Granules, granule-containing pharmaceutical preparation, and granule-containing food

Abstract

One of the purposes of the present invention is to provide granules which can be applied to a granular or tablet preparation containing a fat-soluble or oily drug or food or a water- or oxygen-labile drug or food. In one embodiment, one of the purposes of the present invention is to provide granules containing a solidified liquid oil and applicable to a granular or tablet preparation containing a fat-soluble or oily drug or food or a water- or oxygen-labile drug or food. According to one embodiment of the present invention, granules are provided, each granule comprising: a gel particle containing a liquid oil and stearic acid, calcium stearate or magnesium stearate; and a powder additive layer disposed on the surface of the gel particle. In the gel particle, the mass ratio of the amount of stearic acid, calcium stearate or magnesium stearate to the amount of the liquid oil may be 1:1 or greater.

Description

Granules, pharmaceutical preparations containing granules, and foods containing granules

[0001] One embodiment of the present invention relates to granules, pharmaceutical formulations comprising the granules, and food products comprising the granules, or to granules comprising solidified liquid oil, pharmaceutical formulations comprising the granules, and food products comprising the granules.

[0002] Conventionally, in order to formulate fat-soluble or oily drugs or drugs that are unstable to water or oxygen while maintaining their stability, a method of dissolving or dispersing the drug in liquid oil has been used. The resulting oily solution or suspension has been encapsulated in a coating such as gelatin to form a soft capsule formulation, or a technique of solidifying the oily solution or suspension has been investigated, but it has been difficult to ensure desirable formulation properties (e.g., hardness, appearance, and disintegrability) and drug stability.

[0003] As a technology for solidifying a fat-soluble drug (oily drug), for example, Patent Document 1 describes a rapidly disintegrating solid preparation containing a water-soluble polymeric substance, a fat-soluble drug uniformly dispersed in the polymeric substance, and an excipient. Also, Patent Document 2 describes an intraorally rapidly disintegrating tablet obtained by compressing a mixture containing granules in which a fat-soluble drug is adsorbed onto an adsorbent, sugars, crystalline cellulose, and a lubricant.

[0004] Patent Document 1: JP 2002-37727 A, International Publication No. 2007 / 072840

[0005] An object of the present invention is to provide granules that can be used for granules or tablets containing fat-soluble or oily drugs or foods, or drugs or foods that are unstable in water or oxygen. In one embodiment, an object of the present invention is to provide granules containing solidified liquid oil that can be used for granules or tablets containing fat-soluble or oily drugs or foods, or drugs or foods that are unstable in water or oxygen.

[0006] According to one embodiment of the present invention, there is provided a granule comprising gel particles comprising a liquid oil and stearic acid, calcium stearate, or magnesium stearate, and a powder additive layer disposed on the surface of the gel particles.

[0007] In the gel particles, the content of stearic acid, calcium stearate or magnesium stearate to the liquid oil may be at a mass ratio of 1:1 or more.

[0008] The gel particles may further contain one or more oil-soluble substances selected from the group consisting of aminoalkyl methacrylate copolymers, methacrylic acid copolymers, and hypromellose acetate succinate.

[0009] The liquid oil may be one or more selected from the group consisting of medium chain triglycerides, medium chain mono- and diglycerides, peanut oil, corn oil, soybean oil, sesame oil, oleic acid, olive oil, esterified corn oil, sunflower oil, cottonseed oil, safflower oil, and peppermint oil.

[0010] According to one embodiment of the present invention, there is provided a pharmaceutical formulation comprising a drug in gel particles of any of the granules.

[0011] According to one embodiment of the present invention, there is provided a food product comprising any of the granular gel particles described above and a food ingredient therein.

[0012] The present invention can also be applied to cosmetics.

[0013] According to one embodiment of the present invention, liquid oil is solidified to provide granules that can be used for granules and tablets. According to one embodiment of the present invention, the granules of the present invention have good flowability and can be compressed into tablets. Furthermore, according to one embodiment, pharmaceutical preparations and foods containing the granules are provided.

[0014] 1 is a schematic diagram of a granule 10 according to one embodiment of the present invention; FIG. 2 is a scanning electron microscope image of a granule of Example 3; FIG. 3 is a scanning electron microscope image of a granule of Example 4; FIG. 4 is a scanning electron microscope image of a granule of Example 5; FIG. 5 is a scanning electron microscope image of a granule of Example 6; FIG. 6 is a scanning electron microscope image of a granule of Example 7; FIG. 7 is a scanning electron microscope image of a granule of Example 8; FIG. 8 is a scanning electron microscope image of a granule of Example 9 at 80x magnification; FIG. 9 is a scanning electron microscope image of a granule of Example 9 at 250x magnification; FIG. 10 is a scanning electron microscope image of a granule of Example 9 at 150x magnification; and FIG. 11 is a diagram showing the flow velocity index of granules of an example.

[0015] The granules according to the present invention, the pharmaceutical preparation containing the granules, and the food containing the granules are described in detail below. However, the granules according to the present invention, the pharmaceutical preparation containing the granules, and the food containing the granules are not to be construed as being limited to the description of the following embodiments and examples.

[0016] The granules according to the present invention are granules having a powder additive layer on the surface of gel particles formed by solidifying liquid oil with a gelling agent. Fig. 1 is a schematic diagram of a granule 10 according to this embodiment. Fig. 1 shows an end view of a cross section passing through the center of the granule 10. In one embodiment, the granule 10 comprises gel particles 11 containing liquid oil and stearic acid, calcium stearate, or magnesium stearate, and a powder additive layer 15 disposed on the surface of the gel particle 11.

[0017] The liquid oil contained in the gel particles 11 is not particularly limited as long as it is an oily substance that is liquid at room temperature and acceptable for use in pharmaceutical preparations and foods. For example, the gel particles 11 may contain one or more oily substances selected from the group consisting of medium-chain fatty acid triglycerides, medium-chain mono- and diglycerides, peanut oil, corn oil, soybean oil, sesame oil, oleic acid, olive oil, esterified corn oil, sunflower oil, cottonseed oil, safflower oil, and peppermint oil. The content of the liquid oil contained in the gel particles 11 may be 40% by mass or less or 50% by mass or less relative to the total mass of the gel particles 11. In one embodiment, the content of the liquid oil contained in the gel particles 11 is 5% by mass or more relative to the total mass of the gel particles 11 for the purpose of dissolving drugs and the like, as described below. Therefore, in one embodiment, the content of the liquid oil contained in the gel particles 11 is 5% by mass or more and 50% by mass or less, or 5% by mass or more and 40% by mass or less, relative to the total mass of the gel particles 11.

[0018] The gel particles 11 contain stearic acid, calcium stearate, or magnesium stearate. Stearic acid, calcium stearate, or magnesium stearate is a component (gelling agent) that gels liquid oil. Therefore, the content of stearic acid, calcium stearate, or magnesium stearate in the gel particles 11 can be set arbitrarily within a range that achieves the desired properties (solid state) of the gel particles 11. Furthermore, the content of stearic acid, calcium stearate, or magnesium stearate in the gel particles 11 can be set arbitrarily within a range that achieves adhesion that allows a powder additive layer 15 to be disposed on the surface of the gel particles 11. For example, the content of stearic acid, calcium stearate, or magnesium stearate in the gel particles 11 may be 30% by mass or more, or 40% by mass or more, relative to the total mass of the gel particles 11. In one embodiment, the content of stearic acid, calcium stearate, or magnesium stearate in the gel particles 11 is 90% by mass or less relative to the total mass of the gel particles 11 in order to incorporate other additives. Therefore, in one embodiment, the content of stearic acid, calcium stearate, or magnesium stearate contained in gel particle 11 is 30% by mass or more and 90% by mass or less, or 40% by mass or more and 90% by mass or less, relative to the total mass of gel particle 11. Furthermore, the content of stearic acid, calcium stearate, or magnesium stearate in gel particle 11 to the liquid oil is preferably at a mass ratio of 1:1 or more.

[0019] In one embodiment, the gel particles 11 may further contain one or more oil-soluble substances selected from the group consisting of aminoalkyl methacrylate copolymers, methacrylic acid copolymers, and hypromellose acetate succinate esters. These oil-soluble substances are optional components that can impart viscosity to the liquid (solution before solidification to form the gel particles 11) containing the liquid oil and gelling agent that constitute the gel particles 11, thereby improving manufacturability. The oil-soluble substance also lowers the melting point of the liquid containing the liquid oil and gelling agent, reducing the thermal load on a drug optionally contained in the liquid and suppressing the increase in drug-related substances during manufacturing. The content of the oil-soluble substance contained in the gel particles 11 may be 0% by mass or more, 10% by mass or more, or 20% by mass or less, or 30% by mass or less, relative to the total mass of the gel particles 11. For example, the content of the oil-soluble substance contained in gel particle 11 is from 0% by mass to 30% by mass, from 10% by mass to 30% by mass, from 0% by mass to 20% by mass, or from 10% by mass to 20% by mass, relative to the total mass of gel particle 11. Furthermore, the mass ratio of the oil-soluble substance content in gel particle 11 to the liquid oil is preferably 1:1 or less, and more preferably 1:0.5 or less.

[0020] In the granule 10, the powder additive layer 15 has the function of retaining droplets of the gel particles 11 as they solidify. The powder additive layer 15 also has the function of preventing the solidified gel particles 11 from adhering to each other. The powder additive constituting the powder additive layer 15 is not particularly limited as long as it is acceptable for pharmaceutical preparations and foods, can adhere to the gel particles 11, and can produce the granules of the present invention. For example, the powder additive layer 15 can contain one or more powder additives selected from the group consisting of light anhydrous silicic acid, stearic acid, calcium stearate, magnesium stearate, polyvinyl alcohol, methacrylic acid copolymer, partially pregelatinized starch, hypromellose, gelatin, carnauba wax, bentonite, cumulite, talc, and titanium oxide. The amount of the powder additive constituting the powder additive layer 15 is not particularly limited.

[0021] [Pharmaceutical Preparation] In one embodiment, the granules 10 may contain a drug in the gel particles 11. The drug contained in the gel particles 11 is not particularly limited, and may be a water-unstable drug or a fat-soluble drug. The amount of drug contained in the gel particles 11 is not particularly limited, as long as it is an effective amount in the pharmaceutical preparation to be taken and is an amount that allows the granules of the present invention to be formed.

[0022] Granules 10 can be mixed with pharmaceutically acceptable additives and compressed into tablets. Alternatively, granules containing granules 10 may be prepared. Alternatively, granules 10 may be enclosed in hard capsules. Examples of pharmaceutically acceptable additives include, but are not limited to, excipients, binders, disintegrants, lubricants, stabilizers, preservatives, buffers, flavoring agents, fragrances, and coloring agents.

[0023] In the pharmaceutical preparation according to this embodiment, when the drug is unstable in water, the drug can be contained in gel particles 11, thereby making it possible to form granules without using water while maintaining stability.

[0024] [Food] In one embodiment, granule 10 may contain food ingredients in gel particles 11. The food ingredients contained in gel particles 11 are not particularly limited, and may be water-unstable food ingredients or fat-soluble foods. The content of the food ingredients contained in gel particles 11 is not particularly limited, as long as the amount is sufficient to form the granules of the present invention. In one embodiment, when the food is a dietary supplement or a food for specified health uses, the amount of food ingredient is sufficient to be an effective amount in the food and sufficient to form the granules of the present invention.

[0025] In one embodiment, a gummy candy can be provided that includes the granules 10. In addition to the main food ingredient, the granules 10 may also include one or more selected from stabilizers, preservatives, buffers, flavoring agents, fragrances, and coloring agents.

[0026] Granules 10 can be mixed with food-acceptable additives and compressed into tablets. Alternatively, granules containing granules 10 may be prepared. Alternatively, granules 10 may be encapsulated in hard capsules. Examples of food-acceptable additives include, but are not limited to, excipients, binders, disintegrants, lubricants, stabilizers, preservatives, buffers, flavorings, fragrances, and coloring agents.

[0027] In the food product according to this embodiment, when the food component is unstable in water, the food component can be contained in the gel particles 11, thereby making it possible to form granules without using water while maintaining stability.

[0028] In one embodiment of the present invention, the granules 10 can also be applied to cosmetics.

[0029] [Manufacturing Method] Granules 10 are produced by dissolving, for example, stearic acid, calcium stearate, or magnesium stearate in liquid oil, dropping the solution into a powder additive, and solidifying the solution to obtain gel particles 11. At this time, the powder additive adheres to the surface of gel particles 11, forming a powder additive layer 15, thereby producing granules 10. For example, granules 10 may be produced by spraying a liquid containing liquid oil and a gelling agent onto the powder additive using a high-speed agitating granulator.

[0030] In one embodiment, stearic acid, calcium stearate, or magnesium stearate and an oil-soluble substance are dissolved in liquid oil, and the resulting solution is dropped into a powder additive and allowed to solidify, thereby obtaining gel particles 11. At this time, the powder additive adheres to the surface of gel particles 11, forming a powder additive layer 15, thereby producing granules 10. By further including an oil-soluble substance in a liquid containing liquid oil and a gelling agent, viscosity can be imparted to the liquid, improving manufacturability. Furthermore, by including an oil-soluble substance in a liquid containing a drug or food ingredient, liquid oil, and gelling agent, the melting point of the liquid containing the drug or food ingredient, liquid oil, and gelling agent can be lowered, reducing the thermal load on the drug or food ingredient and suppressing the increase of drug-related substances during production.

[0031] Reference Example 1 A liquid was prepared by heating 45 g of a medium-chain fatty acid triglyceride (Triester F-810, Nikko Chemicals Co., Ltd.) to 60° C., adding 5 g of stearic acid (NOF Corporation), and dissolving at 60° C. The obtained liquid was allowed to cool, and the properties after cooling were visually confirmed.

[0032] [Reference Example 2] A liquid of Reference Example 2 was prepared in the same manner as in Reference Example 1, except that 5 g of calcium stearate (NOF Corporation) was added instead of stearic acid and dissolved at 100° C. or higher. The obtained liquid was allowed to cool, and the properties after cooling were visually confirmed.

[0033] Comparative Example 1 A liquid of Comparative Example 1 was prepared in the same manner as in Reference Example 1, except that 5 g of hardened oil (Freund Corporation) was added instead of stearic acid and dissolved at 40° C. The obtained liquid was allowed to cool, and the properties after cooling were visually confirmed.

[0034] Comparative Example 2 A liquid of Comparative Example 2 was prepared in the same manner as in Reference Example 1, except that 5 g of Macrogol 6000 (NOF Corporation) was added instead of stearic acid and dissolved at 60° C. The obtained liquid was allowed to cool, and the properties after cooling were visually confirmed.

[0035] [Reference Example 3] A liquid of Reference Example 3 was prepared in the same manner as in Reference Example 1, except that the amount of medium-chain fatty acid triglyceride was changed to 40 g and the amount of stearic acid was changed to 40 g. The obtained liquid was allowed to cool as is, and the properties after cooling were visually confirmed.

[0036] The properties of the liquids of Reference Examples 1 to 3 and Comparative Examples 1 and 2 after standing to cool are shown in Table 1. [Table 1]

[0037] The results in Table 1 reveal that Reference Examples 1 to 3, which contain stearic acid or calcium stearate, can solidify liquid oil to form gel particles, while Comparative Examples 1 and 2, which contain hydrogenated oil or macrogol, cannot solidify liquid oil.

[0038] Example 1 371.25 g of medium-chain fatty acid triglyceride (Triester F-810, Nikko Chemicals Co., Ltd.) was heated to 60°C, and 187.5 g of aminoalkyl methacrylate copolymer (Eudragit (registered trademark) EPO, Evonik Röhm GmbH) was dissolved therein. 562.5 g of stearic acid (NOF Corporation) was added to this liquid oil and dissolved at 60°C to prepare a liquid.

[0039] Partially pregelatinized starch (PCS, Asahi Kasei Corporation) was placed in a petri dish as a powder additive, and the prepared liquid was added dropwise onto it using a dropper, causing the powder additive to adhere uniformly around the droplets, thereby obtaining granules of Example 1.

[0040] Example 2 A liquid was prepared in the same manner as in Example 1, except that no aminoalkyl methacrylate copolymer was added, and granules of Example 2 were obtained in the same manner as in Example 1.

[0041] Comparative Example 3 A liquid was prepared in the same manner as in Example 1, except that stearic acid was not added, and granules of Comparative Example 3 were obtained in the same manner as in Example 1.

[0042] The granules of Examples 1 and 2 and Comparative Example 3 were evaluated for properties and adhesion (the granules were placed in a petri dish and checked for adhesion of granule components) immediately after production (initial) and after storage at 25°C and 60% relative humidity for 10 days. The evaluation results are shown in Table 2. [Table 2]

[0043] As can be seen from the results in Table 2, for Examples 1 and 2, solid, non-adhesive granules were obtained both initially and after storage. However, for the granules of Example 1, to which aminoalkyl methacrylate copolymer was added, the liquid viscosity was high, and the droplets remained spherical until solidification, resulting in more spherical gel particles. On the other hand, the granules of Comparative Example 3, to which no stearic acid was added, remained liquid even when cooled, were highly adhesive, and were difficult to handle.

[0044] [Melt Point Measurement of Gel Particles 11] The effect of adding aminoalkyl methacrylate copolymer to gel particles 11 was evaluated. A mixed solution was prepared by adding medium-chain fatty acid triglyceride (Triester F-810, Nikko Chemicals Co., Ltd.), stearic acid (vegetable stearic acid, NOF Corporation), and aminoalkyl methacrylate copolymer (Eudragit (registered trademark) EPO, Evonik Röhm GmbH) in the weight ratio shown in Table 2, and the solution was added dropwise to water with a dropper to prepare granules. The melting point of the prepared granules was measured using a differential scanning calorimeter. The measurement results are shown in Table 3. The measurement results for stearic acid and aminoalkyl methacrylate copolymer alone are also shown. [Table 3]

[0045] The results in Table 3 clearly show that the melting point decreases as the content ratio of aminoalkyl methacrylate copolymer increases. This result indicates that the oil-soluble substance can lower the melting point of a liquid containing a liquid oil and a gelling agent, thereby reducing the thermal load on an optionally contained drug.

[0046] Example 3 4.0 g of medium-chain fatty acid triglyceride (Triester F-810, Nikko Chemicals Co., Ltd.) was heated to 60°C, and 2.0 g of aminoalkyl methacrylate copolymer (Eudragit (registered trademark) EPO, Evonik Röhm GmbH) was dissolved therein. 4.0 g of stearic acid (NOF Corporation) was added to this liquid oil and dissolved at 60°C to prepare a liquid.

[0047] Light anhydrous silicic acid (Adsolider (registered trademark)-101, Freund Corporation) was placed in a petri dish as a powder additive, and the prepared liquid was added dropwise onto it using a dropper, causing the powder additive to adhere uniformly around the droplets, thereby obtaining granules of Example 3.

[0048] Example 4 Granules of Example 4 were obtained in the same manner as in Example 3, except that stearic acid (NOF Corporation) was used as the powder additive.

[0049] Example 5 Granules of Example 5 were obtained in the same manner as in Example 3, except that calcium stearate (NOF Corporation) was used as the powder additive.

[0050] Example 6 Granules of Example 6 were obtained in the same manner as in Example 3, except that polyvinyl alcohol (PE-05JPS, Nippon Vinyl Acetate & Poval Co., Ltd.) was used as the powder additive.

[0051] Example 7 Granules of Example 7 were obtained in the same manner as in Example 3, except that a methacrylic acid copolymer (Eudragit (registered trademark) L 100-55, Evonik Roehm GmbH) was used as the powder additive.

[0052] Example 8 Granules of Example 8 were obtained in the same manner as in Example 3, except that partially pregelatinized starch (PCS, Asahi Kasei Corporation) was used as the powder additive.

[0053] The properties and adhesiveness of the granules of Examples 3 to 8 are shown in Table 4. Also, scanning electron microscope (SEM) images of the granules of Examples 3 to 8 are shown in Figures 2A to 2F. [Table 4]

[0054] In Examples 3 to 8, solid, non-adhesive granules of 2 to 3 mm were obtained.

[0055] Example 9 371.25 g of medium-chain fatty acid triglyceride (Triester F-810, Nikko Chemicals Co., Ltd.) was heated to 60°C, and 187.5 g of aminoalkyl methacrylate copolymer (Eudragit (registered trademark) EPO, Evonik Röhm GmbH) was dissolved therein. 562.5 g of stearic acid (NOF Corporation) was added to this liquid oil and dissolved at 60°C to prepare a liquid.

[0056] The prepared liquid was sprayed onto partially pregelatinized starch (PCS, Asahi Kasei Corporation) using a high-speed mixer (FS-GS-5J, Fukae Powtec Co., Ltd.) to obtain the granules of Example 9.

[0057] SEM images of the granules of Example 9 are shown in Figures 3A-3D, where Figure 3A shows an SEM image at 80x magnification, Figure 3B shows an SEM image at 250x magnification, Figure 3C shows an SEM image at 150x magnification, and Figure 3D shows an SEM image at 600x magnification.

[0058] The granules of Example 9 were evaluated for properties and adhesion (the granules were placed in a petri dish and checked for adhesion of granule components) immediately after production (initial) and after storage at 25°C and 60% relative humidity for 10 days. The evaluation results are shown in Table 5. [Table 5]

[0059] The results in Table 5 demonstrate that Example 9, which contained an aminoalkyl methacrylate copolymer, produced solid, non-adhesive granules both initially and after storage. Furthermore, the granules of Example 9 had a high liquid viscosity, and the droplets remained spherical until solidification, resulting in more spherical gel particles.

[0060] [Evaluation of Granule Fluidity] Using a powder rheometer (FT4, Freeman Technology), the flow rate index (FRI) of the granules of Example 9 and various powder additives was measured to evaluate their fluidity. FIG. 4 shows the FRI of the granules of Example 9 and various powder additives. From the results of FIG. 4, Example 9 exhibited a fluidity (approximately 1.0) comparable to that of microcrystalline cellulose (UF-702), D-mannitol (Perteck® M100), D-mannitol (PEARLITOL® 100SD), premix additive (PEARLITOL® Flash), lactose hydrate (Dilactose® S), and premix additive (Granfiller D® 211), which are direct compression additive grades generally requiring excellent fluidity. From the above, it was revealed that the granules of Example 9 have excellent fluidity.

[0061] [Physical Properties of Pharmaceutical Formulation] [Example 10] In order to evaluate the physical properties of tablets containing the granules, 4.5 g of the granules of Example 9, 21.12 g of Granutol F (registered trademark) (Freund Corporation), 4.2 g of hydroxypropyl cellulose (NISSO HPC SSL SFP, Nippon Soda Co., Ltd.), 8.4 g of low-substituted hydroxypropyl cellulose (L-HPC (registered trademark) NBD-022, Shin-Etsu Chemical Co., Ltd.), 1.26 g of croscarmellose sodium (Ac-Di-Sol (registered trademark), FMC International), 2.1 g of light anhydrous silicic acid (Adsolider (registered trademark)-101, Freund Corporation), and 0.42 g of magnesium stearate (plant-derived, Taihei Chemical Industry Co., Ltd.) were mixed and compressed to obtain the pharmaceutical formulation of Example 10 having a diameter of 7 mm.

[0062] Comparative Example 3 In Comparative Example 3, a pharmaceutical preparation was obtained in the same manner as in Example 10, except that the granules of Example 9 were not added.

[0063] [Hardness] The hardness of the tablets of Example 10 and Comparative Example 3 was measured using a tablet hardness tester (DC-50, Okada Seiko Co., Ltd.), and the average value of the measurements for three tablets was calculated.

[0064] [Disintegration Time] A disintegration test was carried out according to the disintegration test method described in the 17th edition of the Japanese Pharmacopoeia. The disintegration test used water as the test liquid and measured the average disintegration time of six tablets of each pharmaceutical formulation.

[0065] The physical properties of the pharmaceutical preparations of Example 10 and Comparative Example 3 are shown in Table 6. [Table 6]

[0066] The results in Table 6 reveal that the pharmaceutical preparation containing approximately 10% of the granules of Example 10 did not exhibit any particular problems in terms of compactibility or disintegration, and satisfied the physical properties of the preparation as a tablet.

[0067] Example 11: 0.04 g of eldecalcitol was dissolved in 1.96 g of absolute ethanol as a drug. 24.75 g of medium-chain fatty acid triglyceride (Triester F-810, Nikko Chemicals Co., Ltd.) was heated to 60°C, and 12.5 g of aminoalkyl methacrylate copolymer (Eudragit (registered trademark) EPO, Evonik Röhm GmbH) was dissolved therein. 37.5 g of stearic acid (NOF Corporation) was added to this liquid oil and dissolved at 60°C. 0.04 g of an ethanol solution of eldecalcitol was added to 11.96 g of this solution and dissolved at 60°C to prepare a liquid containing a drug and additives.

[0068] The prepared liquid was added dropwise to light anhydrous silicic acid (Adsolider (registered trademark)-101, Freund Corporation) using a dropper to obtain the granules of Example 11.

[0069] Example 12 Granules of Example 12 were obtained in the same manner as in Example 11, except that methacrylic acid copolymer (Eudragit (registered trademark) L 100-55, Evonik Roehm GmbH) was used instead of light anhydrous silicic acid.

[0070] Example 13 Granules of Example 12 were obtained in the same manner as in Example 11, except that partially pregelatinized starch (PCS, Asahi Kasei Corporation) was used instead of light anhydrous silicic acid.

[0071] The properties and adhesiveness of the granules of Examples 11 to 13 are shown in Table 7. [Table 7]

[0072] In Examples 11 to 13 containing eldecalcitol, solid, non-adhesive granules were obtained. The granules of Examples 11 to 13 were stored at 25°C under tightly sealed conditions for one month, or at 40°C under tightly sealed conditions for one month, and the content of the preform of eldecalcitol, including the initial state immediately after production, was evaluated by high-performance liquid chromatography. The results showed stability comparable to that of Edirol (registered trademark) capsules of 0.5 μg and 0.75 μg. This indicates that the inclusion of eldecalcitol in the granules of the present invention poses no problem in terms of the stability of eldecalcitol. Furthermore, since the granules can be prepared at a relatively low temperature of 60°C, it is believed that the effect on the stability of eldecalcitol during production is minimal.

[0073] 10 Granules, 11 Gel particles, 15 Powder additive layer

Claims

1. A granule comprising: a gel particle comprising a liquid oil and stearic acid, calcium stearate or magnesium stearate; and a powder additive layer disposed on the surface of the gel particle.

2. The granules according to claim 1, wherein the content of said stearic acid, said calcium stearate or said magnesium stearate in said gel particles is at a mass ratio to said liquid oil of 1:1 or more.

3. The granules according to claim 1, further comprising one or more oil-soluble substances selected from the group consisting of aminoalkyl methacrylate copolymers, methacrylic acid copolymers and hypromellose acetate succinate in said gel particles.

4. The granules of claim 1, wherein the liquid oil is one or more selected from the group consisting of medium chain triglycerides, medium chain mono- and diglycerides, peanut oil, corn oil, soybean oil, sesame oil, oleic acid, olive oil, esterified corn oil, sunflower oil, cottonseed oil, safflower oil, and peppermint oil.

5. A pharmaceutical formulation comprising a drug in said gel particles of granules according to any one of claims 1 to 4.

6. A food product comprising a food ingredient in the gel particles of the granules according to any one of claims 1 to 4.

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