JP6987528B2 - Curcuminoid-containing tablets - Google Patents

Description

The present invention relates to tablets containing curcuminoids. More specifically, the present invention relates to a curcuminoid-containing tablet having good disintegration property and a method for producing the same. The present invention also relates to a curcuminoid-containing tablet and a method for producing the same, which contains a disintegrant but significantly suppresses the occurrence of appearance defects such as mottled patterns and spots.

Curcuminoid is a yellow polyphenol compound contained in turmeric (turmeric, scientific name Curcuma longa ), etc., and has the effect of strengthening the detoxification function of the liver and promoting the secretion of bile, so it has the effect of improving liver function from the past. And is expected to have the effect of lowering cholesterol levels. Recently, it has also been reported that it has the effect of improving memory and attention, which decline with age.

However, since curcuminoid is a fat-soluble component, it is difficult to dissolve in water, and even if it is ingested as it is, its absorption rate into the body is not very high. For this reason, many attempts have been made to improve the bioabsorbability of curcuminoids. For example, Gotta et al., et al. Reported that coating the curcuminoid powder with oil and fat significantly improved the absorption into the body from the small intestine (Non-Patent Document 1). .. Sally A. et al., et al. Also combined curcuminoids with antioxidants and, optionally, glucuronidation inhibitors to form lipid micelles, microencapsulates, or lipid nanoparticles. It has been reported that the bioavailability of curcuminoids is improved (Patent Document 3).

By the way, tablets are preferred as a dosage form for easily and easily taking pharmaceuticals, dietary supplements, supplements and the like. However, unlike granules, powders, capsules, etc., tablets take a certain amount of time to disintegrate in the stomach or intestine even when taken, and have the disadvantage of lacking immediate effect. In particular, by using curcuminoid powder whose surface is coated with oil or fat as a raw material for producing tablets, it is expected that its disintegration property will be further reduced. Further, when a tablet contains a component that is difficult to mix, a component that easily discolors, or a coloring component as a part of the compounding component, there is a problem that appearance defects such as mottled patterns and spots are likely to occur during molding or storage. In order to eliminate this, it is necessary to add a discoloration reducing agent (Patent Document 1) or to separately coat the surface of the bare tablet with a colored coating agent (coating layer) (Patent Document 1). Patent Document 2). In particular, curcuminoids themselves have a brown color, so when they are mixed with normally white pharmaceutical additives such as excipients and disintegrants and tableted, there is a problem that appearance defects such as mottled patterns and spots become noticeable. be.

Japanese Unexamined Patent Publication No. 2014-47182 Japanese Unexamined Patent Publication No. 2013-179905 U.S. Pat. No. 9,192,644

Gota et al., J Agric Food Chem. 2010 Feb 24; 58 (4): 2095-9. Doi: 10.1021 / jf9024807.

The present invention is a curcuminoid-containing tablet having good disintegration while using a lipid-coated curcuminoid having excellent absorbability in the body as a raw material, that is, a curcuminoid-containing tablet having good disintegration and absorbability, and a method for producing the same. The purpose is to provide. Further, in the present invention, even when a pharmaceutical additive such as a disintegrant is blended, there are few appearance defects such as mottled patterns and spots, so that the surface does not need to be covered with a coating layer, and the tablet is in a bare tablet state. An object of the present invention is to provide a curcuminoid-containing tablet that can be supplied and a method for producing the same.

The present inventors have been diligently studying to solve the above problems, and obtained by tableting by using pregelatinized starch as a disintegrant together with lipid-coated curcuminoid as a compounding component of curcuminoid-containing tablets. It has been found that the disintegration property of the tablets to be obtained is significantly improved. In addition, when tablets are produced using a white disintegrant and brown lipid-coated curcuminoids, tablets with mottled patterns or spots are usually obtained, but when producing curcuminoid-containing tablets, pregelatinized starch is used as a white disintegrant. By wet granulation in the presence of an aqueous solvent and / or granulation under warming conditions, the generation of mottled patterns and spots caused by lipid-coated curcuminoids and disintegrants is significantly suppressed. It has been found that a bare tablet (uncoated tablet) having a good appearance can be obtained.

The present invention has been completed based on these findings, and is characterized by having the following embodiments.

(I) Curcuminoid-containing tablet with good disintegration property (I-1) A tablet containing curcuminoid and a disintegrant.
The curcuminoid is a lipid-coated curcuminoid.
A curcuminoid-containing tablet, characterized in that the disintegrant is pregelatinized starch.
(I-2) The curcuminoid-containing tablet according to (I-1), wherein the pregelatinized starch has a degree of pregelatinization of 30% or more, preferably 40% or more, more preferably 50% or more.
(I-3) The curcuminoid-containing tablet according to (I-1) or (I-2), wherein the pregelatinized starch is derived from at least one selected from the group consisting of potato and cornstarch.
(I-4) The lipid coating the curcuminoid is at least one fatty acid selected from the group consisting of saturated fatty acids and unsaturated fatty acids having 8 to 22 carbon atoms or a mixture thereof (I-1) to (I-1). The curcuminoid-containing tablet according to any one of I-3).

(II) Method for producing curcuminoid-containing tablet (II-1) Method for producing curcuminoid-containing tablet having the following steps:
(1) A step of mixing a lipid-coated curcuminoid and pregelatinized starch to prepare a mixture.
(2) A step of preparing a granulated product by granulating the mixture obtained in the above step (1) in the presence of at least one selected from the group consisting of an aqueous solvent and heat.
(3) A step of preparing a tablet by mixing the granulated product obtained in the above step (2) with other components as necessary and tableting and molding.
(II-2) The production method according to (II-1), wherein the granulation step of (2) above is a step of performing granulation in the presence of heat, specifically, in a temperature atmosphere of 70 ° C. or higher. ..
(II-3) The production method according to (II-1) or (II-2), wherein the pregelatinized starch has a degree of pregelatinization of 30% or more, preferably 40% or more, more preferably 50% or more.
(II-4) The production method according to any one of (II-1) to (II-3), wherein the pregelatinized starch is derived from at least one selected from the group consisting of potato and cornstarch.
(II-5) The lipid coating the curcuminoid is at least one fatty acid selected from the group consisting of saturated fatty acids and unsaturated fatty acids having 8 to 22 carbon atoms or a mixture thereof, (II-1) to. The manufacturing method according to any one of (II-4).

(III) Method for improving disintegration of curcuminoid-containing tablets (III-1) Method for improving disintegration of curcuminoid-containing tablets.
In the production of the tablet, curcuminoids and disintegrants are used as compounding ingredients.
The method described above, wherein the curcuminoid is a lipid-coated curcuminoid and the disintegrant is pregelatinized starch.
(III-2) The method according to (III-1), wherein the degree of pregelatinization of the pregelatinized starch is 30% or more, preferably 40% or more, more preferably 50% or more.
(III-3) The method according to (III-1) or (III-2), wherein the pregelatinized starch is a starch derived from at least one selected from the group consisting of potato and cornstarch.
(III-4) In the process of producing a curcuminoid-containing tablet, the step of granulating a powder mixture of a lipid-coated curcuminoid and pregelatinized starch is performed in the presence of at least one selected from the group consisting of an aqueous solvent and heat. The method for improving disintegration of a curcuminoid-containing tablet according to any one of (III-1) to (III-3).

(IV) A method for suppressing color unevenness of curcuminoid-containing tablets ( uncoated tablets) (IV-1) A method for suppressing color unevenness of curcuminoid-containing tablets containing a lipid-coated curcuminoid and a disintegrant.
Pregelatinized starch was used as the disintegrant.
The method described above, wherein the granulation step of the powder mixture of the lipid-coated curcuminoid and pregelatinized starch is carried out in the presence of at least one selected from the group consisting of an aqueous solvent and heat.

By using a lipid-coated curcuminoid as the curcuminoid and using pregelatinized starch as the disintegrant, a curcuminoid-containing preparation having excellent disintegration property can be prepared. As mentioned above, it is known that coating curcuminoids with lipids improves absorption in the body (oral availability). Therefore, the curcuminoid-containing preparation of the present invention is considered to be excellent in disintegration property and absorption in the body, and thus can exhibit high oral availability.

In addition, the granulation step of the powder mixture of lipid-coated curcuminoid and pregelatinized starch is performed in the presence of water, under heating conditions, or under both conditions, without adopting any of the conditions. Compared with the case of granulation, the occurrence of appearance defects (color unevenness) such as mottled patterns or spots can be significantly suppressed. Therefore, by using pregelatinized starch as a disintegrant in addition to the lipid-coated curcuminoid and producing tablets by adopting the above granulation step, the tablets are excellent in disintegration and absorbability in the body, and oral bioavailability is improved. Not only can curcuminoid-containing tablets be prepared, but color unevenness can be significantly suppressed, so it is possible to produce curcuminoid-containing tablets (bare tablets, bare tablets) with good appearance without adding coloring agents or coating the surface. can.

An image showing the appearance of each curcuminoid-containing tablet (samples A to E) prepared in Experimental Example 2 is shown. The color difference of the surface of each curcuminoid-containing tablet (samples A to E) prepared in Experimental Example 2 was measured, and the result of obtaining the ΔE value using the sample A as a control is shown. The results of observing the surface of each curcuminoid-containing tablet (samples A to E) prepared in Experimental Example 2 using an SEM microscope are shown.

(I) Curcuminoid-containing tablet The curcuminoid-containing tablet targeted by the present invention is tableted using at least two types of curcuminoid coated with lipid (lipid-coated curcuminoid) and pregelatinized starch. Hereinafter, these components will be described.

(A) Lipid-coated curcuminoids Curcuminoids are a type of pigment of polyphenols contained in curcuma longa. The curcuma longa pigment contains curcumin, demethoxycurcumin (also referred to as dimethoxycurcumin), and bisdemethoxycurcumin (also referred to as bisdimethoxycurcumin) as curcuminoids in a proportion of 3 to 6% by mass. It has been known. The composition ratio of curcuminoids contained in the curcuma longa pigment is said to be about 70 to 75% by mass of curcumin, about 15 to 20% by mass of demethoxycurcumin, and about 15 to 20% by mass of bisdemethoxycurcumin. In addition to the above three types, the curcuminoids targeted by the present invention also include tetrahydrocurcumin, which is a metabolite of curcumin, and curcumin ester, which is a prodrug of curcumin. Of these curcuminoids, tetrahydrocurcumin is hydrophobic like curcumin, sparingly soluble in water, and although it is rapidly oxidized or sulfated in the body, unlike curcumin, it has a physiological pH (basic pH). ) It is stable even under conditions and is characterized by high bioavailability. The curcuminoids are preferably curcumin and tetrahydrocurcumin, more preferably curcumin. The curcuminoid-containing tablet of the present invention contains one or more of these curcuminoids, and preferably contains at least curcumin. Further, curcumin and one or more other curcuminoids may be contained in an arbitrary combination, and for example, curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which are called turmeric pigments, may be contained. good.

The lipid-coated curcuminoid targeted by the present invention is obtained by coating the powder surface of the curcuminoid with a lipid. The target lipid here may be any edible one, and specific examples thereof include fatty acids, edible oils, phospholipids, and bile acids. These lipids may be used alone or in any combination of two or more.

Examples of the fatty acid include at least one fatty acid selected from the group consisting of saturated fatty acids having 8 to 22 carbon atoms and unsaturated fatty acids. Fatty acids having 8 to 22 carbon atoms include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, isopalmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, and arachidic acid. Examples thereof include decanoic acid and behenic acid, and one or more of these can be used. It is preferably a fatty acid selected from saturated fatty acids and unsaturated fatty acids having 10 to 20 carbon atoms, and more preferably, saturated fatty acids having 12 to 18 carbon atoms and non-saturated fatty acids having a melting point in the range of about 45 to 70 ° C. It is a fatty acid selected from saturated fatty acids (lauric acid: about 48 ° C, myristic acid: about 53 ° C, palmitic acid: about 64 ° C, stearic acid: about 69 ° C). These fatty acids (fats and oils) may be used alone or in combination of two or more. Further, as the fatty acid, a mixed fatty acid derived from a natural fat or oil containing the above fatty acid can also be used.

Natural fats and oils include, for example, flaxseed oil, eno oil, citrus oil, olive oil, cacao oil, capoc oil, white mustard oil, sesame oil, rice bran oil, safflower oil, shea nut oil, cinnamon oil, soybean oil, and tea seed oil. Vegetable fats and oils such as camellia oil, corn oil, rapeseed oil, palm oil, palm kernel oil, sunflower oil, sunflower oil, cottonseed oil, palm oil, and peanut oil; horse fat, beef fat, pig fat, goat fat, milk fat, fish fat , Fish oil, whale oil and other animal fats and oils; hardened oils hydrogenated from these fats and oils; ester exchanges of these fats and oils (including ester exchanges of fats and oils with fatty acids or fatty acid esters); Fractional oils and fats obtained by collecting the melting point parts can be mentioned. These are included in the above-mentioned cooking oil. As described above, a natural fat or oil containing a fatty acid having 8 to 22 carbon atoms, preferably a fatty acid having 10 to 20 carbon atoms, more preferably a fatty acid having 10 to 18 carbon atoms, and particularly preferably a fatty acid having 12 to 18 carbon atoms. It is a processing oil. It is preferably an oil or fat having a melting point in the range of 45 to 70 ° C. These fats and oils (edible oils) may be used alone or in combination of two or more. Further, it can be used in any combination with the above fatty acid.

Examples of the phospholipid include phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol, and lecithin containing these (soy lecithin, egg lecithin, etc.). These phospholipids may be used alone or in any combination of two or more. Further, it can be used in any combination with the above fatty acid or cooking oil.

Examples of bile acids include deoxycholic acid and conjugates thereof (for example, amino acid conjugates such as glycocholate and taurocholic acid). These bile acids may be used alone or in any combination of two or more. Further, it can be used in any combination with the above fatty acids, cooking oils, or phospholipids.

Such a lipid-coated curcuminoid (lipid-coated curcuminoid) is described above in a place where the curcuminoid is put into a stirring mixer such as a kneader mixer, a pony mixer, a vertical screw type mixer, a flash mixer, a pressure mixer, etc. and stirred. It can be prepared by adding and mixing lipids. In this case, it is preferable to heat and melt the lipid to be added in advance at a temperature equal to or higher than the melting point so that the lipid to be added becomes liquid.

The method of coating with a lipid is not limited to the above method, and a lipid micelle formation method can be exemplified as another method.

As the lipid micelle formation method, for example, a protocol modified from the method of Began G et al. (Began G et al., J Agric Food Chem., 1999 December; 47 (12): 4992-7) can be used. A specific method for forming lipid micelles is described in US Pat. No. 9,192,644, which states that, for example, curcumin (100 mg) is a mixture of deoxycholate (DOC) and phosphatidylcholine (PC) (mol of DOC / PC). Ratio: In addition to 2), solubilize together in a chloroform / methanol (2: 1 vol) mixture, then evaporate the solvent from this mixture and dry with nitrogen, then in phosphate buffered physiological saline (pH 7.4). ) Resuspend (5 mg / ml) and ultrasonically treat this for 5 minutes to prepare lipid micelleized (lipid-coated) curcumin.

It can be confirmed by, for example, electron microscopy that the curcuminoids are coated by these coating steps.

In order to prevent curcuminoids from being hydrolyzed, an antioxidant (antioxidant) may be used in combination with curcuminoids when coating with lipids, and the lipids may be coated and powdered together. Here, examples of the antioxidant include, but are not limited to, ascorbic acid, ascorbic acid acylated derivatives, α-lipoic acid, vitamin E and its derivatives, N-acetylcysteine, reduced glutathione and the like. can. It is preferably a water-soluble antioxidant, and examples thereof include ascorbic acid and an acylated derivative thereof.

Further, for the purpose of increasing the oral bioavailability of curcuminoids, a glucuronidation inhibitor may be used in combination with curcuminoids when coating with lipids, and the lipids may be coated and powdered together. Here, examples of the glucuronidation inhibitor include, but are not limited to, tetrahydrocurcumin, piperine (Bioperine [registered trademark]), and provenside (Probene [registered trademark]). As described above, tetrahydrocurcumin is a metabolite of curcumin and is a component contained in curcuminoids, but it is more stable than curcumin in metabolism and excretion due to glucuronidation (glucuronidation), and also. It is known that when used in combination with curcumin, it suppresses glucuronidation of curcumin and has an effect of increasing the oral bioavailability of curcumin (see Patent Document 3 and the like).

The lipid-coated curcuminoid used in the present invention has a powder shape, and its surface is coated with lipid as described above. The average particle size of the lipid-coated curcuminoid powder is not limited, but is preferably 100 to 500 μm, and more preferably 150 to 365 μm. Here, the average particle size can be measured by using the sieving test method (JIS 8815-1994). Specifically, the lipid-coated curcuminoid powder is sifted using a sieve specified in JIS Z 8801, the mass of the sample remaining on each sieve is measured, and the cumulative distribution is described in the graph to obtain the average particle size. demand.

As the lipid-coated curcuminoid (lipid-coated curcuminoid powder) having such a powder shape, those prepared by the above method may be used, or those which are conveniently commercially available may be used. Examples of commercially available products include the product "Long Vida" (trade name) (Omnica Co., Ltd.) in which the powder surface of the curcuma longa pigment is coated with higher fatty acid, lecithin, or the like.

(B) Pregelatinized starch In the curcuminoid-containing tablets of the present invention, pregelatinized starch functions as a disintegrant.

The pregelatinized starch may be any as long as it fulfills the above-mentioned functions, and is not particularly limited as long as it is used. Examples thereof include corn starch, tapioca starch, sago palm starch, green bean starch, corn starch, and sweet potato starch. These can be used individually by 1 type, or can be used in any combination of 2 or more types. Preferably, cornstarch completely or partially gelatinized, and potato starch can be exemplified.

The degree of pregelatinization (gelatinization degree) can be 30% or more. It is preferably 40% or more, more preferably 50% or more. The upper limit of pregelatinization (gelatinization degree) is not limited to 100%, but is preferably 90%, more preferably 80%. In the present specification, the degree of pregelatinization means a value measured by the second method of glucoamylase.

As the pregelatinized starch, those having a powder shape are used in the production of the curcuminoid-containing tablet of the present invention, similarly to the above-mentioned lipid-coated curcuminoid. Without limitation, it should be adjusted to have the same or similar average particle size and particle size distribution as the lipid-coated curcuminoid powder used so that it is dispersed and mixed as uniformly as possible when mixed with the lipid-coated curcuminoid powder. Is preferable. Although not limited, the average particle size is preferably 50 to 150 μm. The average particle size can also be measured by using the sieving test method (JIS 8815-1994) in the same manner as the lipid-coated curcuminoid powder.

(C) Curcuminoid-containing tablet The curcuminoid-containing tablet of the present invention is characterized by containing the above-mentioned lipid-coated curcuminoid and pregelatinized starch, and is produced by compression-molding a mixture containing at least these two components into a tablet shape. be able to.

The proportion of the lipid-coated curcuminoid contained in the curcuminoid-containing tablet of the present invention can be set and adjusted from the range of usually 10 to 95% by mass per 100% by mass of the curcuminoid-containing tablet. It is preferably 20 to 80% by mass, and more preferably 30 to 70% by mass.

Further, the proportion of pregelatinized starch contained in the curcuminoid-containing tablet of the present invention can be set and adjusted from the range of usually 5 to 50% by mass per 100% by mass of the curcuminoid-containing tablet. It is preferably 10 to 50% by mass, and more preferably 20 to 50% by mass. The pregelatinized starch is not limited, but is preferably blended in the range of 30 to 200 parts by mass with respect to 100 parts by mass of the lipid-coated curcuminoid contained in the curcuminoid-containing tablet. It is preferably 50 to 150 parts by mass, and more preferably 50 to 100 parts by mass.

The curcuminoid-containing tablet of the present invention has a disintegrant other than pregelatinized starch, a binder, an excipient, a fluidizing agent, and a pH adjuster (buffering agent) in addition to the above-mentioned components, as long as the effects of the present invention are not impaired. It can be prepared by blending at least one additive selected from the group consisting of agents), wetting agents, flavoring agents, lubricants and the like. Here, the additive is a substance other than the active ingredient (curcuminoid) contained in the pharmaceutical product (tablet), in other words, a substance that does not exert a pharmacological action, and facilitates tableting, stabilizes quality, and is easy to use. Includes those that are formulated for the purpose of enhancing.

Although not limited, the binder is, for example, crystalline cellulose, crystalline cellulose / fine-grained silicon oxide, cellulose derivative, sugar alcohol, reduced maltose water candy, etc.; the excipient is, for example, lactose, dextrin, starch such as corn starch, etc. The pH adjuster (buffer) is, for example, sodium citrate, sodium acetate, sodium phosphate, etc .: The fluidizing agent is, for example, fine silicon dioxide, etc.; The lubricant is, for example, stearic acid, etc. Examples thereof include calcium stearate, magnesium stearate, stearyl sodium fumarate, sucrose fatty acid ester, talc, fine silicon dioxide, light anhydrous silicic acid, hydrous silicon dioxide, vegetable fats and oils, and hardened oil.

In the curcuminoid-containing tablet of the present invention, since the curcuminoid itself is a colored component, it is not necessary to add a colorant, but the combination is not limited. Examples of the colorant include titanium oxide and iron oxide.

These additives may be blended in a ratio according to the blending purpose of each additive as long as the effects of the present invention are not impaired, and are not particularly limited as long as they are blended.

The curcuminoid-containing tablet of the present invention can be produced by the method described in (II) below.

(II) Method for Producing Curcuminoid-Containing Tablets The curcuminoid-containing tablet of the present invention can be produced by using a known method for producing a tablet (tablet tapping method). Preferably, a step of mixing the above-mentioned lipid-coated curcuminoid powder and pregelatinized starch powder (mixing step), a step of granulating the powder mixture obtained by the mixing step (granulation step), and a prepared preparation. It can be produced by a method including at least a step of tableting granules and molding into a tablet (tablet step), and if necessary, further including other steps.

(1) Mixing Step The mixing step is a step of mixing the above-mentioned lipid-coated curcuminoid powder and pregelatinized starch powder. The mixing ratio is as described above, and the description can be incorporated herein by reference. In addition to the lipid-coated curcuminoid powder and pregelatinized starch powder, components other than the lipid-coated curcuminoid powder and pregelatinized starch powder can be blended as long as the effects of the present invention are not impaired. Examples thereof include an inhibitor, an inhibitor of glucuronidation, and the like.

The mixing method is not particularly limited and can be mixed by a conventional method. An apparatus can be used for the mixing, and examples of the apparatus include a container tumbler, a V-type mixer, and a bore container mixer. Further, the mixing step can be carried out under normal humidity conditions (relative humidity 30 to 80%) and room temperature (25 ± 5 ° C.) adopted in the conventional formulation step, although not limited.

(2) Granulation step The granulation step is a step of granulating the powder mixture prepared in the above-mentioned (1) mixing step to prepare a granulated product.

The granulation method may be any method as long as the powder mixture can be granulated, and a known method can be appropriately selected depending on the intended purpose. Specifically, the lipid-coated curcuminoid powder, pregelatinized starch powder, and, if necessary, a powder mixture of other components are kneaded, kneaded, and / or stirred, and an aqueous solvent is appropriately added or added. Examples include the method of spraying.

The aqueous solvent used here may be any one that can wet the powder mixture, and is not particularly limited, and examples thereof include water, ethanol, and hydrous ethanol. Water is preferred. As the water, distilled water, ion-exchanged water, pure water, RO water can be used, but distilled water, ion-exchanged water, pure water, and RO water are preferable, and more preferably ion-exchanged water. Is.

The amount of the aqueous solvent used is not particularly limited, but can be appropriately set and adjusted from the range of usually 10 to 30 parts by mass with respect to 100 parts by mass of the powder mixture. When the amount of the solvent is much less than 10 parts by mass, it tends to be difficult to obtain the effect of the present invention, particularly the effect of suppressing appearance defects such as mottled patterns and spots. On the other hand, if the amount of the solvent greatly exceeds 30 parts by mass, it tends to take a long time to granulate and the production efficiency deteriorates, and the granulated granules become too large to cause tableting defects. be.

The method for adding the aqueous solvent (spraying method) is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a spraying means provided in the granulation apparatus to be used, for example, a method of spraying from a spray gun, a spray nozzle, or the like is preferable. At this time, the spraying conditions are not particularly limited, and the spraying amount, the size of the mist particles (mist) to be sprayed, the spraying time, the spraying interval, and the like can be appropriately selected from known conditions.

As shown in Sample C of Experimental Example 2 described later, by adding (spraying) an aqueous solvent to the powder mixture in the granulation step and granulating in the presence of the solvent, the aqueous solvent is not used. Compared with the case of granulation, it is possible to significantly suppress appearance defects such as mottled patterns and spots. However, the addition of the aqueous solvent is not an essential operation. For example, by performing the granulation step under heating conditions as shown in Sample D of Experimental Example 2 described later, the above-mentioned poor appearance is significant even without using the aqueous solvent. Can be suppressed.

The granulation apparatus used in the granulation step is not particularly limited, and can be appropriately selected from known granulation apparatus according to the purpose. For example, rolling fluidized coating equipment (for example, rolling fluidized coating equipment-MP-1, manufactured by Paulek Co., Ltd.), centrifugal fluidized coating granulation equipment (for example, Granurex (for example, manufactured by Freund Sangyo Co., Ltd.), composite type). Granulation coating equipment (for example, Spiraflow (manufactured by Freund Sangyo Co., Ltd.), fluidized bed granulation drying equipment (for example, GPCG / WSG-T series (manufactured by Paulek Co., Ltd.), flow coater (manufactured by Freund Sangyo Co., Ltd.)) , Fine particle coating / granulation equipment-SFP series (manufactured by Paulek Co., Ltd.), Fine particle coating equipment GPCG-SCP series (manufactured by Paulek Co., Ltd.), Stirring and mixing granulation equipment (for example, vertical granulator, manufactured by Paulek Co., Ltd.), etc. Among these, a rolling fluidized coating apparatus and / or a fluidized bed granulation drying apparatus is preferable.

The temperature conditions adopted in the granulation step can be appropriately selected in the range of 5 to 100 ° C. depending on the purpose. Specifically, in order to achieve the effect of the present invention of suppressing appearance defects such as mottled patterns and spots, when the above-mentioned aqueous solvent is added (sprayed) in the granulation step, the above-mentioned 5 to 5 It can be selected from the range of 100 ° C. It is preferably 5 to 80 ° C, more preferably 10 to 40 ° C. On the other hand, when the above-mentioned aqueous solvent is not added (sprayed) in the granulation step, it is preferable to carry out the above-mentioned effect under a temperature condition of 40 ° C. or higher. It is preferably in the range of 40 to 100 ° C, more preferably 40 to 70 ° C. That is, in order to achieve the effect of the present invention of suppressing appearance defects such as mottled patterns and spots, the granulation step is carried out in the presence of an aqueous solvent and under at least one of heating conditions. It is preferable to carry out under both conditions. That is, even when the granulation step is performed in the presence of an aqueous solvent, it can be performed under heating conditions of 40 ° C. or higher. As the temperature condition in this case, a range of 40 to 100 ° C., preferably 40 to 70 ° C. can be exemplified.

The heating in the granulation step can be performed by heating the granulation apparatus or by controlling the temperature of the gas supplied to the granulation apparatus.

Therefore, the air supply temperature in the granulation step can be appropriately selected according to the above purpose. As described above, when the aqueous solvent is added (sprayed) in the granulation step, 5 to 100 ° C., preferably 5 to 80 ° C. can be adopted. On the other hand, when the aqueous solvent is not added (sprayed) in the granulation step, 50 ° C. or higher, preferably 50 to 100 ° C., more preferably 50 to 70 ° C. can be adopted.

The exhaust temperature in the granulation process is not particularly limited and can be appropriately selected depending on the purpose. Usually, 20 to 45 ° C. is preferable, and about 25 to 40 ° C. is more preferable.

The time of the granulation step is not particularly limited as long as the desired granulation can be achieved, and can be appropriately selected according to the purpose. Usually, it can be about 15 to 60 minutes, preferably about 20 to 50 minutes.

The size of the granulated product thus prepared (median diameter: d50) is not particularly limited and can be appropriately selected. Although not limited, 100 to 700 μm is preferable, and 300 to 500 μm is more preferable. If the median diameter (d50) is less than 100 μm, aggregation may occur in the tableting process and the production efficiency may deteriorate, and if it exceeds 700 μm, segregation may occur in the tableting process. .. The median diameter (d50) can be measured by a laser diffraction / scattering type particle diameter / particle size distribution measuring device Microtrac MT3000II (manufactured by Nikkiso Co., Ltd.). In order to make the granulated product have a desired particle size, it can be adjusted by adjusting the supply air temperature, the exhaust temperature, the time, the amount of the solvent sprayed, and the like.

(3) Drying Step The granulated product prepared in the above-mentioned (2) Granulation step may be subjected to a drying step, if necessary.

The drying step is advantageous in that the handleability (operability) is improved and the quality of the obtained product is also improved in the subsequent mixing / / and tableting steps of other components. .. The method for drying is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include an air-drying method and a heat-drying method. The air-drying method is preferable. The granulated product obtained in the granulation step is subjected to a drying step as needed, and can be preferably dried until the water content reaches about 3 to 5% by mass.

(4) Mixing Steps of Other Components The granulated product prepared in the above ((2) step or (3) step) may be further blended with other components and mixed, if necessary. Examples of the other components to be blended here include disintegrants other than the above-mentioned pregelatinized starch, binders, excipients, fluidizers, pH adjusters (buffers), wetting agents, flavoring agents, lubricants and the like. At least one additive selected from the group can be exemplified. As the mixing method, the method described in (1) above can be similarly adopted.

(5) Tableting step The tableting step is a step of preparing a tablet (bare tablet, bare tablet) by tableting a granule of at least a mixture of a lipid-coated curcuminoid powder and pregelatinized starch powder. ..

The pressure (tablet pressure) at the time of filling and pressurizing in the tableting step is not particularly limited and may be appropriately selected depending on the intended purpose. It is usually 1 to 2 tons (10 to 20 kN). If the pressure is much lower than 1t (10kN), sufficient hardness may not be obtained and the tablet may become brittle or sticking may occur. If it greatly exceeds 2t (20kN), capping may occur. On the other hand, when the pressure is in a more preferable range than the above, a tablet having sufficient hardness can be obtained, and it is advantageous in that tableting failure can be suppressed such that the occurrence of sticking and capping can be suppressed.

The device used for tableting is not limited, but for example, a tableting machine (for example, HT-APSS type, HT-AP-MS type, HT-X-SS type, HT-X-MS type (above, stock). Company Hata Iron Works); VIRGO, AQUARIUS, LIBRA (all manufactured by Kikusui Seisakusho Co., Ltd.)) and the like.

(6) Other Steps The other steps are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a crushing step and a sizing step.

The pulverization step can be adopted as a pre-grinding process, for example, in order to control the particle size of the powder mixture used for granulation so as not to become too large before the granulation step. The method for pulverizing is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a pulverizing granulator (power mill). The granulation step is a step of sizing a granulated product of a lipid-coated curcuminoid powder, pregelatinized starch, and / or a mixture of these powders to obtain a uniform particle size. This makes it possible to improve the handleability (operability) in the locking process. The sizing method is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a method using a sieve having a desired opening.

Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to these examples.

Experimental Example 1 Production of curcuminoid-containing tablets and evaluation of disintegration (1) Production of curcuminoid-containing tablets Various curcuminoid-containing tablets (Examples 1 and 2, Comparative Examples 1 and 2) were prepared using the ingredients shown in Table 1. Manufactured. Here, a lipid-coated curcuminoid powder preparation (trade name: Long Vida, obtained from Omnica Co., Ltd., the same applies to the following experimental examples) was used as the curcuminoid. The lipid-coated curcuminoid powder formulation is characterized in that the surface of the curcuminoid powder is coated with at least one lipid selected from the group consisting of saturated or unsaturated fatty acids having 8 to 22 carbon atoms.

Preparation Methods for Examples 1 and 2 and Comparative Examples 1 and 2 Various curcuminoid-containing tablets (Examples 1 and 2 and Comparative Examples 1 and 2) were prepared according to the following methods based on the compositions shown in Table 1. ..

[Production method]
1. 1. The lipid-coated curcuminoid powder preparation and the disintegrant are mixed at the ratios shown in Table 1, and the obtained mixed powder is heated to 40 ° C. with a fluidized bed granulator (MP-01, manufactured by Paulec).

2. 2. While supplying air at 50 ° C to the fluidized bed granulator, an amount of ion-exchanged water equivalent to 20% (part by mass) of the total amount of the mixed powder is sprayed at a flow rate of 0.59 kg / min and an atomizing air volume of 800 L / min. ..

3. 3. Dry until the water content of the mixed powder reaches 3 to 5% by mass.

4. The granulated product thus prepared is mixed with other raw materials to obtain a mixture.

5. Weigh 280 mg from the prepared mixture and place it in a rotary tableting machine (Virgo, manufactured by Kikusui Co., Ltd.) having a mortar capable of producing tablets with a diameter of 9 mm. Tablets are manufactured with a setting of 0.6 mm and a main pressure compression thickness of 1.2 mm, and a tableting pressure display of about 1.5 t (15 kN).

(2) Evaluation of disintegration of curcuminoid-containing tablets The curcuminoid-containing tablets produced above (Examples 1 and 2 and Comparative Examples 1 and 2) were subjected to a disintegration test according to the regulations of the Japanese Pharmacopoeia, and the disintegration time was measured.

Specifically, each curcuminoid-containing tablet (Examples 1 and 2 and Comparative Examples 1 and 2) prepared above is put into one grain in six holes of the basket of the disintegration tester (manufactured by Toyama Sangyo Co., Ltd .: NT-1HM). I put them one by one, and put the auxiliary board from above. The basket is then immersed in a predetermined amount of water (37 ° C ± 2 ° C) in a beaker and vibrated up and down in water (29-32 reciprocations / min, amplitude 53-57 mm) to complete the tablets from the basket. The time at which it disappeared was measured and used as the decay time (minutes).

The results are shown in Table 2.

From the comparison of the results of Comparative Examples 1 and 2, the disintegration time was slightly shortened by using the disintegrant (hydroxypropyl cellulose) as compared with the case where the disintegrant was not used (Comparative Example 2), but the effect was almost the same. I was not able to admit. On the other hand, it was confirmed that the disintegration time was significantly shortened by using pregelatinized starch (Examples 1 and 2) as the disintegrant. From this, it was found that by using a lipid-coated curcuminoid as a curcuminoid and using pregelatinized starch as a disintegrant, a curcuminoid-containing preparation having excellent disintegration property and absorption into the body can be prepared.

Experimental Example 2 Production of Curcuminoid-Containing Tablets and Evaluation of Appearance The following curcuminoid-containing tablets were produced and their appearance was evaluated.
[sample]
・ A: Tableted product of lipid-coated curcuminoid powder ・ B: Tableted product of pregelatinized starch granulated with lipid-coated curcuminoid powder ・ C: Decapsulated product of lipid-coated curcuminoid powder and pregelatinized starch granulated with water Tablets ・ D: Tablets obtained by heating and granulating lipid-coated curcuminoid powder and pregelatinized starch ・ E: Tablets obtained by granulating lipid-coated curcuminoid powder and pregelatinized starch with water and heat.

1. 1. Method for Producing Curcuminoid-Containing Tablets The above samples A to E were produced according to the following methods.

(1) Sample A:
a. Each component was mixed according to the formulation of Comparative Example 2 in Table 1.
b. Weigh 280 mg from the prepared mixture and measure it with a φ9 mm sugar-coated R-usuki (using a rotary tableting machine) at 25 ° C, filling depth of 7.0 mm, preload compression thickness of 1.6 mm, and main pressure compression thickness of 1.2 mm. A tablet containing curcuminoid (Sample A) was prepared by setting and tableting at a tableting pressure display of about 1.5 t (15 kN).

(2) Sample B:
a. While supplying air at 50 ° C in a fluidized bed granulator to pregelatinized starch (derived from potato), while spraying ion-exchanged water equivalent to 20% by mass of the total amount of pregelatinized starch (flow rate 0.59 kg / min, Atomize air volume 800L / min), granulated.
b. The pregelatinized starch granules prepared above were dried to a moisture content of 3-5% by weight.
c. The pregelatinized starch granules prepared above were used as the "pregelatinized starch" shown in Table 1 and mixed with other raw materials according to the formulation of Example 1 in Table 1.
d. Weigh 280 mg from the prepared mixture and measure it with a φ9 mm sugar-coated R-usuki (using a rotary tableting machine) at 25 ° C, filling depth of 7.0 mm, preload compression thickness of 1.6 mm, and main pressure compression thickness of 1.2 mm. A tablet containing curcuminoid (Sample B) was prepared by setting and tableting at a tableting pressure display of about 1.5 t (15 kN).

(3) Sample C:
a. The lipid-coated curcuminoid powder preparation and pregelatinized starch were mixed at the ratios shown in Table 1 (Example 1).
b. In a fluidized bed granulator, while supplying air at 20 ° C, ion-exchanged water equivalent to 20% by mass of the total amount of the mixture prepared above was sprayed (flow velocity 0.59 kg / min, atomizing air volume 800 L / min). ).
c. The granulated product prepared above was dried until the moisture content reached 3 to 5% by mass.
d. The dried granules prepared above were mixed with other raw materials according to the formulation of Example 1 in Table 1.
e. Weigh 280 mg from the prepared mixture and measure it with a φ9 mm sugar-coated R-usuki (using a rotary tableting machine) at 25 ° C, filling depth of 7.0 mm, preload compression thickness of 1.6 mm, and main pressure compression thickness of 1.2 mm. A tablet containing curcuminoid (Sample C) was prepared by setting and tableting at a tableting pressure display of about 1.5 t (15 kN).

(4) Sample D:
a. The lipid-coated curcuminoid powder preparation and pregelatinized starch (derived from potato) were mixed at the ratio of the formulation of Example 1 in Table 1, and the obtained mixture was granulated while heating to 40 ° C. with a fluidized bed granulator.
b. The granulated product prepared above is mixed with other raw materials at the ratios shown in Example 1 of Table 1.
c. Weigh 280 mg from the mixture prepared above, and weigh it with a φ9 mm sugar-coated R mortar (using a rotary tableting machine) at 25 ° C., filling depth 7.0 mm, preload compression thickness 1.6 mm, main pressure compression thickness 1. The tablet was set to 2 mm and the tableting pressure was about 1.5 t (15 kN), and a curcuminoid-containing tablet (Sample D) was prepared.

(5) Sample E:
a. The lipid-coated curcuminoid powder preparation and pregelatinized starch (derived from potato) were mixed at the ratio of the formulation of Example 1 in Table 1, and the obtained mixture was heated to 40 ° C. with a fluidized bed granulator.
b. Ion-exchanged water equivalent to 20% by mass of the total amount of the mixture prepared above is sprayed into the fluidized bed granulator while supplying air at 50 ° C (flow velocity 0.59 kg / min, atomizing air volume 800 L /). min) Granulated.
c. The granulated product obtained above was dried until the moisture content was 3 to 5% by mass.
d. The dried granules obtained above were mixed with other raw materials at the ratios shown in Example 1 of Table 1.
e. Weigh 280 mg from the obtained mixture, and weigh it with a φ9 mm sugar-coated R mortar (using a rotary tableting machine) at 25 ° C., pressure filling depth 7.0 mm, preload compression thickness 1.6 mm, main pressure compression thickness 1. A curcuminoid-containing tablet (Sample E) was prepared by setting the tablet to 2 mm and tableting at a tableting pressure display of about 1.5 t (15 kN).

2. 2. Appearance Evaluation of Curcuminoid-Containing Tablets FIG. 1 shows images showing the appearance of various curcuminoid-containing tablets (samples A to E) prepared above. The appearance of each of these tablets was evaluated by the three methods described later.

(1) Evaluation of color unevenness using color difference A powdered sample (tablet powder) before tableting and molding curcuminoid-containing tablets (samples A to E) using a color difference meter (CR-300, manufactured by Konica Minolta). ), And each color difference (ΔE value) was measured using the tableting powder of sample A as a control (reference). The results are shown in FIG. As shown in FIG. 2, the color difference ΔE value of sample A from the tableting end is as follows: sample B (locking end)> sample C (locking end)> sample D (locking end)> sample E (locking end). In this order, sample B (tablet powder) was the largest, and sample E (locking powder) was the smallest.

(2) Measurement of the mottled pattern size of the tablet surface using the contamination measurement chart The size of the brown pattern on the surface of the curcuminoid-containing tablets (samples A to E) is measured using the contamination measurement chart (manufactured by Chaoyang Co., Ltd.). did. Tablets with an average brown pattern size of 0.5 mm ² or more were defined as poor-looking tablets. As a result, Sample B was determined to be a tablet having a poor appearance.

(3) Observation of tablet surface using SEM microscope The surface of curcuminoid-containing tablets (Samples A to D) was observed using an SEM microscope (manufactured by KEYENCE CORPORATION). The results are shown in FIG. As shown in FIG. 3, in sample B, granulated pregelatinized starch is aggregated. In sample C, pregelatinized starch is granulated and solidified, but it is also scattered among curcuminoid particles. Sample D is evenly dotted with pregelatinized starch than sample C.

As for the appearance of the curcuminoid-containing tablets (Samples A to E), as can be seen from the results obtained by the above three methods, whether the granulation step of the powder mixture of the lipid-coated curcuminoid and the pregelatinized starch is performed in the presence of water. By performing under heating conditions or under both conditions, the occurrence of poor appearance (color unevenness) such as mottled patterns or spots is significant compared to the case of granulation without adopting any of the conditions. Was suppressed. Therefore, by using pregelatinized starch as a disintegrant in addition to the lipid-coated curcuminoid and producing tablets by adopting the above granulation step, the tablets are excellent in disintegration and absorbability in the body, and oral bioavailability is improved. Not only can curcuminoid-containing tablets be prepared, but color unevenness can be significantly suppressed, so it is possible to produce curcuminoid-containing tablets (bare tablets, bare tablets) with good appearance without adding coloring agents or coating the surface. can.

Claims (5)

A tablet containing curcuminoids and disintegrants
The curcuminoid is a lipid-coated curcuminoid.
The lipid coating the curcuminoid is at least one fatty acid selected from the group consisting of saturated fatty acids and unsaturated fatty acids having 8 to 22 carbon atoms, or a mixture thereof.
The disintegrant is pregelatinized starch.
Ratio 30 to 70 wt% of the lipid coating curcuminoids per the tablet 100 wt%, the percentage of pregelatinized starch and wherein 10 to 50% by mass Rukoto, curcuminoid-containing tablets
(However, when a tablet having a mass of 330 mg and a diameter of 9 mm is prepared at a tableting pressure of 10 kN, a solid preparation containing an active ingredient having a hardness of 25 N or less and inferior moldability and pregelatinized starch is excluded.) The curcuminoid-containing tablet according to claim 1, wherein the pregelatinized starch has a degree of pregelatinization of 30% or more. The curcuminoid-containing tablet according to claim 1 or 2, wherein the pregelatinized starch is derived from at least one selected from the group consisting of potatoes and cornstarch. The method for producing a curcuminoid-containing tablet according to any one of claims 1 to 3, which comprises the following steps:
(1) Curcuminoids and pregelatinized starch coated with at least one fatty acid selected from the group consisting of saturated fatty acids and unsaturated fatty acids having 8 to 22 carbon atoms or a mixture thereof , respectively, 30 to 70 per 100% by mass of tablets. The step of mixing so as to be 10% by mass and 10 to 50% by mass,
(2) A step of granulating the mixture obtained in the above step (1) in the presence of at least one selected from the group consisting of an aqueous solvent and heat.
(3) A step of tableting and molding the granulated product obtained in the above step (2) by mixing it with other components as necessary. The production method according to claim 4 , wherein the step (2) is a granulation step in the presence of heat, and the granulation step is a step of performing granulation in a temperature atmosphere of 40 to 70 ° C.

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