JP2015071542A - Method of producing solid dispersion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of producing a solid dispersion having improved leachability of a poorly soluble medicine or the like.SOLUTION: A method of producing a solid dispersion comprises a step of (1) subjecting a nuclear material comprising spherical silicon dioxide, having an average particle diameter of 50 μm or more, and having a specific surface area of 100 m/g or more, to a fluid bed coating with an active ingredient containing liquid, or (2) mixing an active ingredient with the nuclear material for heat melting.

Description

  The present invention relates to a method for producing a solid dispersion.

It is known that elution of hardly soluble drugs and the like is improved by using a predetermined porous silica and forming a solid dispersion by a solvent removal method or a spray drying method (Non-patent Document 1).
In addition, as a method for coating a drug on silica or the like, for example, a method using a general crystalline excipient of about 1 μm to about 150 μm as a core of sustained release fine particles for intraoral quick disintegrating tablets, specifically, There is known a method (Patent Document 1) in which silicon dioxide (silica gel) having an average particle size of about 48 μm is charged into a fluidized bed granulator and a nicardipine hydrochloride solution is coated by a side spray method.
Furthermore, in a drug delivery system containing a weakly basic drug and an organic acid, a method in which an inert core such as spherical silicon dioxide is coated with a drug solution by a fluidized bed granulation method (Patent Document 2), an average particle size of 1 to 50 μm In addition, as a porous silicon-based carrier having physical properties such as a specific surface area of 250 to 1200 m ² / g by the BET method, a drug suspension is spray-dried with a spray dryer against spherical hydrous silicon dioxide and amorphous light anhydrous silicic acid. Then, a method of obtaining a solid dispersion powder (Patent Document 3), mixing a dispersion in water of pyrogenic silica having an average particle size of 10 to 120 μm and a BET surface area of 40 to 400 m ² / g with a drug solution or the like. A method of adsorbing a drug, evaporating the solvent, and drying (Patent Document 4) is disclosed.

JP 2004-196829 A Special table 2011-513498 gazette International Publication No. 2009/113522 JP 2005-508977 gazette

“Pharmacology” Vol. 67, no. 2,101-105 (2007)

  The problem to be solved by the present invention is to provide a method for producing a solid dispersion that improves the dissolution of an active ingredient.

The present inventor has (1) a step of performing fluidized bed coating with a liquid containing an active ingredient on a core material made of spherical silicon dioxide, having an average particle diameter of 50 μm or more and a specific surface area of 100 m ² / g or more. Or (2) The step of mixing the active ingredient and heating and melting it to produce a solid dispersion, thereby improving the elution of the active ingredient from the solid dispersion, and the present invention completed.

The present invention is as follows.
[1] For a nuclear material consisting of spherical silicon dioxide, having an average particle size of 50 μm or more and a specific surface area of 100 m ² / g or more,
(1) A step of fluidized bed coating with an active ingredient-containing liquid, or
(2) A step of mixing active ingredients and performing heat melting,
A process for producing a solid dispersion comprising:
[2] The production method according to [1], wherein the average particle diameter of the nuclear material is 50 μm to 1 mm.
[3] The production method according to [1] or [2], wherein the specific surface area of the nuclear material is 100 to 2000 m ² / g.
[4] The manufacturing method according to any one of [1] to [3], wherein the fluidized bed coating is performed by an upper spray method, a side spray method, or a lower spray method.
[5] The manufacturing method according to any one of [1] to [4], wherein the fluidized bed coating is performed by a Wurster type coating machine.
[6] The production method according to any one of [1] to [5], wherein the active ingredient is a poorly soluble drug.
[7] A step of obtaining a solid dispersion by the production method according to any one of [1] to [6];
And a step of obtaining a fine granule, granule, tablet or capsule using the solid dispersion.

  ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of the solid dispersion which the elution property of the active ingredient improved can be provided. The obtained solid dispersion can be further used for the production of various pharmaceutical compositions such as fine granules, granules, tablets, and capsules.

The result of the elution test of ibuprofen in water of Test Example 1-1 is shown. The result of the elution test of indomethacin in artificial intestinal fluid (pH 6.8 phosphate buffer aqueous solution) of Test Example 1-2 is shown. The result of the elution test of phenytoin in the artificial intestinal fluid (pH 6.8 phosphate buffer aqueous solution) of Test Example 1-3 is shown. The result of the dissolution test of the ibuprofen tablet in water of Test Example 1-4 is shown. The result of the elution test of the ibuprofen capsule in water of Test Example 1-5 is shown. The result (ibuprofen) of the differential scanning calorimetry (DSC) of Test Example 2-1 is shown. The result (indomethacin) of the differential scanning calorimetry (DSC) of the test example 2-2 is shown. The result (phenytoin) of the differential scanning calorimetry (DSC) of Test Example 2-3 is shown. The result of the differential scanning calorimetry (DSC) of each ibuprofen solid dispersion from which the amount of drug adsorption of Test Example 2-4 differs is shown. The result of the differential scanning calorimetry (DSC) of each ibuprofen solid dispersion from which the drug adsorption method of Test Example 2-7 differs is shown. The result of the differential thermal analysis (DTA) of the solid dispersion using mannitol of Test Example 3-1 is shown. The result of the differential thermal analysis (DTA) of the solid dispersion obtained by the solvent removal method of Test Example 3-2 is shown. The result of the stability test (75% RH 60 degreeC, 3 weeks) of the ibuprofen solid dispersion of Experiment 4 is shown. The measurement result by powder X-ray diffraction of ibuprofen in Test Example 5-1 is shown. The measurement result by the powder X-ray diffraction of the test example 5-2 of phenytoin is shown. The measurement result by the powder X-ray diffraction of indomethacin of Test Example 5-3 is shown.

  Hereinafter, the present invention will be described in more detail. In addition, this invention is not limited to the following embodiment, It can implement by changing variously within the range of the summary.

The present invention comprises (1) a fluidized bed coating with an active ingredient-containing liquid on a core material composed of spherical silicon dioxide, having an average particle size of 50 μm or more and a specific surface area of 100 m ² / g or more, Or (2) It is related with the manufacturing method of a solid dispersion including the process of mixing an active ingredient and heat-melting.

  “Solid dispersion” means a solid state product comprising at least two components in which one component is almost averagely dispersed in the other component or components. In the present invention, a solid dispersion is a substance in which an active ingredient is dispersed in a predetermined nuclear material that is an inert carrier.

The core material used in the present invention is a core material made of spherical silicon dioxide, the average particle diameter of the core material is 50 μm or more, and the specific surface area of the core material is 100 m ² / g or more.
When the average particle size is in the above range, the yield is good in fluidized bed coating and heat melting, handling is easy, and fluidity is good. Above all, in the Wurster type coating, by using the nuclear material whose average particle size is in the above range, it is possible to dissipate from the bugs and meshes of concern (if the particle size of the nuclear material is too small, the yield cannot be recovered. This is preferable in that it can be prevented.
The average particle size of the nuclear material is preferably 50 μm to 1 mm, more preferably 60 to 500 μm, still more preferably 70 to 300 μm, still more preferably 80 to 250 μm, and most preferably 90 to 230 μm.
When the specific surface area is within the above range, the active ingredient can be efficiently supported.
The specific surface area of the nuclear material is preferably 200 m ² / g or more, more preferably 400 m ² / g or more, still more preferably 500 m ² / g or more, and even more preferably 600 m ² / g or more. A relatively large specific surface area makes it easier to make the drug amorphous by increasing the amount of drug coating. For example, 2000 m ² / g or less, 1800 m ² / g or less, 1500 m ² / g or less, 1200 m ² / g or less, it can also be 1000 m ² / g or less, for ^{example, 100~2000m 2 / g, 200~1800m 2} / g, 400~1500m 2 / g, 500~1200m 2 / g, 600~1000m 2 / G.
In the present invention, the average particle diameter and specific surface area of the nuclear material can be measured by the measurement method described later in the Examples. In the present invention, a commercial product having an average particle diameter of 50 μm or more and a specific surface area of 100 m ² / g or more can also be used as a nuclear substance.

The particle size of the nuclear material is preferably 1 to 1000 μm, more preferably 20 to 800 μm, and still more preferably 40 to 550 μm.
The particle size of the nuclear material is preferably 50 to 700 μm, more preferably 60 to 600 μm, still more preferably 70 when the specific surface area of the nuclear material is 200 to 500 m ² / g, preferably 250 to 400 m ² / g. ˜550 μm.
In the present invention, the particle size of the nuclear material can be measured by a sieving method.

The pore volume of the nuclear material is preferably 0.1 to 2.0 ml / g, more preferably 0.5 to 1.5 ml / g, still more preferably 0.7 to 1.2 ml / g.
The pore volume of the nuclear material can be measured by a water titration method.
The pore diameter of the nuclear material is preferably 1 to 100 nm, more preferably 5 to 50 nm, and still more preferably 10 to 30 nm.
The pore diameter of the nuclear material can be measured by mercury porosimetry, and may also be calculated from the pore volume and specific surface area.

  The core material is made of spherical silicon dioxide, and preferably spherical silica.

In the present specification, the active ingredient in the present invention may be referred to as “drug”, “medicine” or “API”.
The active ingredient is not particularly limited, but is preferably a drug that can be dispersed or dissolved in at least one liquid medium.
When the active ingredient is a poorly soluble drug or a drug for which immediate release is desired, it is preferable in that the effect of improving the elution can be sufficiently exhibited in the solid dispersion obtained by the production method of the present invention.

Here, “sparingly soluble” means “dissolvable” or “extremely insoluble” among the terms described in the 16th revision Japanese Pharmacopoeia (also referred to as Japanese Pharmacopoeia) as the solubility of a drug in a solvent. Or, a state of “almost insoluble” is indicated. Specifically, according to JP, the solubility is 30 minutes when the drug is solid, after being powdered, placed in a solvent and shaken vigorously for 30 seconds every 5 minutes at 20 ± 5 ° C. The amount of water required to dissolve 1 g of drug is 100 mL or more and less than 1000 mL. Further, “very difficult to dissolve” means that the amount of water required to dissolve 1 g of drug is 1000 mL or more and less than 10,000 mL, and “almost insoluble” means that the amount of water required to dissolve 1 g of drug is 10,000 mL. It is shown above.
In the present invention, preferably, the poorly soluble drug is a drug that is “extremely insoluble” or “almost insoluble” as a solubility in water, that is, a drug in which the amount of water required to dissolve 1 g of the drug is 1000 mL or more. is there. Preferably, the poorly soluble drug is a drug that is “almost insoluble” in terms of solubility in water, that is, a drug in which the amount of water required to dissolve 1 g of drug is 10,000 mL or more.

  Although it does not specifically limit as a poorly soluble drug, For example, a steroid agent, an enzyme inhibitor, an analgesic agent, an antifungal agent, a cancer therapeutic agent, an antiemetic agent, an analgesic agent, a cardiovascular agent, an anti-inflammatory agent, an anthelmintic Agents, antiarrhythmic agents, antibiotics (including penicillin), anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antidementia agents, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, anti Malignant tumor agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenergic receptor blockers, blood products and substitutes, cardiotonic agents, contrast agents , Corticosteroids, antitussives (an expectorants and mucolytic agents), diagnostic agents, diagnostic contrast agents, diuretics, dopaminergic agents (antiparkinsonian agents), hemostatic agents, immunizing agents, lipid regulators, muscle relaxants, Prostaglandin, radiologist , Hormonal agents, anti-allergic agents, stimulants and appetite-reducing agents, sympathomimetics agents, thyroid agents, a vasodilator, etc., can be selected from a variety of drugs. These poorly soluble drugs can be used alone or in combination of two or more.

(1) Process of performing fluidized bed coating with active ingredient-containing liquid In the present invention, the core material can be introduced into a fluidized bed coating apparatus in advance. Therefore, it is not necessary to suspend the nuclear material in the liquid containing the active ingredient, but it does not prevent the suspension.

  In the present invention, the active ingredient-containing liquid is a liquid in which an active ingredient is dispersed or dissolved in a solvent, and can be used as a spray liquid in fluidized bed coating.

The solvent used in the active ingredient-containing liquid in the present invention is not particularly limited as long as it can disperse or dissolve the active ingredient, but a solvent that dissolves the active ingredient well is more preferable.
Examples of the solvent include methanol, ethanol, tetrahydrofuran, methylene chloride, acetone or a mixed solvent thereof, and a mixed solvent thereof with water. Ethanol, methanol, methylene chloride or a mixed solvent thereof is preferably used. It is done.

  In the present invention, the active ingredient-containing liquid can be obtained by adding an active ingredient to a solvent and stirring to prepare a spray liquid in which the active ingredient is dispersed or dissolved.

The compounding amount of the active ingredient is preferably 0.1 to 100 parts by mass, more preferably 1 to 50 parts by mass, and further preferably 1 to 25 parts by mass with respect to 100 parts by mass of the solvent used in the active ingredient-containing liquid. Even more preferably, it is 1 to 20 parts by mass. The said lower limit is good also as 5 mass parts in each range, and also 10 mass parts.
In the present invention, the amount of the nuclear material introduced into the apparatus for performing fluidized bed coating is preferably 0.1 to 100 parts by mass with respect to 100 parts by mass of the active ingredient-containing liquid, and the upper limit is more preferably 80 parts by mass, more preferably 60 parts by mass, and even more preferably 40 parts by mass. The lower limit may be 1 part by mass, 10 parts by mass, or even 20 parts by mass, The lower limit is preferably 1 part by mass in that a certain amount of drug can be loaded even if the amount of the active ingredient is increased to reduce the amount of the nuclear material.

In the present invention, the input amount of the active ingredient with respect to 100 parts by mass of the nuclear material is (i) when the specific surface area of the nuclear material is 100 m ² / g or more and less than 250 m ² / g, preferably 1 part by mass or more and 40 masses. Less than 1 part, more preferably 1 part by weight or more, less than 20 parts by weight, still more preferably 1 part by weight or more and less than 10 parts by weight, still more preferably 1 to 8 parts by weight, and (b) the specific surface area of the nuclear material. In the case of 250 m ² / g or more and less than 550 m ² / g, preferably 1 part by mass or more and less than 100 parts by mass, more preferably 1 part by mass or more and less than 50 parts by mass, further preferably 1 part by mass or more and 40 quantities. less parts, is even more preferably 1 to 36 parts by weight, (c) the specific surface area of the nuclear material 550 meters ² / g or more, preferably when a 550~1000m ² / g, preferably from 1 part by mass or more, 100 quality Less parts, more preferably 1 part by mass or more, less than 60 parts by weight, more preferably 1 part by weight or more and less than 50 parts by weight, still more preferably 1 to 48 parts by weight.

In the present invention, since the adsorption (support) and drying of the drug can be performed continuously and the efficiency is high, the fluidized bed coating is more preferably an upward spray method (top spray method), a side spray method (side spray method). Spraying method) or downward spraying method (bottom spraying method), more preferably downward spraying method.
Fluidized bed coating is preferably performed by the downward spray method using a Wurster type coater.
The fluidized bed coating is performed by, for example, a rolling fluidized coating apparatus “Multiplex” (trade name) manufactured by POWREC, and the upper spray method is performed by, for example, a coating apparatus “FLOW COATER” (trade name) manufactured by Freund Sangyo Co., Ltd. The obtained solid dispersion generally has a granular shape.

In the present invention, the fluidized bed coating is sprayed with an active ingredient-containing liquid, preferably under the operating conditions of a liquid feed rate of 1 to 100 g / min and an air volume of 0.1 to ² m ² / min. Spraying is preferably performed at a temperature of 10 ° C., a spray air (atomized air) amount of 10 to 100 L / min, and a rotational speed of 50 to 500 min− ¹ .
More preferably, spraying is performed under the operating conditions of a liquid feeding speed of 1 to 20 g / min, an air volume of 0.1 to ¹ m ² / min, a supply air temperature of 20 to 50 ° C., a spray air volume of 20 to 90 L / min, and a rotation speed. Spraying is preferably performed at 100 to 450 minutes ⁻¹ , more preferably spraying under operating conditions of a liquid feeding speed of 1 to 10 g / min and an air volume of 0.2 to 0.7 m ² / min. It is preferable to spray at ~ 40 ° C, an amount of spray air of 30 ~ 80 L / min, and a rotational speed of 150 ~ 400 min- ¹ . The rotational speed is for the rolling function generally used in the side spray method.

The collected product obtained by the above fluidized bed coating is placed in a tray and further dried to remove the solvent to prepare a solid dispersion. The drying is preferably vacuum drying, and a vacuum dryer can be used.
In the present invention, the drying condition is preferably 5 to 48 hours at 25 to 100 ° C, more preferably 8 to 35 hours at 30 to 80 ° C, and still more preferably 10 to 24 hours at 35 to 60 ° C.

(2) Step of mixing active ingredients and heating and melting In the present invention, a solid dispersion can be prepared by heating and melting using a core material (melting method).
In the case of the melting method, the solid dispersion can be prepared by including a step of mixing the active ingredient with the core material and performing heat melting.
Specifically, a solid dispersion is prepared by mixing a nuclear substance and an active ingredient, heating and melting, and solidifying by cooling. Preferably, the nuclear material and the active ingredient are first mixed, and the resulting mixture is kneaded for 1 to 60 minutes at 50 to 300 ° C. and at a rotational speed of 1 to 100 rpm (may be 10 to 100 rpm), followed by injection molding. ,Cooling. The kneading can be performed, for example, with a torque meter, a biaxial kneading / extrusion apparatus (extruder) or the like.
In the present specification, the term “melting method” or “heat melting” is used for convenience in that an apparatus similar to the heat melting method for producing a conventional solid dispersion can be used. In, the core material composed of spherical silicon dioxide is not melted.
In the present invention, it is not necessary to use an adhesive polymer such as polyvinylpyrrolidone, polyethylene glycol (PEG), or hypromellose phthalate, which has been used in the production of a solid dispersion by a conventional melting method. It is not necessary to consider the melting temperature and decomposition temperature of the material, and it is possible to set the heating temperature while paying attention only to the decomposition temperature of the active ingredient to be used. For example, it can be applied to an active ingredient having a high melting temperature. it can.
Further, in the present invention, since the above-mentioned nuclear material is used, pulverization that is usually required in the post-process is not necessary, and the manufacturing process can be simplified.
The compounding amount of the active ingredient with respect to 100 parts by mass of the nuclear material is preferably 1 to 100 parts by mass, more preferably 10 to 90 parts by mass, and still more preferably 20 to 80 parts by mass.
The mixing of the nuclear material and the active ingredient can be performed by a usual method, and for example, a tumbler mixer, a vertical mixer, or the like can be used.

The solid dispersion obtained in the present invention may be further added with an additive as a third component as required. The additive may be mixed with the active ingredient-containing liquid, or may be mixed with the core substance and the active ingredient in the melting method.
Additives include excipients, binders, disintegrants, lubricants, colorants, flavoring / odorants, solubilizers, antioxidants, emulsifiers, absorption enhancers, and surfactants. It is done.
About the following additive, it shows as an illustration and is not specifically limited to these.

  Examples of the excipient include lactose, sucrose, glucose, corn starch, mannitol, sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium aluminate metasilicate, And calcium hydrogen phosphate.

  Examples of the binder include polyvinyl pyrrolidone, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, and polyvinyl alcohol.

  Examples of disintegrants include crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl. Starch, sodium carboxymethyl starch, etc. are mentioned.

  Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, stearic acid, sodium stearyl fumarate, and talc.

  Examples of the colorant include iron sesquioxide, yellow iron sesquioxide, carmine, caramel, β-carotene, titanium oxide, talc, riboflavin sodium phosphate, and yellow aluminum lake.

  Examples of the flavoring / flavoring agent include cocoa powder, peppermint oil, and cinnamon powder.

  Examples of the solubilizer include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polysorbate 80, and nicotinamide.

  Examples of the antioxidant include ascorbic acid, α-tocopherol, ethoxyquin, dibutylhydroxytoluene, butylhydroxyanisole and the like.

  Examples of the emulsifier, the absorption accelerator and the surfactant include stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, glyceryl monostearate, sucrose fatty acid ester, and glycerin fatty acid ester.

According to the production method of the present invention, it is possible to improve the elution of the supported active ingredient in the obtained solid dispersion. This improvement in elution is usually thought to be due to the fact that the active ingredient becomes amorphous when a solid dispersion is used. In the present invention, the amount of the active ingredient adsorbed to the nuclear material is observed, and crystallization is observed in the conventional method. Even in such a ratio, it can be made amorphous.
In the solid dispersion obtained by the present invention, the larger the amount of the active ingredient adsorbed with respect to 100 parts by mass of the nuclear material, the more industrially preferable. In this respect, preferably 1 to 200 parts by mass, more preferably 5 to 150 parts. Part by mass, more preferably 10 to 100 parts by mass, even more preferably 10 to 50 parts by mass, and most preferably 10 to 30 parts by mass.
The amount of the active ingredient adsorbed on 100 parts by mass of the nuclear material is (i) when the specific surface area of the nuclear material is 100 m ² / g or more and less than 250 m ² / g from the viewpoint that the active ingredient is likely to become amorphous. Preferably 1 part by mass or more and less than 40 parts by mass, more preferably 1 part by mass or more and less than 20 parts by mass, still more preferably 1 part by mass or more and less than 10 parts by mass, and even more preferably 1 to 8 parts by mass. (B) When the specific surface area of the nuclear material is 250 m ² / g or more and less than 550 m ² / g, preferably 1 part by mass or more and less than 100 parts by mass, more preferably 1 part by mass or more and less than 50 parts by mass, more preferably 1 part by mass or more, less than 40 volume parts, and even more preferably 1 to 36 parts by weight, (c) the specific surface area of the nuclear material 550 meters ² / g or more, preferably 550~1000m ² / g If Preferably it is 1 part by weight or more and less than 100 parts by weight, more preferably 1 part by weight or more and less than 60 parts by weight, even more preferably 1 part by weight or more and less than 50 parts by weight, and even more preferably 1 to 48 parts by weight. is there. The adsorption amounts of (A), (B) and (C) above are particularly preferable for fluidized bed coating.

According to the present invention, the active ingredient to be used can be efficiently adsorbed on the nuclear material, and the amount of the active ingredient that is sprayed or mixed on the nuclear material but not adsorbed can be suppressed as much as possible.
In the present invention, it is considered that the active ingredient-containing liquid infiltrates even inside the nuclear material, which contributes to amorphization or improvement of dissolution, and efficiently produces an amorphous preparation with a high drug concentration. Is considered to be possible. Furthermore, according to the present invention, it is possible to obtain a solid dispersion that is stable even when stored under high-temperature humidification and maintains high drug dissolution properties.

The present invention also relates to a pharmaceutical composition comprising the steps of obtaining the above solid dispersion and obtaining a pharmaceutical composition such as a fine granule, granule, tablet or capsule using the solid dispersion. It relates to a manufacturing method.
The pharmaceutical composition is a composition containing the solid dispersion of the present invention. Also in the pharmaceutical composition, the active ingredient has improved dissolution characteristics. Therefore, in the present invention, the bioavailability of the active ingredient can be increased by using the solid dispersion as a pharmaceutical composition.

In the present invention, the pharmaceutical composition can be produced by mixing the solid dispersion and the additive as described above according to a conventional method.
The pharmaceutical composition can be used as oral preparations such as fine granules, tablets, granules, capsules and the like.

  As the fine granule, a solid dispersion may be used as it is, or a mixture obtained by adding an additive to a solid dispersion may be used. Further, the solid dispersion may be coated with a film coating agent as required.

  As the granule, a solid dispersion may be used as it is, or a granulated product obtained by adding an additive to the solid dispersion may be used. Furthermore, you may use a solid dispersion or its granulated material by coating with a film coating agent as needed.

  Tablets are those obtained by adding additives to solid dispersions, or those obtained by adding additives to solid dispersions and granulating them as tableting powders. Obtained by compression molding. In the present invention, since the core material having the above-mentioned predetermined average particle diameter is used, it is easy to handle, has good fluidity, and can be easily tableted.

  Capsule is a solid dispersion, or a solid dispersion added with an additive, or a granulated product obtained by adding an additive to a solid dispersion is used as a filler. Is added to fill the capsule. Since the nuclear material having the above-mentioned predetermined average particle diameter is used, it is easy to handle, has good fluidity, and can be easily encapsulated.

  In the present invention, when the pharmaceutical composition is a tablet, it is not particularly limited, but the content of the solid dispersion is preferably 0.10 to 0.50 parts by mass with respect to 1 part by mass of the tablet. . When the pharmaceutical composition is a granule or a capsule, a solid dispersion that is usually granular can be used as it is as a granule or capsule content. Further, the content of the solid dispersion is preferably 0.1 to 1 part by mass with respect to 1 part by mass of the granule. When the pharmaceutical composition is a capsule, the content of the solid dispersion is preferably 0.1 to 1 part by mass with respect to 1 part by mass of the total content of the capsule contents.

EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples.

<Measurement method of average particle diameter>
Irradiating a powder from a particle size distribution measuring device (AEROTRACK SPR MODEL 7340, manufactured by Nikkiso Co., Ltd.) onto a powder obtained by spraying an appropriate amount of nuclear material with a dry dispersion device (PD-10S, manufactured by Nikkiso Co., Ltd.) at an air pressure of 0.1 MPa. Then, the particle diameter of the nuclear material was measured by a laser diffraction method, and the average particle diameter was calculated.

<Method for measuring specific surface area>
The specific surface area of the nuclear material was measured using a specific surface area measuring device (SA-3100, manufactured by Beckman Coulter, Inc.). That is, nitrogen gas was adsorbed to the degassed sample, and the specific surface area of the nuclear material was calculated by the BET multipoint method.

[Example 1] Preparation of solid dispersion (lower spraying method 1)
[Example 1-1]
As a core material, spherical silica (MB4B 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 108.8 μm, and a specific surface area of 611.35 m ² / g is fluidized bed granulator (multiplex MP- 01, manufactured by POWREC Co., Ltd.), 40 g of ibuprofen (Japanese Pharmacopoeia standard, Yonezawa Hamari Pharmaceutical Co., Ltd.) under the conditions of an air supply temperature of 25 ° C., an air volume of 0.5 m ³ / min and a spray air volume of 50 L / min. Was dissolved in 800 g of absolute ethanol and sprayed from below at a feeding rate of 5 g / min (Worster method) to obtain a spherical preparation containing 10 mg of ibuprofen in a coating amount per 50 mg of spherical silica.
The obtained spherical preparation was vacuum dried at 40 ° C. for 14 hours with a vacuum dryer (DP-63, manufactured by Yamato Scientific Co., Ltd.) to obtain a granule preparation. The mass (hereinafter referred to as yield) of the spherical preparation after the moisture correction was 86.1% with respect to the total mass of the spherical silica and the active ingredient charged. The moisture correction is performed by calculating the moisture value calculated by an infrared moisture meter (FD-240, manufactured by Kett) from the mass reduced by heating the spherical preparation at 80 ° C. for 30 minutes from the mass of the spherical preparation before the heating. This was done by subtracting.

[Example 1-2]
Instead of MB4B 100-200, spherical silica (MB5D 200-350, manufactured by Fuji Silysia) having a particle size of 45 to 75 μm, an average particle size of 57.4 μm, and a specific surface area of 315.80 m ² / g is used as the nuclear material. And the granule formulation was obtained like Example 1-1 except having performed vacuum drying for 16 hours. The yield was 7.6%.

[Example 1-3]
Instead of MB4B 100-200, spherical silica (MB5D 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm, and a specific surface area of 348.87 m ² / g is used as the nuclear material. And the granule formulation was obtained like Example 1-1 except having performed vacuum drying for 12 hours. The yield was 90.0%.

[Example 1-4]
Instead of MB4B 100-200, spherical silica (MB5D 30-200, manufactured by Fuji Silysia) having a particle size of 75 to 500 μm and an average particle size of 228.6 μm was used as the nuclear material, and vacuum drying was performed for 15 hours. Except for this, a granule preparation was obtained in the same manner as Example 1-1. The yield was 92.2%.

[Example 1-5]
Instead of ibuprofen, 5 mg of indomethacin was adsorbed per 50 mg of spherical silica in the same manner as in Example 1-3, except that 20 g of indomethacin (Japanese Pharmacopoeia standard, manufactured by Kongo Chemical Co., Ltd.) was used and vacuum drying was performed for 17 hours. A granular preparation was obtained. The yield was 77.3%.

[Example 1-6]
In place of ibuprofen, except that 10 g of phenytoin (Japanese Pharmacopoeia / USP / EP standard, manufactured by Katwijk Chemie BV) was used and vacuum drying for 19 hours was performed, the same as in Example 1-3, A granule preparation in which 2.5 mg of phenytoin was adsorbed per 50 mg of spherical silica was obtained. The yield was 84.6%.

[Example 2] Preparation of solid dispersion (lower spraying method 2)
[Example 2-1]
As a core material, spherical silica (MB3A 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 99.5 μm, and a specific surface area of 772.03 m ² / g is fluidized bed granulator (multiplex MP- 01, manufactured by POWREC Co., Ltd.) and 100 g of ibuprofen (Japanese Pharmacopoeia Standard, Yonezawa Hamari Pharmaceutical Co., Ltd.) under the conditions of an air supply temperature of 25 ° C., an air volume of 0.5 m ³ / min and a spray air volume of 50 L / min. Was dissolved in 2000 g of absolute ethanol and sprayed from below at a feeding rate of 5 g / min to obtain spherical preparations each containing 5 mg, 10 mg, 15 mg, 20 mg and 25 mg of ibuprofen in a coating amount per 50 mg of spherical silica. .
The obtained spherical granules were vacuum-dried at 40 ° C. for 17 hours with a vacuum dryer (DP-63, manufactured by Yamato Scientific Co., Ltd.) to obtain a granule preparation as a solid dispersion.

[Example 2-2]
Instead of MB3A 100-200, spherical silica (MB5D 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm, and a specific surface area of 348.87 m ² / g is used as the nuclear material. In the same manner as in Example 2-1, except that ibuprofen 5 mg, 10 mg, 15 mg, and 20 mg were adsorbed per 50 mg of spherical silica, respectively.

[Example 2-3]
As a nuclear material, instead of MB3A 100-200, spherical silica (MB300 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 100.8 μm and a specific surface area of 140.89 m ² / g is used. A granule preparation in which 5 mg of ibuprofen was adsorbed per 50 mg of spherical silica was obtained in the same manner as in Example 2-1, except that the drying time was 15 hours.

[Example 3] Preparation of solid dispersion (upper spray method)
A flow in which spherical silica (MB5D 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm, and a specific surface area of 348.87 m ² / g is assembled as a core material so as to form an upward spray. Ibuprofen (Japanese Pharmacopoeia standard) under the conditions of 200 g in a layer granulator (Multiplex MP-01, manufactured by Paulek Co., Ltd.), air supply temperature 25 ° C., air volume 0.5 m ³ / min and spray air volume 50 L / min. Yonezawa Hamari Chemical Co., Ltd.) 40 g dissolved in absolute ethanol 800 g was sprayed from above at a feed rate of 5 g / min to obtain a spherical preparation containing 10 mg of ibuprofen in a coating amount per 50 mg of spherical silica. .
The obtained spherical granules were vacuum dried at 40 ° C. for 14 hours with a vacuum dryer (DP-63, manufactured by Yamato Kagaku Co., Ltd.) to obtain a granule preparation as a solid dispersion. The yield was 91.8%.

[Example 4] Preparation of solid dispersion (side spray method)
As a core material, spherical silica (MB5D 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm and a specific surface area of 348.87 m ² / g was assembled so as to be a side spray. 200 g was charged into a fluidized bed granulator (Multiplex MP-01, manufactured by Paulec Co., Ltd.), ibuprofen (Japanese Pharmacopoeia) under conditions of a supply air temperature of 25 ° C., an air volume of 0.5 m ³ / min, and a spray air volume of 50 L / min Standard Yonezawa Hamari Chemical Co., Ltd.) 40 g dissolved in absolute ethanol 800 g is sprayed at a feed rate of 5 g / min from the side of the powder input container, which is one component in the fluid bed granulator, A spherical preparation containing 10 mg of ibuprofen in a coating amount per 50 mg of spherical silica was obtained. At this time, the lower disk was rolled at 300 rpm.
The obtained spherical preparation was vacuum-dried at 40 ° C. for 14 hours with a vacuum dryer (DP-63, manufactured by Yamato Scientific Co., Ltd.) to obtain a granular preparation as a solid dispersion. The yield was 79.4%.

[Example 5] Preparation of solid dispersion (heat melting method)
As a core substance, 10 g of spherical silica (MB5D 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm and a specific surface area of 348.87 m ² / g and ibuprofen (Japanese Pharmacopoeia Standard, Yonezawa) 2 g) (mixed by Hamari Pharmaceutical Co., Ltd.), mixed in a small amount of small torque meter (Unitest), kneaded at a heating temperature of 100 ° C. and a rotation speed of 5 rpm for 20 minutes, injection molded, and left at room temperature. As a solid dispersion, a granule preparation in which 10 mg of ibuprofen was adsorbed per 50 mg of spherical silica was obtained. The yield (however, no moisture correction was performed) was 90.0%.

[Comparative Example 1] Preparation of solid dispersion (downward spray method)
Example 1 is used except that spherical silica (SYLOSPHERE C-1510, manufactured by Fuji Silysia) having an average particle size of 9.3 μm and a specific surface area of 542.65 m ² / g is used as the nuclear material instead of MB4B 100-200. In the same manner as in Example 1, an attempt was made to produce a solid dispersion, but it was not obtained.

[Comparative Example 2] Preparation of solid dispersion (downward spray method)
As a nuclear material, instead of MB4B 100-200, use mannitol (Nonparell 108, manufactured by Freund Sangyo Co., Ltd.) having a particle size of 150 to 250 μm, an average particle size of 200 μm (catalog value) and a specific surface area of 0.663 m ² / g; A granule preparation was obtained in the same manner as in Example 1-1 except that the amount of spray air was 30 L / min. The yield was 94.5%.

[Comparative Example 3] Preparation of solid dispersion (solvent removal method)
As a core material, 10 g of spherical silica (MB5D 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm and a specific surface area of 348.87 m ² / g was used as ibuprofen (Japanese Pharmacopoeia Standard, Yonezawa). 2 g of Hamari Pharmaceutical Co., Ltd.) was put into a solution in a vat dissolved in 40 g of ethanol, and the ethanol was removed by vacuum drying at 40 ° C. for 17 hours with a vacuum dryer (DP-63, manufactured by Yamato Scientific Co., Ltd.). A granule preparation containing 10 mg of ibuprofen per 50 mg of spherical silica was obtained.

[Comparative Example 4] Preparation of solid dispersion (spray drying method)
As a nuclear material, ²⁰ g of spherical silica (MB5D 100-200, manufactured by Fuji Silysia) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm, and a specific surface area of 348.87 m ² / g, ibuprofen (Japanese Pharmacopoeia Standard, Yonezawa) 4 g (manufactured by Hamari Pharmaceutical Co., Ltd.) was put into a solution dissolved in 80 g of ethanol, and spray-dried by a spray dryer (B-290, manufactured by BUCHI). At this time, the supply air temperature was 65 ° C., and the liquid feeding speed was 5 g / min. The yield was 88.1%. The obtained granules were vacuum-dried at 40 ° C. for 12 hours with a vacuum dryer (DP-63, manufactured by Yamato Scientific Co., Ltd.) to remove ethanol to obtain a granule preparation containing 10 mg of ibuprofen per 50 mg of spherical silica.

Reference Example 1 Preparation of Physical Mixture Ibuprofen (Japanese Pharmacopoeia Standard, Yonezawa Hamari Pharmaceutical Co., Ltd.) 10 mg, spherical shape with a particle size of 75 to 150 μm, an average particle size of 92.1 μm and a specific surface area of 348.87 m ² / g 50 mg of silica (MB5D 100-200, manufactured by Fuji Silysia) was mixed to obtain a physical mixture (IBP + MBS PM). In the present specification, the “physical mixture” means a product obtained by simply mixing two or more components in a solid state at room temperature to obtain a homogeneous state.

[Example 6] Preparation of tablets 600 mg of the granule preparation obtained in Example 1-3 was mixed with 880 mg of lactose (SuperTAB 11SD, manufactured by DMV), 400 mg of crystalline cellulose (Theolas KG1000, manufactured by Asahi Kasei), crospovidone (XL- 10, 100 mg of ISP) and 20 mg of magnesium stearate (malincklot) in a mortar, and 200 mg (containing 10 mg of ibuprofen) at 8 kN using an autograph (AG-5000A, Shimadzu Corporation). Compression molding was performed to obtain a tablet having a diameter of 8 mm.

[Comparative Example 5] Preparation of tablet In place of the granule preparation obtained in Example 1-3, 100 mg of ibuprofen (Japanese Pharmacopoeia Standard, Yonezawa Hamari Pharmaceutical Co., Ltd.) as the drug substance crystal, particle size of 75 to 150 µm, average particle size A tablet having a diameter of 8 mm was obtained in the same manner as in Example 6 except that 500 mg of spherical silica (MB5D 100-200, manufactured by Fuji Silysia) having 92.1 μm and a specific surface area of 348.87 m ² / g was used. That is, ibuprofen, spherical silica, crystalline cellulose, crospovidone and magnesium stearate are mixed in a mortar without previously mixing ibuprofen and spherical silica.

[Example 7] Preparation of capsules 60 mg of granule preparation obtained in Example 1-3 (containing 10 mg of ibuprofen) was filled into No. 2 hypromellose capsules (Qualicaps, formerly HPMC capsules), and capsules Got.

[Comparative Example 6] Preparation of capsules In place of the granule preparation obtained in Example 1-3, 10 mg of ibuprofen (Japanese Pharmacopoeia standard, Yonezawa Hamari Pharmaceutical Co., Ltd.) as the drug substance crystals and particle size of 75 to 150 μm, average particle A mixture of 50 mg of spherical silica (MB5D 100-200, manufactured by Fuji Silysia) having a diameter of 92.1 μm and a specific surface area of 348.87 m ² / g, that is, 60 mg of the physical mixture obtained in Reference Example 1 (containing 10 mg of ibuprofen) ) Was used in the same manner as in Example 7 except that a capsule was obtained.

[Test Example 1] Dissolution test [Test Example 1-1]
Granule preparation (IBP-MBS) obtained in Example 1-3, physical mixture (IBP + MBS PM) obtained in Reference Example 1-1 and ibuprofen (Japanese Pharmacopoeia Standard, Yonezawa Hamari Pharmaceutical Co., Ltd.) as the drug substance crystals For IBP), an elution test with a 50 rpm paddle was performed according to the Japanese Pharmacopoeia dissolution test method (paddle method) using an amount of 10 mg of ibuprofen. As a test solution, 900 mL of distilled water was used. The elution rate was calculated by measuring the absorbance at a wavelength of 222 nm. The results are shown in FIG.
From FIG. 1, it was confirmed that the granule preparation (IBP-MBS) obtained in Example 1-3 has improved dissolution characteristics over the physical mixture (IBP + MBS PM) and drug substance crystals (IBP). .

[Test Example 1-2]
In place of the ibuprofen sample, the granule preparation (IND-MBS) obtained in Example 1-5 and indomethacin (Japanese Pharmacopoeia standard, manufactured by Kongo Chemical Co., Ltd .; IND) as the drug substance crystals are each in an amount of 10 mg of indomethacin. Elution was conducted in the same manner as in Test Example 1-1 except that 900 mL of artificial intestinal fluid (pH 6.8 phosphate buffered aqueous solution) was used instead of distilled water as the test solution, and the elution rate was calculated from the absorbance at 320 nm. The test was conducted. The results are shown in FIG.
From FIG. 2, it was confirmed that the granule preparation (IND-MBS) obtained in Example 1-5 has improved dissolution characteristics than the drug substance crystal (IND).

[Test Example 1-3]
About the granule preparation (PNT-MBS) obtained in Example 1-6 in place of the ibuprofen sample and phenytoin (Japanese Pharmacopoeia / USP / EP standard, manufactured by Katwijk Chemie BV; PNT) as the drug substance crystal , Respectively, using an amount of 2.5 mg of phenytoin, using 900 mL of artificial intestinal fluid (pH 6.8 phosphate buffered aqueous solution) instead of distilled water as a test solution, and measuring the elution amount (1200 series, Agilent) The dissolution test was carried out in the same manner as in Test Example 1-1 except that the dissolution rate was calculated from the absorbance at 258 nm using Technologies). The results are shown in FIG.
From FIG. 3, it was confirmed that the granule preparation (PNT-MBS) obtained in Example 1-6 has improved dissolution characteristics than the drug substance crystal (PNT).

[Test Example 1-4]
Instead of the ibuprofen sample used in Test Example 1-1, the tablet obtained in Example 6 (IBP-MBS / Tab) and the tablet obtained in Comparative Example 5 (IBP + MBS (PM) / Tab) were respectively used for ibuprofen. The elution test was carried out in the same manner as in Test Example 1-1 except that the amount used was 10 mg. The results are shown in FIG.
FIG. 4 confirms that the tablet (IBP-MBS / Tab) obtained in Example 6 has improved dissolution characteristics compared to the tablet obtained in Comparative Example 5 (IBP + MBS (PM) / Tab). It was.

[Test Example 1-5]
In place of the ibuprofen sample used in Test Example 1-1, the capsule obtained in Example 7 (IBP-MBS / Cap) and the capsule obtained in Comparative Example 6 (IBP + MBS (PM) / Cap) The elution test was carried out in the same manner as in Test Example 1-1 using an amount of 10 mg of ibuprofen. The results are shown in FIG.
From FIG. 5, it can be seen that the capsule (IBP-MBS / Cap) obtained in Example 7 has improved elution characteristics over the capsule (IBP + MBS (PM) / Cap) obtained in Comparative Example 6. confirmed.

[Test Example 2] Differential scanning calorimetry [Test Example 2-1]
Granule preparation (IBP-MBS) obtained in Example 1-3, which was separately put in a glass bottle and stored in an open bath at 60 ° C. and a relative humidity of 75% for 3 weeks (IBP-MBS stored) ), Spherical silica (MB5D 100-200, manufactured by Fuji Silysia; MBS) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm, and a specific surface area of 348.87 m ² / g, and ibuprofen (Japanese Pharmacopoeia Standard) , Manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .; IBP), 10 mg each was used as a sample, and measured with a differential scanning calorimeter (DSC6200, manufactured by Seiko Instrument). At this time, the temperature increase rate was 5 ° C./min, and the measurement was performed after sampling into an aluminum pan. The results are shown in FIG.
From FIG. 6, due to the disappearance of the peak of the drug substance crystal (IBP), the granule preparation (IBP-MBS) obtained in Example 1-3 and the granule preparation after storage (IBP-MBS stored) are amorphized. It was confirmed. The latter granule preparation was confirmed to maintain a high dissolution property even after storage in Test Example 4 described later.

[Test Example 2-2]
Granule preparation (IND-MBS) obtained in Example 1-5, spherical silica (MB5D 100-200, Fuji Silysia Ltd.) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm and a specific surface area of 348.87 m ² / g Manufactured by MBS) and indomethacin (Japanese Pharmacopoeia standard, manufactured by Kongo Chemical Co., Ltd .; IND) as a drug substance crystal, differential scanning calorimetry was measured in the same manner as in Test Example 2-1. The results are shown in FIG.
From FIG. 7, it was confirmed that the granule preparation (IND-MBS) obtained in Example 1-5 was amorphized due to the disappearance of the peak of the drug substance crystal (IND).

[Test Example 2-3]
Granule preparation (PNT-MBS) obtained in Example 1-6, spherical silica (MB5D 100-200, Fuji Silysia Ltd.) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm and a specific surface area of 348.87 m ² / g Manufactured by MBS) and phenytoin (Japanese Pharmacopoeia / USP / EP Standard, manufactured by Kongo Chemical Co., Ltd .; PNT) as drug substance crystals, differential scanning calorimetry was measured in the same manner as in Test Example 2-1. The results are shown in FIG.
From FIG. 8, it was confirmed that the granule preparation (PNT-MBS) obtained in Example 1-6 was amorphized due to the disappearance of the peak of the drug substance crystal (PNT).

[Test Example 2-4]
For each granule preparation obtained in Example 2-2, the differential scanning calorific value was measured in the same manner as in Test Example 2-1. The results are shown in FIG.
From FIG. 9, it was confirmed that the smaller the drug coating amount, the easier it becomes amorphous.

[Test Example 2-5]
The granule preparations obtained in Example 2-1 (only the granule preparations adsorbed with 10 mg, 20 mg, and 25 mg of ibuprofen per 50 mg of spherical silica, respectively) and the granule preparations obtained in Example 2-3 were the same as in Test Example 2-1. The differential scanning calorific value was measured. The results are shown in Table 1 as appropriate in comparison with the results of Test Example 2-4 for the granular preparation obtained in Example 2-2.

In the table, ◎ indicates that it is amorphous (the same applies to Table 2).

  From Table 1, it was confirmed that the larger the specific surface area, the more easily the amorphous state. In addition, as in the results of Test Example 2-4, it was confirmed that the smaller the amount of drug coating, the easier it was to become amorphous.

[Test Example 2-6]
For the granule preparations obtained in Example 1-2 and Example 1-4, the differential scanning calorific value was measured in the same manner as in Test Example 2-1. The results are shown in Table 2 in comparison with the results of Test Example 2-1 for the granule preparation obtained in Example 1-3.

  From Table 2, among Example 1-2, Example 1-3, and Example 1-4 using spherical silica with a similar specific surface area, Example 1-3 using spherical silica with a relatively large particle size. And it was confirmed that Example 1-4 was easier to be amorphous than Example 1-2.

[Test Example 2-7]
For the granule preparations obtained in Example 3, Example 4, Example 5, Comparative Example 3 and Comparative Example 4, respectively, the differential scanning calorimetry was measured in the same manner as in Test Example 2-1. The results are shown in FIG.
From FIG. 10, the disappearance of the peak of the drug substance crystal (IBP) in FIG. 6 was obtained in Example 3 by the upper spray method, Example 4 by the side spray method, and Example 5 by the heat melting method, respectively. It was confirmed that all of the granule preparations were amorphous. On the other hand, crystal structures were observed in the granule preparation obtained by the solvent removal method in Comparative Example 3 and the granule preparation obtained by the spray drying method in Comparative Example 4.

[Test Example 3] Differential thermal analysis [Test Example 3-1]
About 14 mg of granule preparation (IBP-NP) obtained in Comparative Example 2 and 4 mg of ibuprofen (Japanese Pharmacopoeia standard, Yonezawa Hamari Pharmaceutical Co., Ltd .; IBP) as the drug substance crystal, a differential thermal analyzer (TG / DTA200, Seiko Instrument) ). The results are shown in FIG.
From FIG. 11, the peak of the drug substance crystal (IBP) did not disappear, and it was confirmed that the granule preparation (IBP-NP) obtained using mannitol in Comparative Example 2 was not amorphous.

[Test Example 3-2]
Differential heat of the granule preparation (IBP-MBP) obtained in Comparative Example 3 and 4 mg of ibuprofen (Japanese Pharmacopoeia Standard, Yonezawa Hamari Pharmaceutical Co., Ltd .; IBP) as the drug substance crystals were the same as in Test Example 3-1. Measured with an analyzer. The results are shown in FIG.
In FIG. 12, the differential thermal analysis curve shows the results for IBP-MBS and IBP in order from the top.
From FIG. 12, it was confirmed that the drug substance crystal (IBP) peak did not disappear, and the granule preparation obtained by the solvent removal method in Comparative Example 3 was not amorphous.

[Test Example 4] Stability test (75% RH 60 ° C, 3 weeks)
About 60 mg of granule preparation (IBP-MBS) obtained in Example 1-3 (containing 10 mg of ibuprofen), (1) Evaluation of dissolution was performed in the same manner as in Test Example 1-1 (Initial), (2) The sample was placed in a glass bottle and stored for 3 weeks in an open-temperature bath at 60 ° C. and a relative humidity of 75%, and then the dissolution property was evaluated in the same manner as in Test Example 1-1 (After storage). The results are shown in FIG.
From FIG. 13, it was confirmed that the high dissolution property of the granule preparation obtained in Example 1-3 was maintained before and after storage despite being stored for 3 weeks under high temperature humidification.

[Test Example 5] Powder X-ray evaluation [Test Example 5-1]
Granule preparation (IBP-MBS) obtained in Example 1-3, granule preparation (IBP-MBS) obtained by the spray drying method in Comparative Example 4, particle size 75-150 μm, average particle diameter 92.1 μm and specific surface area Powder X-ray diffraction of spherical silica (MB5D 100-200, manufactured by Fuji Silysia; MBS) and ibuprofen (Japanese Pharmacopoeia Standard, manufactured by Yonezawa Hamari Chemical Co., Ltd .; IBP) as the drug substance crystal, which is 348.87 m ² / g Measurement was performed using an apparatus (RINT2000, manufactured by Rigaku Corporation). At that time, the scan speed was 1 ° / min, and measurement was performed with CuKα rays (40 kV, 200 mA). The results are shown in FIG.
In FIG. 14, ▼ indicates a peak derived from a crystal, (a) shows the result of MBS, and (b) to (d) show the following results, respectively.
From FIG. 14, the drug substance crystal (IBP; d) retains the crystal structure, and in the granule preparation (IBP-MBS; c) obtained by the spray drying method in Comparative Example 4, such crystal structure still exists. On the other hand, in the granule preparation (IBP-MBS; b) obtained by the Wurster method in Example 1-3, it was confirmed that the crystal structure disappeared and became amorphous.

[Test Example 5-2]
Granule preparation (IND-MBS) obtained in Example 1-5, spherical silica (MB5D 100-200, Fuji Silysia Ltd.) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm and a specific surface area of 348.87 m ² / g Manufactured by MBS) and indomethacin (Japanese Pharmacopoeia standard, manufactured by Kongo Chemical Co., Ltd .; IND) as a drug substance crystal were measured by a powder X-ray diffractometer in the same manner as in Test Example 5-1. The results are shown in FIG.
In FIG. 15, (b) shows the results of MBS, and (a) and (c) show the following results, respectively.
From FIG. 15, the drug substance crystal (IND; a) retains the crystal structure, whereas in the granule preparation (IND-MBS; c) obtained in Example 1-5, the crystal structure disappears. It was confirmed that the material was amorphous.

[Test Example 5-3]
Granule preparation (PNT-MBS) obtained in Example 1-6, spherical silica (MB5D 100-200, Fuji Silysia Ltd.) having a particle size of 75 to 150 μm, an average particle size of 92.1 μm and a specific surface area of 348.87 m ² / g Manufactured by MBS) and phenytoin (Japanese Pharmacopoeia / USP / EP Standard, manufactured by Kongo Chemical Co., Ltd .; PNT) as drug substance crystals were measured by a powder X-ray diffractometer in the same manner as in Test Example 5-1. The results are shown in FIG.
In FIG. 16, (b) shows the results of MBS, and (a) and (c) show the following results, respectively.
From FIG. 16, the drug substance crystal (PNT; a) retains the crystal structure, whereas in the granule preparation (PNT-MBS; c) obtained in Example 1-6, the crystal structure disappears. It was confirmed that the material was amorphous.

  The present invention has industrial applicability in that it can provide a method for producing a solid dispersion with improved elution of active ingredients. Moreover, the solid dispersion obtained by the production method of the present invention can be used as a pharmaceutical composition.

Claims (7)

For a nuclear material composed of spherical silicon dioxide, having an average particle diameter of 50 μm or more and a specific surface area of 100 m ² / g or more,
(1) A step of fluidized bed coating with an active ingredient-containing liquid, or
(2) A step of mixing active ingredients and performing heat melting,
A process for producing a solid dispersion comprising:   The average particle diameter of the said nuclear substance is a manufacturing method of Claim 1 which is 50 micrometers-1 mm. The manufacturing method according to claim 1, wherein the specific surface area of the nuclear material is 100 to 2000 m ² / g.   The said fluidized bed coating is a manufacturing method as described in any one of Claims 1-3 performed by the upper spraying method, the side spraying method, or the downward spraying method.   The said fluidized bed coating is a manufacturing method as described in any one of Claims 1-3 performed with a Wurster type | mold coating machine.   The production method according to any one of claims 1 to 5, wherein the active ingredient is a poorly soluble drug. A step of obtaining a solid dispersion by the production method according to any one of claims 1 to 6,
And a step of obtaining a fine granule, granule, tablet or capsule using the solid dispersion.