JP2019151584A - Curcumin-containing preparations, and method for evaluating absorbency or elution thereof - Google Patents

Abstract

To provide curcumin-containing preparations enabling efficient intake of curcumin.SOLUTION: Provided is a curcumin-containing preparation which contains amorphous curcumin and substantially no crystalline curcumin, in which (a) the half-width is 68 or more and/or (b) T1 is 1.30 seconds or less, in the peak having the maximum intensity within the chemical shift range of 6.7 to 6.9 ppm in the chart ofH-NMR spectrum measured under the following conditions. <Measurement condition> measurement solvent: heavy water (DO);H resonant frequency: 600 MHz; temperature: 37°C; experimental method: Inversion Recovery method; and waiting time of Inversion Recovery method: 0.1 to 1.3 seconds.SELECTED DRAWING: None

Description

The present invention relates to a curcumin-containing preparation.
Furthermore, the present invention relates to a method for evaluating the absorbability or dissolution property.

Curcumin is said to have physiological effects such as cholesterol elevation inhibitory action, blood pressure rise inhibitory action, blood sugar rise inhibitory action, antiallergic action, and body fat inhibitory action. In order to expect such physiological effects, it is necessary to ingest a large amount of curcumin.
Curcumin is an ingredient contained in edible plants and the like, and can be taken even in a normal meal, etc., but it is convenient and efficient to take it in the form of a solid composition such as a tablet containing the curcumin. .
However, since curcumin is sparingly water-soluble, even if a solid composition containing it is ingested, the rate of dissolution and absorption into body fluids is slow.
Regarding such a problem, for example, Patent Document 1 proposes an oral composition containing curcuminoid and turmeric essential oil.
However, further development of new technology is required from the viewpoint of efficient intake of curcumin.

JP 2012-188450 A

In view of the background art described above, an object of the present invention is to provide a curcumin-containing preparation that enables efficient intake of curcumin.
Further, in order to efficiently develop such an excellent curcumin-containing preparation, (1) a method for predicting curcumin elution in a body fluid, and (2) curcumin in vivo of curcumin-containing preparation It would be useful if a method for predicting absorbency was provided.
Accordingly, it is an object of the present invention to provide these methods and a medium or apparatus usable for the methods.

As a result of intensive studies, the present inventors have
A curcumin-containing preparation,
Contains amorphous curcumin and is substantially free of crystalline curcumin,
In the chart of ¹ H-NMR spectrum measured under the following conditions, the peak having the maximum intensity within the range of chemical shift of 6.7 to 6.9 ppm is (a) the half width is 68 or more, and / or (b ) Formulation with T1 of 1.43 seconds or less.
<Measurement conditions>
Measuring solvent: heavy water (D ₂ O)
¹ H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
It has been found that the above problem can be solved by waiting time of the reverse recovery method: 0.1 to 1.3 seconds, and the present invention has been completed.

  The present invention includes the following aspects.

Item 1.
A curcumin-containing preparation,
Contains amorphous curcumin and is substantially free of crystalline curcumin,
The peak having the maximum intensity within the range of chemical shift of 6.7 to 6.9 ppm in the chart of 1H-NMR spectrum measured under the following conditions:
(A) The half width is 68 Hz or more and / or (b) T1 is 1.43 seconds or less.
Formulation.
<Measurement conditions>
Measuring solvent: heavy water (D2O)
1H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
Inversion recovery method waiting time: 0.1 to 1.3 seconds
Item 2. The formulation according to Item 1, wherein the curcumin content is 10% by mass or more based on the entire formulation.
Item 3.
A method for predicting curcumin elution in a body fluid of a curcumin-containing preparation,
(1) Stage of 1H-NMR analysis of curcumin-containing preparation under the following measurement conditions to obtain a chart of 1H-NMR spectrum <Measurement conditions>
Measuring solvent: heavy water (D2O)
1H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
Inversion recovery method waiting time: 0.1 to 1.3 seconds,
(2) identifying a peak having a maximum intensity within a chemical shift range of 6.7 to 6.9 ppm in the chart of 1H-NMR spectrum obtained by step (1);
(3) (a) calculating the full width at half maximum and / or (b) T1 of the peak identified in step (2), and (4) (a) when the full width at half maximum is large, and / or (b) T1. A method comprising a step of estimating that curcumin is highly soluble in a body fluid when is small.
Item 4.
A method for predicting curcumin absorption of a curcumin-containing preparation into a living body,
(1) A step of 1H-NMR analysis of a curcumin-containing preparation under the following measurement conditions to obtain a chart of 1H-NMR spectrum,
<Measurement conditions>
Measuring solvent: heavy water (D2O)
1H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
Inversion recovery method waiting time: 0.1 to 1.3 seconds,
(2) identifying a peak having a maximum intensity within a chemical shift range of 6.7 to 6.9 ppm in the 1H-NMR spectrum chart obtained by step (1);
(3) (a) calculating the full width at half maximum and / or (b) T1 of the peak identified in step (2), and (4) (a) when the full width at half maximum and / or (b) T1 is large, And / or (b) a method comprising estimating when curcumin absorption into a living body is high when T1 is small.
Item 5.
A computer-readable medium storing a computer code,
The computer code is
(1) Identify the peak having the maximum intensity within the chemical shift range of 6.7 to 6.9 ppm in the 1H-NMR spectrum chart of the curcumin-containing preparation,
(2) calculating (a) half-width and / or (b) T1 of the peak identified in step (1), and (3) based on (a) half-width and / or (b) T1.
(A) computer code for calculating an estimated value of curcumin elution in a body fluid and / or (b) an estimated value of curcumin absorbability in a living body,
Computer readable medium.
(1) Item 6.
An analysis unit for identifying a peak having a maximum intensity within a chemical shift range of 6.7 to 6.9 ppm in a 1H-NMR spectrum chart of a curcumin-containing preparation;
(2) Based on (a) the full width at half maximum and / or (b) T1 of the peak, and (3) based on the (a) full width at half maximum and / or (b) T1,
An apparatus including an output unit that outputs (a) an estimated value of curcumin elution in a body fluid and / or (b) an estimated value of curcumin absorbability in a living body.
Item 7.
Item 7. The apparatus according to Item 6, which causes a computer to function as the analysis unit (1), the calculation unit (2), and the output unit (3).

According to the present invention, there is provided a curcumin-containing preparation that enables efficient intake of curcumin.
Furthermore, according to the present invention, in order to efficiently develop such an excellent curcumin-containing preparation, a simple (1) method for predicting curcumin elution in a body fluid, and (2) a curcumin-containing preparation A method of predicting curcumin absorbability in vivo is provided.

It is an example of a structure of the prediction apparatus of this invention.

Terms Symbols and abbreviations in this specification can be understood within the context of this specification unless otherwise specified, and can be understood as meanings commonly used in the technical field to which the present invention belongs.
In this specification, the phrase “containing” is intended to encompass the phrase “consisting essentially of” and the phrase “consisting of”.
Unless specifically limited, the steps, processes, or operations described herein can be performed at room temperature.
In this specification, room temperature means a temperature within the range of 10 to 40 ° C.

[1] Curcumin-containing preparation The curcumin-containing preparation of the present invention comprises:
Contains amorphous curcumin and is substantially free of crystalline curcumin,
In the chart of ¹ H-NMR spectrum measured under the following conditions, the peak having the maximum intensity within the range of chemical shift of 6.7 to 6.9 ppm is (a) the half width is 68 or more, and / or (b ) T1 is 1.43 seconds or less.
In the present invention, it is preferable that (a) the condition for the half width and (b) the condition for T1 are simultaneously satisfied.
That is, for example, it is preferable that (a) the full width at half maximum is 68 or more and (b) T1 is 1.43 seconds or less.
<Measurement conditions>
Measuring solvent: heavy water (D ₂ O)
¹ H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
Reversal recovery waiting time: 0.1-1.3 seconds

[1-1] Curcumin The curcumin-containing preparation of the present invention contains amorphous curcumin and substantially does not contain crystalline curcumin.

  Curcumin can be obtained, for example, as an extract derived from a natural product, or is commercially available.

The lower limit of the curcumin content in the preparation of the present invention is, for example, 5% by mass, preferably 7% by mass, more preferably 10% by mass, still more preferably 15% by mass, and even more preferably 20% by mass.
The upper limit of the curcumin content in the preparation of the present invention is, for example, 60 mass%, 50 mass%, 45 mass%, 40 mass%, 35 mass%, or 30 mass%.
The curcumin content in the preparation of the present invention is, for example, 5 to 60% by mass, preferably 7 to 50% by mass, more preferably 10 to 45% by mass, and further preferably 15 to 40% by mass. And even more preferably in the range of 20-35% by weight.

The formulations of the present invention contain amorphous curcumin and are substantially free of crystalline curcumin. In the present specification, “not containing” can include “essentially not containing”, “substantially not containing”, or “not containing completely”.
The proportion of crystalline curcumin in the curcumin contained in the preparation of the present invention is specifically less than 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, and even more preferably less than 1% by weight. Can be.

It can be confirmed by a known method such as powder X-ray diffraction or differential scanning calorimetry that the curcumin-containing preparation of the present invention contains amorphous curcumin and does not substantially contain crystalline curcumin.
Similarly, the ratio of crystalline curcumin to the total curcumin in the formulation can also be determined by powder X-ray diffraction or differential scanning calorimetry.
Here, when the content of crystalline curcumin is below the analysis limit by powder X-ray diffraction, the actual crystalline curcumin ratio can be estimated to be less than 3% by mass at most. This can mean that it is substantially free of crystalline curcumin.
Further, when the content of crystalline curcumin is below the analysis limit in differential scanning calorimetry, the actual crystalline curcumin ratio can be estimated to be less than 1% by mass at most. This can mean that it is substantially free of crystalline curcumin.

In the ¹ H-NMR spectrum measured according to the above conditions, the curcumin-containing preparation of the present invention has a half width of a peak having the maximum intensity among one or more peaks in the range of 6.7 to 6.9 ppm.
68 or more,
Preferably it is 70 or more,
More preferably 80 or more,
More preferably 90 or more,
More preferably, it is 100 or more, and particularly preferably 110 or more.
The upper limit of the half width is not particularly limited, but can be, for example, 200 or less.

The curcumin-containing preparation of the present invention has a peak T1 having the maximum intensity among one or more peaks in the range of 6.7 to 6.9 ppm in the 1H-NMR spectrum measured under the above conditions.
1.43 seconds or less,
Preferably it is 1.41 seconds or less,
More preferably 1.39 seconds or less,
More preferably 1.37 seconds or less,
Even more preferred is 1.35 seconds or less, and particularly preferred is 1.33 seconds or less.
The T1 is
Preferably 0.8 seconds or more, more preferably 1.05 seconds or more,
More preferably, it can be 1.10 seconds or more, and even more preferably 1.15 seconds or more.

[1-2] Components other than curcumin The curcumin-containing preparation of the present invention may contain components other than curcumin.
Ingredients other than curcumin usually include ingredients used in preparations (eg, orally administered preparations).
Examples of components other than the curcumin include a hydrophilic polymer and a nonionic surfactant.
A preferred example of the curcumin-containing preparation of the present invention is:
(1) Curcumin,
It can be a preparation containing (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.

[1-2-1] Hydrophilic polymer The hydrophilic polymer need not 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 is preferably solid at room temperature.
The hydrophilic polymer preferably has a glass transition temperature (Tg) in the range of about 50 ° C. or higher, more preferably from about 80 ° C. to about 180 ° C. The glass transition temperature (Tg) can be determined according to JIS K 7121: 2012.

  The preparation of the present invention can contain one kind or two or more kinds of hydrophilic polymers.

Examples of the hydrophilic polymer include the following.
(1) A homopolymer of N-vinyl lactam (preferably N-vinyl pyrrolidone) [eg, polyvinyl pyrrolidone (ie, PVP or povidone) (eg, Kollidon ^™ 12PF, Kollidon ^™ 17PF, Kollidon ^™ 25, Kollidon ^™ 30 , Kollidon ^™ 90F, or equivalents thereof], and copolymers thereof (eg, N-vinyl pyrrolidone, and those containing monomers of vinyl acetate (ie, copovidone), or N-vinyl pyrrolidone, and vinyl propionate) Including monomers)];
(2) Cellulose esters and cellulose ethers, in particular methylcellulose, ethylcellulose, (hydroxyalkyl) cellulose [eg, hydroxypropylcellulose (ie, HPC)], (hydroxyalkyl) alkyl-cellulose [eg, hydroxypropylmethylcellulose (ie, HPMC)], or hypromellose (eg, Methocel ^™ E3, Methocel ^™ E5, Methocel ^™ E6, Methocel ^™ E15, or equivalents thereof, Methocel ^™ K3, or equivalents), cellulose phthalate, and cellulose succinate [ Examples, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, and hydroxypropylmethylcellulose succinate (ie HPMC-AS)];
(3) high molecular weight polyalkylene oxide [eg, polyethylene oxide, polypropylene oxide, and copolymers of ethylene oxide and propylene oxide (eg, poloxamer)];
(4) Polyacrylates and polymethacrylates [eg, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, butyl methacrylate / methacrylic acid 2-dimethylaminoethyl copolymer, poly (hydroxyalkyl acrylate), and poly (Hydroxyalkyl methacrylate)];
(5) polyacrylamide;
(6) vinyl acetate polymers, and copolymers of polyvinyl alcohol; and oligosaccharides and polysaccharides (eg, carrageenan, galactomannan, and xanthan gum);
As well as mixtures of two or more of these.

In a preferred embodiment of the present invention, the preparation of the present invention contains at least one or more selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose as the hydrophilic polymer, Other hydrophilic polymers may be contained.
In a particularly preferred embodiment of the present invention, the preparation of the present invention contains at least polyvinylpyrrolidone as the hydrophilic polymer, and may further contain another hydrophilic polymer.

In another preferred embodiment of the present invention, 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 can be preferably in the range of 5 to 90% by mass, more preferably in the range of 20 to 90% by mass, and still more preferably in the range of 40 to 90% by mass.

[1-2-2] Nonionic surfactant The nonionic surfactant is one or more nonionic surfactants selected from the group consisting of polyglycerin fatty acid esters, sucrose fatty acid esters, and lecithin. It is an agent.

Examples of the polyglycerin fatty acid ester used in the present invention are (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. Includes esters with fatty acids (eg, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid).
Specific examples of polyglycerol fatty acid esters used in the present invention include diglycerol monolaurate, diglycerol monostearate, diglycerol monooleate, decaglycerol monolaurate, decaglycerol monostearate, and decaglycerol monooleate. To do.
The polyglycerin fatty acid ester may be a single type or a combination of two or more types.

The HLB value of the sucrose fatty acid ester is preferably 5 or more, more preferably 7 or more, still more preferably 10 or more, and still more preferably 12 or more.
The carbon number of the fatty acid in the sucrose fatty acid ester is preferably 12 or more, and more preferably in the range of 12-20.
Preferred specific examples of the sucrose fatty acid ester include sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose stearate, sucrose oleate, sucrose behenate, and sucrose Includes erucic acid esters.
The sucrose fatty acid ester may be a single type or a combination of two or more types.

The lecithin is a phosphate derivative adduct of glycerin difatty acid ester (diglyceride) and is widely distributed in animals and plants.
Examples of the lecithin include egg yolk lecithin contained in egg yolk, soybean lecithin contained in soybean, and sunflower lecithin contained in sunflower.
Examples of the lecithin 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.
That is, specific examples of the lecithin include lecithin, enzyme-decomposed lecithin (phosphatidic acid), lysolecithin, soybean lecithin (soybean phospholipid), and egg yolk lecithin.
The lecithin is commercially available, and examples thereof include SLP-white (trade name, Sakai Oil Co., Ltd.).
The lecithin may be a single type or a combination of two or more types.

  Particularly preferred examples of the nonionic surfactant contained in the preparation of the present invention include polyglycerol fatty acid esters.

  The formulation of this invention can contain 1 type, or 2 or more types of nonionic surfactant.

  In a preferred embodiment of the present invention, the nonionic surfactant is a polyglycerol fatty acid ester.

  The content of the nonionic surfactant in the preparation 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 in the range of 10 to 40% by mass. Is within.

[1-3] Other components The preparation of the present invention may further contain components other than the above components, as long as the effects of the present invention are not significantly impaired.
Examples of such components 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.

[1-4] Method for producing curcumin-containing preparation The curcumin-containing preparation of the present invention (sometimes referred to herein as the preparation of the present invention) is, for example,
(1) crystalline curcumin,
(2) 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 curcumin to an amorphous | non-crystalline substance.
In the mixing, the components may be mixed simultaneously or sequentially.
In the mixing, it is preferable not to use a solvent such as an organic solvent.
Even when the solvent is used, the components such as curcumin may not be completely dissolved in the solvent.
Thereby, the formulation 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 curcumin into an amorphous state may be separate, a part of them may be common, or they may be completely common. Also good.
Here, it is more preferable that the crystalline curcumin is changed into an amorphous state at a higher rate. It is particularly preferred that substantially all or all of the crystalline curcumin changes to amorphous.
The preparation 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 preparation of the present invention is preferably
(1) crystalline curcumin,
(2) 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.
In the kneading, it is preferable that the crystalline curcumin, the hydrophilic polymer, and the nonionic surfactant are kneaded simultaneously.
By the kneading, a part, preferably substantially all or all of the crystalline curcumin 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, 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.
In the kneading, for example, the components are heated and kneaded to a temperature at which each component is melted, cooled to room temperature after melting each component, and the resulting formulation is pulverized into powder by a pulverizer to obtain the formulation of the present invention. be able to.

  The primary particle size of the preparation of the present invention can be preferably in the range of 0.1 to 500 μm, for example. The particle diameter is measured by a dynamic light scattering method (DLS).

The preparation of the present invention is preferably, for example,
Preparing a slurry in which the curcumin is dissolved by thoroughly mixing the crystalline curcumin, 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.

[2] Method for Predicting Curcumin Dissolution in Body Fluid of Curcumin-Containing Formulation The method for predicting curcumin dissolution in a body fluid of a curcumin-containing preparation of the present invention comprises the following steps (1) to ( 4).

In step (1), the curcumin-containing preparation is analyzed by ¹ H-NMR under the following measurement conditions to obtain a chart of ¹ H-NMR spectrum.
<Measurement conditions>
Measuring solvent: heavy water (D ₂ O)
¹ H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
Reversal recovery waiting time: 0.1-1.3 seconds

In step (2), the peak having the maximum intensity is specified within the chemical shift range of 6.7 to 6.9 ppm in the chart of ¹ H-NMR spectrum obtained in step (1).

  In step (3), (a) half-value width and / or (b) T1 of the peak specified in step (2) are calculated.

  In step (4), when the half width (a) is large and / or (b) T1 is small, it is estimated that the curcumin-dissolving property of the curcumin-containing preparation in the body fluid is high.

  That is, in step (4), when the full width at half maximum (a) is larger and / or (b) when T1 is smaller, it is judged or predicted that curcumin elution in body fluid is higher, When the half width is smaller, it is estimated that curcumin elution into body fluid is lower.

Specifically, in the step (4), the half-value widths of the two curcumin-containing preparations are compared, and it is estimated that the preparations having a larger half-value width have higher curcumin elution in body fluids. To do.
In other words, in step (4), the half-value widths of the two curcumin-containing preparations are compared, and it is estimated that the preparation having a smaller half-value width has a lower curcumin-dissolving property in the body fluid.
This is also true when comparing more than two formulations, as is normally understood by those skilled in the art.

Here, as one of the two or more preparations, a preparation whose curcumin elution property in body fluid is measured can be used as a control.
This
It can be presumed that the preparation whose half-width is larger than the half-width of the control preparation has a dissolution property higher than the dissolution property of the control preparation in the body fluid,
It can be presumed that the half-width is equivalent to the half-width of the control preparation, and that the half-width is equivalent to that of the control preparation in the body fluid. It can be presumed that a preparation smaller than the half-value width has a dissolution property lower than the dissolution property of the control preparation in the body fluid.

Specifically, in step (4), T1 of the two curcumin-containing preparations is compared, and it is estimated that the preparation having a smaller T1 has a higher curcumin-eluting property in body fluid.
In other words, in step (4), the T1 of the two curcumin-containing preparations is compared, and it is estimated that the preparation with a higher T1 has lower curcumin elution in body fluid.
This is also true when comparing more than two formulations, as is normally understood by those skilled in the art.

Here, as one of the two or more preparations, a preparation whose curcumin elution property in body fluid is measured can be used as a control.
As the control preparation, the preparation of Comparative Example A1 in the Examples of the present specification can be used.
This
It can be presumed that the preparation with T1 smaller than T1 of the control preparation has a dissolution property higher than the dissolution property of the control preparation agent into a body fluid,
It can be presumed that a preparation in which the T1 is equivalent to the T1 of the control preparation has an elution property equivalent to that of the control preparation in body fluid, and the T1 is larger than the T1 of the control preparation It can be presumed that the preparation has a dissolution property lower than the dissolution property of the control preparation agent in the body fluid.

  In the present specification, examples of body fluids include mammalian (eg, human) blood, gastric fluid, intestinal fluid, extracellular fluid, and intracellular fluid.

According to the present invention, for example, the fact that the half width is 68 or more means that the AUC (area under the blood concentration-time curve) obtained by the method of the absorption test (blood curcumin concentration) described in the examples below will be described. It can be predicted that it is 10,000 or more.
In addition, for example, the half width is 70 or more when the AUC (area under the blood concentration-time curve) obtained by the method of the absorption test (blood curcumin concentration) described in Examples below is 15000 or more. It can be predicted that there will be.
This is just a reminder, but
AUC (blood concentration-time curve area) value B obtained by the method of the absorption test (blood curcumin concentration) described in the below-described examples due to being a predetermined half-value width A (eg, 68) or more, The act of predicting that it is greater than or equal to a predetermined value (e.g. 10,000)
It includes an act of predicting an AUC value (for example, 15000) larger than the B by a half-value width A ′ (for example, 70) larger than the half-value width A.
This inclusion relationship is the same for T1.
That is,
According to the present invention, for example, the fact that the T1 is 1.41 seconds or less indicates that the area under the AUC (blood concentration-time curve) obtained by the method of the absorption test (blood curcumin concentration) described in Examples below. ) Can be predicted to be 10,000 or more.
Further, for example, the fact that the T1 is 1.1.43 seconds or less indicates that the AUC (area under the blood concentration-time curve) obtained by the method of the absorption test (blood curcumin concentration) described in the examples below is 15000 or more.
This is just a reminder, but
AUC (blood concentration-time curve area) value B obtained by the method of the absorption test (blood curcumin concentration) described in the below-described examples due to being not less than a predetermined T1A (eg, 1.41 seconds) , The act of predicting that it is greater than or equal to a predetermined value (e.g. 10,000)
It includes an act of predicting an AUC value (for example, 15000) larger than B by T1A ′ (for example, 1.43 seconds) larger than the half-value width A.

According to the “method for predicting curcumin elution in a body fluid of a curcumin-containing preparation” of the present invention, curcumin elution can be easily predicted.
Therefore, it can greatly contribute to the efficiency improvement of the newly developed preparation test and the quality evaluation of the actually manufactured preparation.

[3] Method for predicting curcumin-absorbing property of curcumin-containing preparation in vivo of curcumin-containing preparation of the present invention is a method for predicting curcumin-absorbing property of curcumin-containing preparation in the living body according to the following steps (1) to ( 4).
In step (1), the curcumin-containing preparation is analyzed by ¹ H-NMR under the following measurement conditions to obtain a chart of ¹ H-NMR spectrum.
<Measurement conditions>
Measuring solvent: heavy water (D ₂ O)
¹ H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
Reversal recovery waiting time: 0.1-1.3 seconds

In step (2), the peak having the maximum intensity is specified within the chemical shift range of 6.7 to 6.9 ppm in the chart of ¹ H-NMR spectrum obtained in step (1).
In step (3), the half width of the peak specified in step (2) is calculated.
The steps (1) to (3) are the same as steps (1) to (3) in the above-described “method for predicting curcumin absorbability of a curcumin-containing preparation into a body fluid” of the present invention. Can be.

In step (4), when (a) the half width is large and / or (b) T1 is small, it is presumed that the curcumin-absorbing property of the curcumin-containing preparation is high.
That is, in step (4), when the half-width is larger and / or (b) T1 is smaller, it is determined or predicted that curcumin absorbability into the living body is higher, while the ratio half-width is larger. When it is smaller, it is estimated that curcumin absorbability into the living body is lower.

Specifically, in the step (4), the half-value widths of the two curcumin-containing preparations are compared, and it is estimated that the preparation having a larger half-value width has higher curcumin absorbability in the living body. To do.
In other words, in step (4), the half-value widths of the two types of curcumin-containing preparations are compared, and it is estimated that the preparation having a smaller half-value width has a lower curcumin absorbability in vivo.
This is also true when comparing more than two formulations, as is normally understood by those skilled in the art.

Here, as one of the two or more kinds of preparations, a preparation whose curcumin absorbability into a living body is measured can be used as a control.
This
It can be presumed that the preparation whose half-width is larger than the half-width of the control preparation has a higher absorbability than the absorbability of the control preparation into the body fluid,
It can be estimated that a preparation whose half width is equivalent to the half width of the control preparation has an absorbability equivalent to the absorbability of the control preparation into the body fluid, and the half width is that of the control preparation. It can be presumed that a preparation having a width less than the half-value width has lower absorbability than the absorbability of the control preparation in the body fluid.
As the control preparation, the preparation of Comparative Example A1 in the Examples of the present specification can be used.

Specifically, in step (4), T1 of two curcumin-containing preparations is compared, and it is estimated that a preparation having a smaller T1 has higher curcumin absorbability in vivo.
In other words, in step (4), T1 of the two curcumin-containing preparations is compared, and it is estimated that the preparation having a higher T1 has lower curcumin absorbability in vivo.
This is also true when comparing more than two formulations, as is normally understood by those skilled in the art.

Here, as one of the two or more kinds of preparations, a preparation whose curcumin absorbability into a living body is measured can be used as a control.
This
It can be presumed that the preparation in which the T1 is smaller than the T1 of the control preparation has an absorbency higher than the absorbability of the control preparation in the body fluid,
It can be presumed that a preparation in which the T1 is equivalent to the T1 of the control preparation has an absorbability equivalent to that of the control preparation in the body fluid, and the T1 is larger than the T1 of the control preparation It can be presumed that the preparation has a lower absorbability than the absorbability of the control preparation in the body fluid.

  In the present invention, “curcumin absorption into the living body” means absorption of curcumin into cells (eg, in the cytoplasm, in the cell membrane), tissues, organs, and / or organ systems. it can.

According to the “method for predicting curcumin absorbability of a curcumin-containing preparation in vivo” of the present invention, curcumin absorbability can be easily predicted.
Therefore, it can greatly contribute to the efficiency improvement of the newly developed preparation test and the quality evaluation of the actually manufactured preparation.

[4] Computer-readable medium storing computer code The present invention also provides
A computer-readable medium storing a computer code,
The computer code is
(1) Identify the peak having the maximum intensity within the chemical shift range of 6.7 to 6.9 ppm in the ¹ H-NMR spectrum chart of the curcumin-containing preparation,
(2) calculating the full width at half maximum of the peak identified in step (2), and (3) based on the full width at half maximum and / or the T1,
(A) computer code that outputs an estimated value of curcumin elution in a body fluid and / or (b) an estimated value of curcumin absorbability in a living body;
A computer readable medium is also provided.
The medium is understood from the description of the present specification and the common general technical knowledge.

[5] Analyzing unit for identifying a peak having the maximum intensity within a chemical shift range of 6.7 to 6.9 ppm in the ¹ H-NMR spectrum chart of the prediction apparatus curcumin-containing preparation,
(2) Based on the half-value width and / or T1, the calculation unit for calculating the half-value width of the peak,
There is also provided an apparatus including an output unit that outputs (a) an estimated value of curcumin elution into a body fluid and / or (b) an estimated value of curcumin absorbability into a living body.
The apparatus is understood from the description of the present specification and the common general technical knowledge.

In the apparatus, it is preferable that the computer function as the analysis unit (1), the calculation unit (2), and the output unit (3).
FIG. 3 shows an example of the configuration of the prediction apparatus.
The prediction unit ^10, from the ¹ H-NMR spectrum which is provided by 1 H-NMR analysis, the analyzer 11, a peak having a maximum intensity within the range of chemical shifts 6.7~6.9ppm is identified.
From the separated waveform, the full width at half maximum and / or T1 of the peak is calculated by the calculation unit 12.
From the half-width of the peak / or T1 by the calculation unit 12,
(A) An estimated value of curcumin elution in a body fluid and / or (b) an estimated value of curcumin absorbability in a living body are calculated.
The estimated value is not particularly limited, and may be a specific numerical value or a rank.
The estimated value is output by the output unit 13.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to this.

The meanings of symbols and abbreviations in the examples are shown below.
CUR: Curcumin PVP: Polyvinylpyrrolidone PS: Polysorbate PGFE: Polyglycerin fatty acid ester SE: Sucrose fatty acid ester (sugar ester)
NIS: Nonionic surfactant FWHM: NMR half width T1: NMR longitudinal relaxation time Pos. NMR peak position

[Sample preparation method]
Each composition is kneaded by hand with a spatula while heating each composition having the composition shown in Table 1 described later on the hot plate to the melting temperature, and after cooling, cooled to room temperature. The powder was used in a pulverizer.

  Heat kneading was performed by setting the hot plate at 240 ° C. and then kneading by hand using a spatula until the composition was melted.

The components used in Examples or Comparative Examples are described below (hereinafter, these components may be indicated using symbols described here).
[component]
CUR (curcumin): curcumin raw material (purity: curcumin 90% by mass or more) (raw powder)
PVP (Polyvinylpyrrolidone): Koridon K30 (trade name, BASF)
PGFE: Polyglycerol myristate
SE: Ryoto Sugar Ester S-1570 (trade name, Mitsubishi Chemical Foods) (stearate ester)
PS: NIKKOL TO-10F (trade name, Nikko Chemicals) (oleate)

  The composition of the preparation is shown in Tables 1 and 2.

^[1 H-NMR analysis]
For each formulation, ¹ H-NMR analysis was performed. ¹ H-NMR analysis was performed under the following measurement conditions.
<Measurement conditions>
Measurement solvent: heavy water (D ₂ O)
^-1 H resonance frequency: 600 MHz
・ Temperature: 37 ℃
Experimental method: Inversion recovery method (inversion recovery method)
-Reversal recovery waiting time: 0.1-1.3 seconds

^The results of ¹ H-NMR analysis are shown in Table 1.

[Absorption test (blood curcumin concentration)]
The time course of blood curcumin concentration in rats administered with the above preparations was examined by the following test method. As a comparative example, curcumin bulk powder was administered.
(Test method)
Animals: Three SD rats (male, 7 weeks old, fasted from 14-16 hours before administration) were used. Administration: 100 mg / KG / single oral administration as curcumin (Sonte method)
Blood collection: Just before administration and 0.5, 1, 2, 4, 8, and 24 hours after administration, respectively, jugular vein blood collection Analysis: 25 μl of plasma was enzymatically treated with β-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).
AUC (area under the blood concentration-time curve) is shown in Table 1 (Table 1-1).

  From the results, it was confirmed that the preparation of the present invention has high solubility of curcumin contained in blood or absorbability to a living body.

[Dissolution test]
The dissolution test was performed according to the test method described in the 16th revision Japanese Pharmacopoeia, employing the following materials and conditions. The analysis was performed by collecting a small amount of the test solution at each time.
(Materials and conditions for dissolution test)
[1] Curcumin dissolution test Dissolution tester: PJ-32S (product name, Miyamoto Riken Kogyo Co., Ltd.)
Test solution: Japanese Pharmacopoeia second solution (artificial intestinal fluid, pH 6.8)
Sample amount: 10 mg / 100 ml as curcumin
Temperature: 37 ° C
Collection: The filtrate was analyzed after filtration through a 0.2 μm membrane filter.
Analysis: HPLC method

Table 1 (Table 1-2) and Table 2 (Table 2-2) show the test results.

Claims (7)

A curcumin-containing preparation,
Contains amorphous curcumin and is substantially free of crystalline curcumin,
The peak having the maximum intensity within the chemical shift range of 6.7 to 6.9 ppm in the chart of ¹ H-NMR spectrum measured under the following conditions:
(A) The half width is 68 Hz or more and / or (b) T1 is 1.43 seconds or less.
Formulation.
<Measurement conditions>
Measuring solvent: heavy water (D ₂ O)
¹ H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
Reversal recovery waiting time: 0.1-1.3 seconds The preparation according to claim 1, wherein the curcumin content is 10% by mass or more based on the whole preparation. A method for predicting curcumin elution in a body fluid of a curcumin-containing preparation,
(1) Stage of ¹ H-NMR analysis of curcumin-containing preparation under the following measurement conditions to obtain a chart of ¹ H-NMR spectrum <Measurement conditions>
Measuring solvent: heavy water (D ₂ O)
¹ H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
Inversion recovery method waiting time: 0.1 to 1.3 seconds,
(2) identifying a peak having the maximum intensity within a chemical shift range of 6.7 to 6.9 ppm in the chart of ¹ H-NMR spectrum obtained by step (1);
(3) (a) calculating the full width at half maximum and / or (b) T1 of the peak identified in step (2), and (4) (a) when the full width at half maximum is large, and / or (b) T1. A method comprising a step of estimating that curcumin is highly soluble in a body fluid when is small. A method for predicting curcumin absorption of a curcumin-containing preparation into a living body,
(1) A step of ¹ H-NMR analysis of a curcumin-containing preparation under the following measurement conditions to obtain a chart of ¹ H-NMR spectrum,
<Measurement conditions>
Measuring solvent: heavy water (D ₂ O)
¹ H resonance frequency: 600 MHz
Temperature: 37 ° C
Experimental method: Inversion recovery method (inversion recovery method)
Inversion recovery method waiting time: 0.1 to 1.3 seconds,
(2) identifying a peak having a maximum intensity within a chemical shift range of 6.7 to 6.9 ppm in the ¹ H-NMR spectrum chart obtained by step (1);
(3) (a) calculating the full width at half maximum and / or (b) T1 of the peak identified in step (2), and (4) (a) when the full width at half maximum and / or (b) T1 is large, And / or (b) a method comprising estimating when curcumin absorption into a living body is high when T1 is small. A computer-readable medium storing a computer code,
The computer code is
(1) Identify the peak having the maximum intensity within the chemical shift range of 6.7 to 6.9 ppm in the ¹ H-NMR spectrum chart of the curcumin-containing preparation,
(2) calculating (a) half-width and / or (b) T1 of the peak identified in step (1), and (3) based on (a) half-width and / or (b) T1.
(A) computer code for calculating an estimated value of curcumin elution in a body fluid and / or (b) an estimated value of curcumin absorbability in a living body,
Computer readable medium. (1) an analysis unit for identifying a peak having a maximum intensity within a chemical shift range of 6.7 to 6.9 ppm in a ¹ H-NMR spectrum chart of a curcumin-containing preparation;
(2) Based on (a) the full width at half maximum and / or (b) T1 of the peak, and (3) based on the (a) full width at half maximum and / or (b) T1,
An apparatus including an output unit that outputs (a) an estimated value of curcumin elution in a body fluid and / or (b) an estimated value of curcumin absorbability in a living body. The apparatus of Claim 6 which makes a computer function as the said analysis part (1), the said calculation part (2), and the said output part (3).