WO2019070056A1 (ja) | 2017-10-05 | 2019-04-11 | ペトロユーロアジア株式会社 | ルテオリン含有組成物およびその製造方法 |
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CN111726992A (zh) * | 2018-02-19 | 2020-09-29 | 热值株式会社 | 口服摄取用组合物 |
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AU2019222350B2 (en) * | 2018-02-19 | 2023-11-16 | Theravalues Corporation | Oral ingestion composition |
CN111726992B (zh) * | 2018-02-19 | 2024-02-23 | 热值株式会社 | 口服摄取用组合物 |
JP6821863B1 (ja) * | 2019-08-30 | 2021-01-27 | 三栄源エフ・エフ・アイ株式会社 | 非晶質の難水溶性素材を含有する固体組成物、及びその製造方法 |
KR20220054378A (ko) | 2019-08-30 | 2022-05-02 | 산에이겐 에후.에후. 아이. 가부시키가이샤 | 비정질의 난수용성 소재를 함유하는 고체 조성물 및 그 제조 방법 |
Also Published As
Publication number | Publication date |
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EP3360546A1 (en) | 2018-08-15 |
KR20180059883A (ko) | 2018-06-05 |
JPWO2017061627A1 (ja) | 2018-07-26 |
JP6971006B2 (ja) | 2021-11-24 |
KR102662912B1 (ko) | 2024-05-03 |
EP3360546B1 (en) | 2020-11-25 |
CN108366978B (zh) | 2021-06-01 |
CN108366978A (zh) | 2018-08-03 |
US20180289635A1 (en) | 2018-10-11 |
EP3360546A4 (en) | 2019-07-03 |
US10709672B2 (en) | 2020-07-14 |
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