JP2019077644A - Pharmaceutical composition and method of producing pharmaceutical composition - Google Patents

Abstract

To provide a pharmaceutical composition containing nano-size particles of a stable Cox-2 inhibitor, and a method of producing the pharmaceutical composition.SOLUTION: A pharmaceutical composition comprises: particles of a Cox-2 inhibitor having an average particle diameter of 50 nm to 500 nm; and at least one dispersant selected from hydroxypropylcellulose having molecular weight of 100,000 or less and polyvinylpyrrolidone having molecular weight of 100,000 or less. A method of producing the pharmaceutical composition is also provided.SELECTED DRAWING: None

Description

  The present disclosure relates to pharmaceutical compositions and methods of making pharmaceutical compositions.

  Therapeutic and / or prophylactic Cox-2 inhibitors (compounds that have selective cyclooxygenase-2 inhibitory effects) have been reported, and specific Cox-2 caused diseases or related diseases in general It is disclosed that it is useful for treatment or prevention. Cox-2 inhibitors are useful for oral non-steroidal anti-inflammatory agents, analgesics, anticancer agents and the like, and various other medicinal effects have been investigated.

  Many Cox-2 inhibitors are hydrophobic and poorly water soluble. In an orally administered pharmaceutical composition, when early onset of a therapeutic effect is desired, it may be problematic that it does not have solubility that can be rapidly absorbed in the gastrointestinal tract due to low water solubility. Various studies have been made for the purpose of formulating Cox-2 inhibitors with good absorbability.

For example, a pharmaceutical composition has been proposed in which a Cox-2 inhibitor is a particle having a D ₉₀ size of 0.01 μm to 200 μm and in which no particle of 1 μm or more exists (see, for example, Patent Document 1). Furthermore, celecoxib is provided in the form of a porous matrix, and when in contact with an aqueous medium, a powder with a high dissolution rate, with a particle size of 0.01 μm to 5 μm and a specific total surface area It is proposed (for example, refer patent document 2).
In addition, as a novel crystalline form of celecoxib, there has been proposed a pharmaceutical composition containing Form IV crystal which is produced by dissolving celecoxib in a solvent and bringing it into contact with an aqueous solution (see, for example, Patent Document 3).

Japanese Patent Publication No. 2003-523954 Japanese Patent Publication No. 2004-503484 Japanese Patent Publication No. 2008-528568

As mentioned above, when applying a poorly water-soluble Cox-2 inhibitor to a pharmaceutical composition, proposals have been made focusing on the particle size.
However, although the Cox-2 inhibitor described in Patent Document 1 has a particle size of 1 μm or less, for example, nano-order particles that are considered to be able to improve the absorbability when taken orally. The diameter has not been achieved yet. Furthermore, no investigations have been made on powder formulations containing particles of Cox-2 inhibitor.
The composition described in Patent Document 2 is prepared from celecoxib powder by evaporation from an organic solvent system, and there is a concern about residual solvent. Furthermore, as in Patent Document 1, nano-order celecoxib particles have not been obtained.
Although the crystal form of celecoxib described in Patent Document 3 is finer than that of the prior art, the average particle diameter of the celecoxib particles described in the examples is 1 μm or more, and nano-order celecoxib particles have not been obtained. Furthermore, no consideration is given to coexistence with an excipient and formulation as a solid preparation.

The problem to be solved by one embodiment of the present invention is to provide a pharmaceutical composition comprising nano-sized particles of stable Cox-2 inhibitor.
An object of another embodiment of the present invention is to provide a method of producing a pharmaceutical composition comprising nano-sized particles of stable Cox-2 inhibitor.

Means for solving the above problems include the following embodiments.
<1> A medicament comprising particles of Cox-2 inhibitor having an average particle size of 50 nm to 500 nm, and at least one dispersant selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less Composition.
<2> The pharmaceutical composition according to <1>, wherein the dispersing agent contains hydroxypropyl cellulose having a molecular weight of 50,000 or less.
The pharmaceutical composition as described in <1> or <2> whose average particle diameter of the particle | grains of <3> Cox-2 inhibitor is 50 nm-200 nm.
The pharmaceutical composition as described in any one of <1>-<3> whose <4> Cox-2 inhibitor is celecoxib.

The pharmaceutical composition as described in any one of <1>-<4> which is a <5> solid formulation.
<6> The pharmaceutical composition according to <5>, further comprising at least one excipient selected from the group consisting of mannitol, sucrose, inositol, and maltose.
<7> The pharmaceutical composition according to <5> or <6>, further including polyvinyl alcohol and at least one water-soluble polymer selected from hydroxypropyl methylcellulose.
The pharmaceutical composition as described in any one of <5>-<7> which is a <8> tablet.

A medium dispersion process is performed on a mixed solution containing particles of <9> Cox-2 inhibitor, and at least one dispersant selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less. A method for producing a pharmaceutical composition, comprising the step of obtaining particles of Cox-2 inhibitor having an average particle size of 50 nm to 500 nm.
A media dispersion process is performed on a mixed solution containing particles of <10> Cox-2 inhibitor, and at least one dispersant selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less C., obtaining a liquid composition containing particles of Cox-2 inhibitor having an average particle size of 50 nm to 500 nm, the obtained liquid composition, and at least one selected from mannitol, sucrose, inositol, and maltose Drying the mixture obtained by mixing the excipient and the mixture by spray drying to obtain a granulated product.
<11> The method for producing a pharmaceutical composition according to <10>, further comprising the step of tableting the obtained granulated product to obtain a solid preparation.

According to one embodiment of the present invention, a pharmaceutical composition comprising nano-sized particles of stable Cox-2 inhibitor can be provided.
According to another embodiment of the present invention, there can be provided a method of producing a pharmaceutical composition containing nano-sized particles of stable Cox-2 inhibitor.

Hereinafter, the pharmaceutical composition of the present disclosure and the method for producing the pharmaceutical composition will be described in detail.
Although the description of the configuration requirements described below may be made based on the representative embodiments of the present disclosure, the present disclosure is not limited to such embodiments.
In addition, in this specification, "-" which shows a numerical range is used by the meaning which includes the numerical value described before and after that as a lower limit and an upper limit.
In the numerical ranges that are described stepwise in the present specification, the upper limit or the lower limit described in one numerical range may be replaced with the upper limit or the lower limit of the numerical range described in the other stepwise Good. In addition, in the numerical range described in the present specification, the upper limit value or the lower limit value of the numerical range may be replaced with the value shown in the example.
In the present specification, the combination of preferred embodiments is a more preferred embodiment.
In the present disclosure, the amount of each component in the composition is the total amount of the plurality of substances present in the composition unless a plurality of substances corresponding to each component are present in the composition. means.
In the present specification, the term "step" is included in the term if the intended purpose of the step is achieved, even if it can not be distinguished clearly from the other steps, not only an independent step. .

<Pharmaceutical composition>
The pharmaceutical composition of the present disclosure comprises at least one dispersant selected from particles of Cox-2 inhibitor having an average particle size of 50 nm to 500 nm, hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinylpyrrolidone having a molecular weight of 100,000 or less. And.
Hereinafter, each component contained in a pharmaceutical composition is demonstrated one by one.

(Cox-2 inhibitor)
Compounds having selective cyclooxygenase-2 inhibitory effects (Cox-2 inhibitors) are useful for oral non-steroidal anti-inflammatory, analgesics, anticancer agents, etc. As other medicinal effects, for example, allergic rhinitis And its application to treatment and prevention of inflammation-related cardiovascular diseases, angiogenesis-related diseases and the like.
There is no restriction | limiting in particular in the Cox-2 inhibitor used for the pharmaceutical composition of this indication, As long as it is a compound which has a selective cyclooxygenase-2 inhibitory effect, all can be used.
Examples of Cox-2 inhibitors include celecoxib (4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide), delacoxib (4- [ 5- (3-Fluoro-4-methoxyphenyl) -3-difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide), valdecoxib (4- (5-methyl-3-phenyl-1,2-oxazole) -4-yl) benzene-sulfonamide), rofecoxib (4- (4-methanesulfonylphenyl) -3-phenyl-2,5-dihydrofuran-2-one), etodolac (2- [1 RS] -1,8 -Diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) acetic acid), meloxicam (4-hydroxyl) -2-Methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide), 5-chloro-3- (4-methylsulfonyl) phenyl- 2- (2-Methyl-5-pyridinyl) pyridine, 2- (3,5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-1-one, (S) -6, 8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid and the like can be mentioned. These compounds may be in the form of pharmaceutically acceptable salts, such as sodium salts.
Among them, celecoxib, valdecoxib, etodolac and meloxicam are preferable from the viewpoint of high selectivity for Cox-2 inhibitory activity and small side effects in the digestive tract, and celecoxib is more preferable.

Cox-2 inhibitors are included in the pharmaceutical composition of the present disclosure in the form of particles with an average particle size of 50 nm to 500 nm. The average particle size of the Cox-2 inhibitor is preferably 50 nm to 400 nm, more preferably 50 nm to 300 nm, and still more preferably 50 nm to 200 nm.
In the present specification, the average particle size of the Cox-2 inhibitor is obtained by measuring the particle size in the dispersion by the dynamic light scattering method, and accumulating the obtained particle sizes for each channel from the smaller particle size. The value obtained as the value of the volume average particle diameter (hereinafter sometimes referred to as D ₅₀ or simply the average particle diameter) at which the cumulative 50% is reached is adopted. As a particle size measuring apparatus, for example, concentrated system particle size analyzer FPAR-1000 (trade name, manufactured by Otsuka Electronics Co., Ltd.), particle size distribution measuring apparatus Nanotrac (trade name, manufactured by Microtrac Bell, Inc.), dynamic Light scattering type particle size distribution measuring apparatus LB-500 (trade name, manufactured by Horiba, Ltd.), Zetasizer Nano (trade name, manufactured by Malvern Instruments) can be used.
When the average particle diameter of the Cox-2 inhibitor is in the above-mentioned range, the absorbability of the medicinal active ingredient Cox-2 inhibitor in the body becomes good, and rapid onset of medicinal efficacy can be expected.

  The average particle size of the Cox-2 inhibitor can be appropriately adjusted by controlling the types, contents, dispersion conditions, and the like of the Cox-2 inhibitor and the dispersant described later.

  The average particle size of the Cox-2 inhibitor is the particle size after preparing the pharmaceutical composition, and the particle size of the Cox-2 inhibitor raw material used for preparing the pharmaceutical composition is necessarily in the above range. There is no.

The content of the Cox-2 inhibitor in the pharmaceutical composition of the present disclosure can be appropriately selected according to the purpose of treatment or prevention within the pharmaceutically acceptable range.
Generally, the dose of the pharmaceutical composition can be in the range of 25 mg to 500 mg, preferably in the range of 50 mg to 400 mg, and more preferably in the range of 100 mg to 300 mg.

<Dispersing agent>
The pharmaceutical composition of the present disclosure comprises at least one dispersant (hereinafter sometimes referred to as a specific dispersant or simply a dispersant) selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less. Including.
By coexisting with these dispersants, the aforementioned Cox-2 inhibitor is stably present in the pharmaceutical composition in the form of particles having an average particle size of nanosize.
As a dispersing agent, hydroxypropyl cellulose is preferable.
The hydroxypropyl cellulose has a molecular weight of 100,000 or less, preferably 50,000 or less. That is, the pharmaceutical composition of the present disclosure preferably contains hydroxypropyl cellulose having a molecular weight of 50,000 or less as a dispersant.
The lower limit value of the molecular weight of the dispersant is not particularly limited, but can be 10,000 or more from the viewpoint of the effect.
When using a commercial item, the molecular weight of a dispersing agent should just adopt the catalog value of a commercial item.
Examples of the method of directly measuring the molecular weight of the dispersant include gel permeation chromatography (GPC) and size exclusion chromatography (SEC).
For example, the molecular weight of the water-soluble polymer can be determined as a value of weight average molecular weight in terms of polystyrene (PST) or pullulan using GPC. When PST is dissolved in the eluent for measurement when measuring the weight average molecular weight by applying this method, it is measured in terms of PST, and when Pullulan is dissolved in the eluent, it is measured in terms of pullulan. Just do it.

A commercial item can be used for a specific dispersing agent.
Commercial products of hydroxypropyl cellulose include NISSO HPC-SSL (trade name, molecular weight: 40,000), NISSO HPC-SL (trade name, molecular weight: 100,000, above, Nippon Soda Co., Ltd. product), Klucel ELF Pharm ( Trade name, molecular weight: 40,000), Klucel EF Pharm (trade name, molecular weight: 80,000), Klucel LF Pharm (trade name, molecular weight: 95,000, or more, manufactured by Ashland), and the like.
As polyvinyl pyrrolidone, Kollidon 25 (trade name, molecular weight: 28,000 to 34,000), Kollidon 30 (trade name, molecular weight: 44,000 to 54,000, BASF Corporation), Plasodone K -25 (trade name, molecular weight: 34,000), Plasodone K-29 / 32 (trade name, molecular weight: 58,000, above, manufactured by Ashland) and the like.

The content of the dispersant is preferably in the range of 5 parts by mass to 120 parts by mass, and in the range of 10 parts by mass to 100 parts by mass, with respect to 100 parts by mass of Cox-2 inhibitor contained in the pharmaceutical composition. It is more preferable that
When the content of the dispersing agent is in the above range, particles of the Cox-2 inhibitor in the obtained pharmaceutical composition are more stably dispersed and aggregation of the particles is more effectively suppressed, and as a result, the average particle diameter is 50 nm to It tends to be in the range of 500 nm.

  The pharmaceutical composition of the present disclosure may use a dispersion aid in combination with the specific dispersant described above. As a dispersion aid, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, polysorbate 80, polysorbate 65, polysorbate 40, polysorbate 20, polyoxy Ethylene sorbitan monolaurate, polyethylene glycol monostearate, polyethylene glycol monolaurate, pluronics, sodium lauryl sulfate, sodium desoxycolate and the like can be mentioned.

  As a method for preparing a pharmaceutical composition, a method in which a Cox-2 inhibitor is added to a solution in which a dispersing agent is dissolved, and subjected to dispersion processing can be mentioned. However, the preparation method is not limited to this. In addition, the detail of the preferable preparation method of a pharmaceutical composition is mentioned later.

The dosage form of the pharmaceutical composition of the present disclosure is not particularly limited as long as it can be administered to a living body.
Examples of the dosage form include tablets, granules, powders, fine granules, solutions, syrups and the like as dosage forms that can be orally administered, and lotions and creams as dosage forms that can be percutaneously administered. Etc.
Tablets include chewable tablets, troches, drops, granules which dissolve and disintegrate rapidly in the oral cavity, and can be taken without water, and further include re-dissolving tablets such as effervescent tablets which are used after dissolution. .
Granules, powders and fine granules include dry syrup preparations which are dissolved at the time of use, and also include granules which can be dissolved and disintegrated quickly in the oral cavity and can be taken without water, so-called orally disintegrating tablets.
Solutions and syrups may further contain various pharmaceutically acceptable dispersion media.
The pharmaceutical composition of the present disclosure is preferably a solid preparation from the viewpoint of better storage stability and easy portability since it has good redispersibility as described later.
As a solid preparation, a tablet is preferable from the viewpoint of having good manufacturability and storage property and being easy to take the required amount.

The pharmaceutical composition of the present disclosure may contain various commonly used formulation additives as long as the effects are not impaired.
Examples of formulation additives include excipients, disintegrants, binders, lubricants, coloring agents, flavoring agents, sweetening agents, and flavoring agents.

When the pharmaceutical composition of the present disclosure is a solid preparation, an excipient is preferably included to maintain a stable dosage form.
As an excipient, saccharides (eg, glucose, lactose, sucrose, maltose, trehalose, dextrin, cyclodextrin, sucrose etc.), sugar alcohol (eg, mannitol, erythritol, isomalt, lactitol, maltitol, maltitol, sorbitol, xylitol, inositol) Etc.), starch (eg corn starch, potato starch, rice starch, wheat starch etc), crystalline cellulose, calcium salt (eg anhydrous calcium phosphate, light anhydrous calcium silicate, calcium silicate, calcium sulfate, calcium carbonate, calcium lactate) And magnesium metasilicate, anhydrous silicic acid, amino acids (eg, glycine, alanine, asparagine, triprophane etc.) and the like.
In addition, although mannitol is an optically active substance and there exist d-form, l-form, a racemate etc., d-mannitol existing abundantly in nature is suitable as an excipient | filler.
As the excipient, saccharides or sugar alcohols are preferable from the viewpoint of disintegration and inhibition of aggregation of the Cox-2 inhibitor. Among them, the pharmaceutical composition of the present disclosure preferably contains at least one excipient selected from the group consisting of d-mannitol, sucrose, inositol, and maltose.

Pharmaceutical compositions of the present disclosure can include water soluble polymers. The water-soluble polymer can be used in combination with the specific dispersant described above to improve the dispersion stability of the nanoparticles. In addition, it functions as a binder in a solid preparation, improves the stability of the solid preparation, and rapidly dissolves when the solid preparation is orally ingested, thereby redispersing the ingredients contained in the pharmaceutical composition. it can.
Examples of water-soluble polymers include cellulose derivatives (eg, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose etc.), hydroxypropyl starch, dextrin, carbomer (polyacrylic acid) And vinyl pyrrolidone polymers (eg, polyvinyl pyrrolidone, vinyl pyrrolidone / vinyl acetate copolymer, etc.), polyvinyl alcohol, polyethylene glycol and the like.
Among these, as the water-soluble polymer, a cellulose derivative, a vinyl pyrrolidone polymer and a polyvinyl alcohol are preferable.
More specifically, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol and hydroxypropyl methylcellulose are more preferable, and polyvinyl alcohol and hydroxypropyl methyl cellulose are more preferable.
The above-mentioned hydroxypropyl cellulose and polyvinyl pyrrolidone which can be used as a water-soluble polymer in a solid preparation may be the same compound as the dispersant described above, or may be a polymer having a molecular weight of more than 100,000.

The pharmaceutical composition may contain a disintegrant. When the pharmaceutical composition as a solid preparation contains a disintegrant, the orally ingested solid preparation disintegrates more quickly, and early onset of drug efficacy can be expected.
Disintegrants include low substituted hydroxypropyl cellulose, carmellose, crospovidone, carmellose calcium, croscarmellose sodium and the like.

The pharmaceutical composition may contain a lubricant, a coloring agent, a flavoring agent, a sweetening agent, a flavoring agent and the like for the purpose of improving appearance and feeling when taken orally.
As the lubricant, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and the like can be mentioned.
Examples of coloring agents include edible coloring agents such as food yellow No. 5 dye, food red No. 2 dye, food blue No. 2 dye, food lake dye, yellow ferric oxide, titanium oxide and the like.
Examples of the flavoring agent include orange, lemon and other various orally available flavors.

As the sweetening agent, aspartame, stevia, thaumatin, saccharin sodium, dipotassium glycyrrhizinate and the like can be mentioned. Among them, aspartame is preferable because it has the effect of counteracting the saltiness produced by the addition of a sodium salt as a pH adjuster.
When the pharmaceutical composition contains aspartame, the content can be 0.01% by mass to 2% by mass with respect to the total mass of the solid preparation.
Examples of the flavoring agent include L-menthol, camphor, peppermint, sodium L-glutamate, disodium inosinate, magnesium chloride and the like.
Among them, L-menthol is preferable because it has a refreshing feeling and the bitter taste improving effect is improved.
When the pharmaceutical composition contains L-menthol, the content can be 0.01% by mass to 2% by mass with respect to the total mass of the solid preparation.

  The preparation additives described above may be added at an appropriate step, as appropriate, in the production of the pharmaceutical composition.

<Method for producing pharmaceutical composition>
There is no restriction | limiting in particular in the manufacturing method of the pharmaceutical composition of this indication as stated above, It can manufacture by a well-known method. Among them, production by the method of producing a pharmaceutical composition of the present disclosure described below is preferable.
The method for producing the pharmaceutical composition of the present disclosure (hereinafter, may be simply referred to as the production method of the present disclosure) comprises particles of Cox-2 inhibitor, hydroxypropyl cellulose having a molecular weight of 100,000 or less and a molecular weight of 100,000 or less A step of media dispersion treatment of a mixed solution containing at least one dispersant selected from polyvinyl pyrrolidone to obtain particles of Cox-2 inhibitor having an average particle diameter of 50 nm to 500 nm.

The method for producing the above pharmaceutical composition is referred to as the first embodiment of the production method of the present disclosure.
Hereinafter, the distributed processing in the first embodiment of the manufacturing method of the present disclosure will be described in detail.
The average particle size of the particles of Cox-2 inhibitor used as a raw material is arbitrary. A commercially available Cox-2 inhibitor may be used as it is as a raw material.
Preferably, first, at least one dispersant (specific dispersant) selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less is dissolved in a solvent. The solvent is selected according to the purpose. Among them, water is preferably used as the solvent, considering that the solubility of the specific dispersant is better and that the degree of freedom in the formulation of the obtained pharmaceutical composition is higher.
Water used for dissolving the specific dispersant is preferably ion-exchanged water, pure water, ultrapure water, water for injection, purified water, or the like from the viewpoint of less impurities.

A mixed solution is prepared by adding a Cox-2 inhibitor as a raw material to a solution of a specific dispersant. In addition, although the example which used celecoxib as a Cox-2 inhibitor is mentioned and demonstrated below, it is not limited to this.
The celecoxib particles in the resulting mixture are subjected to mechanical dispersion treatment using a solid disperser to prepare a dispersion containing fine celecoxib dispersed particles.

The disperser used for preparation of a dispersion can select and use a well-known disperser suitably. Commonly used solid dispersers are tripological shear type dispersers that apply shear force directly to dispersed particles using drive parts and media, and rheological shear type dispersers that apply shear force to dispersed particles via liquid medium. is there.
As a tripology shear force type disperser, a roll mill for dispersing a slurry containing a solid substance to be dispersed by passing it between a plurality of rolls, a kneader for applying a shearing force to the slurry with a stirring blade, beads in the slurry Media and the like, and a media mill or the like that applies a shear force through the media.
As a rheological shear type dispersing machine, various stirring type dispersing machines, high pressure dispersing machines, ultrasonic dispersing machines and the like can be mentioned.

  In the production method of the present disclosure, it is preferable to use a mechanical disperser which directly disperses celecoxib in solid form by applying high shear force and disperse it, from the viewpoint of easily forming fine dispersion particles, and tripological shear force type. A disperser is more preferable, and it is further preferable to disperse media using a media disperser represented by a media mill. In the manufacturing method of the present disclosure, media distribution processing is performed.

When a dispersion is prepared using a media dispersion machine, fine celecoxib is performed by mixing the mixture containing celecoxib particles, a material selected according to the purpose, and a medium having a particle diameter to perform media dispersion. An aqueous dispersion in which the particles are stably dispersed can be obtained.
Materials of media used for dispersion include zirconia, alumina, steatite, silicon carbide, silicon nitride, silica, sand, mano, steel balls, stainless steel, inorganic compounds such as glass, polystyrene, polymethyl methacrylate, polytetrafluoroethylene, Examples thereof include polymer resins such as polyamide, polyethylene, polypropylene, polyetheretherketone (PEEK) and polyimide. Among them, zirconia beads are preferable from the viewpoint of dispersion power, durability, and no concern of contamination due to media.

Various dispersing machines are known as media dispersing machines for adding motive force to the media, depending on the stirring system, media separating mechanism, vertical type or horizontal type, cooling system, etc., but in particular, micro beads of 0.1 mm or less Preferred is a bead mill equipped with a separation mechanism of
Commercial products of bead mill dispersers having a minute bead separation mechanism such as 0.1 mm or less include Ultra Apex Mill (trade name: Kotobuki Industry), Star Mill (trade name: Ashizawa Finetech), Pearl Mill (trade name: Buehler), OB mill (trade name: Freund Industries), Dyno mill (trade name: WAB) and the like can be mentioned, and any of them can be used in the method for producing the pharmaceutical composition of the present disclosure. Note that the dispersing apparatus that can be used for the distributed processing is not limited to the example described above.

In addition, even if it is a dispersion apparatus which is not equipped with the separation mechanism of beads, it can be used for the manufacturing method of this indication by adding the process after bead filtration after dispersion processing.
Dispersers that do not have a bead separation mechanism that can be used in the manufacturing method of the present disclosure include ball mills, sand grinder mills, and planetary ball mills.
The ball mill is a dispersing device for placing and rotating a pot formed of a material selected from porcelain, nylon, polymer, stainless steel, etc. containing slurry and beads on a rotating table.
As the sand grinder mill, there are many apparatuses in which the shape of the agitator can be changed to a pin type or a disk type according to the viscosity of the slurry, and a Ready Mill (trade name: IMEX) etc. is known.
A planetary ball mill has a structure in which a vessel containing a slurry and balls revolves while rotating, and is superior in dispersion efficiency to a general ball mill. As an example of a planetary ball mill, a planetary ball mill (trade name: Fritsch) And rotation and revolution nano-crusher NP-100 (trade name: Shinky).

In the case of carrying out media dispersion treatment using zirconia beads in preparation of dispersion particles containing celecoxib particles in mechanical dispersion treatment, it is preferable to carry out dispersion treatment in two steps. That is, the first-stage dispersion treatment is a step of grinding coarse particles containing celecoxib to a certain size, for example, about 1 μm to 10 μm. Thereafter, a second stage dispersion is performed to obtain fine particles.
In the first-stage dispersion treatment in the two-stage dispersion, the media disperser does not necessarily have to be used. For example, a rheological shear type disperser such as a high-speed stirring system can also be used. However, from the viewpoint of dispersion efficiency, it is preferable to carry out coarse dispersion with a media disperser using relatively large beads of 0.5 mmφ or more. Following the first-stage dispersion step (hereinafter sometimes referred to as a coarse dispersion step), the second-stage dispersion, that is, the main dispersion is performed. It is preferable to apply a media disperser using minute beads of 0.3 mmφ or less as media for the second stage dispersion processing.
In the second-stage dispersion treatment, as celecoxib particles, for example, the dispersion is finely dispersed to about 50 nm to about 500 nm.

In the mechanical dispersion process, when performing the two-stage dispersion process, a rheological shear type disperser can be used as a disperser other than the media disperser, which can be used supplementary to the coarse dispersion process which is the first-stage dispersion process. There may be used a homomixer, a disperser mixer, an ultramixer, a stirrer such as Clairemix (trade name: Emtechnic), an ultrasonic homogenizer, a high pressure homogenizer, or the like. As high-pressure homogenizers, Microfluidizer (trade name: Microfluidics), Nanomizer (trade name: Yoshida Machine Kogyo), Starburst (trade name: Sugino Machine), Gorin Homogenizer (trade name: APV), Lanier Homogenizer (product name Name: Lanier), high pressure homogenizer (trade name: Niro Soavi), homogenizer (trade name: Sanwa machine), high pressure homogenizer (trade name: Izumi Food Machinery), ultra high pressure homogenizer (trade name: squid), etc. .
The mechanical dispersion process may be a multistage dispersion process of three or more stages.

When mechanical dispersion processing is performed, celecoxib particles as a raw material and a specific dispersant coexist to prepare dispersed particles of celecoxib, whereby the specific dispersant is formed on at least a part of the surface of the dispersed particles which has been miniaturized. The particles are adsorbed to form particles having a so-called protective layer, and in the dispersion medium containing water, reaggregation of adjacent dispersed particles is suppressed. For this reason, in the dispersion containing the obtained celecoxib particles, the average particle diameter of the celecoxib particles is nano-order, and the dispersibility and the dispersion stability of the particles are excellent.
Therefore, preferably, the Cox-2 inhibitor particles in the pharmaceutical composition of the present disclosure have at least one selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less on at least a part of the particle surface. The dispersant of

  By performing mechanical dispersion, the average particle size of the obtained celecoxib particles can be made 500 nm or less as described above. The average particle diameter of the dispersed particles is preferably 50 nm to 400 nm, more preferably 50 nm to 300 nm, and still more preferably 50 nm to 200 nm.

The pharmaceutical composition obtained by the above-described production method of the present disclosure is a dispersion in which fine celecoxib particles are stably dispersed in a dispersion medium containing water.
The resulting dispersion may be used as it is as a solution, syrup or lotion. Moreover, it may be diluted with a pharmaceutically acceptable dispersion medium, a solvent containing water, and the like to adjust to physical properties appropriate for drinking. Furthermore, in order to adjust to taste and appearance suitable for drinking, the coloring agents, flavoring agents, sweetening agents, flavoring agents and the like described above may be added as appropriate. By performing at least one of the above-mentioned adjustments, it is possible to make the composition more suitable for drinking.

Next, a method for producing a pharmaceutical composition as a solid preparation will be described.
There is no limitation in particular in the manufacturing method of the pharmaceutical composition of this indication as a solid preparation, The manufacturing method of a well-known solid preparation can be applied.

Among them, the solid preparation is preferably produced by the method for producing a pharmaceutical composition of the present disclosure shown below.
A method for producing a pharmaceutical composition according to the present disclosure is a mixture comprising particles of Cox-2 inhibitor and at least one dispersant selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less. The liquid was subjected to media dispersion treatment to obtain a liquid composition containing particles of Cox-2 inhibitor having an average particle diameter of 50 nm to 500 nm (hereinafter sometimes referred to as step (I)). A step of drying a mixture obtained by mixing a liquid composition and at least one excipient selected from mannitol, sucrose, inositol, and maltose by a spray drying method to obtain a granulated product (hereinafter referred to as And step (II)).

The method for producing the above pharmaceutical composition for producing the pharmaceutical composition as a solid preparation is referred to as a second embodiment of the production method of the present disclosure.
The above step (I) can be performed in the same manner as the dispersion treatment in the first embodiment of the manufacturing method of the present disclosure described above.
Step (II) is a step of drying the liquid composition obtained in step (I) to prepare a granulated product.

(Step (II))
When the liquid composition which is a dispersion of the obtained celecoxib particles is to be in the form of a powdered pharmaceutical composition, the liquid composition obtained in step (I) and mannitol, sucrose, inositol and maltose are used. A mixture with at least one selected excipient (hereinafter sometimes referred to as a specific excipient) may be prepared, and the resulting mixture may be dried by a drying means such as spray drying.
As the drying means, known drying means can be used, and examples thereof include natural drying, heat drying, hot air drying, high frequency drying, ultrasonic drying, reduced pressure drying, vacuum drying, freeze drying, spray drying and the like. Although a drying means may be used independently, it can also be used combining two or more types of drying means.

As a drying means, lyophilization can also be applied, which sublimes the ice from the frozen material to remove water.
Examples of commercially available lyophilizers that can be used for lyophilization include lyophilizer VD-800F (trade name, Taitec Co., Ltd.), Flexidry MP (trade name, FTS Systems, Inc.), Duratop Durastop ( Brand name, FTS Systems Co., Ltd., Treasure vacuum freeze dryer A type (trade name, Takara Corp.), tabletop freeze dryer FD-1000 (trade name, Tokyo Rika Kikai Co., Ltd.), vacuum freeze dryer FD -550 (trade name, Tokyo Rika Kikai Co., Ltd.), vacuum freeze dryer (trade name, Takara Seisakusho Co., Ltd.) and the like, but it is not limited thereto.

Moreover, as a drying means, a spray drying method is mentioned as a preferable means from a viewpoint of making productive efficiency and quality compatible. In the case of applying the spray drying method, a granulated product is prepared by removing water while spraying a mixture containing the liquid composition which is the dispersion of celecoxib particles obtained in step (I) and the specific covering agent. Good.
Examples of commercially available spray dryers that can be used for spray drying include spray dryer spray dryer SD-1000 (trade name, Tokyo Rika Kikai Co., Ltd.), spray dryer L-8i (trade name, Ogawara Kakoki Co., Ltd.) ), Closed spray dryer CL-12 (trade name, Ogawara Kakohki Co., Ltd.), spray dryer ADL 310 (trade name, Yamato Scientific Co., Ltd.), mini spray dryer B-290 (trade name, Buchi company), PJ- MiniMax (trade name, Powdering Japan Co., Ltd.), PHARMASD (trade name, Niro Co., Ltd.), and the like.
Also, for example, using the apparatus described above, such as processing using a fluidized bed granulating dryer MP-01 (trade name, Powrex Co., Ltd.), a fluidized bed built-in type spray dryer FSD (trade name, Niro Co., Ltd.), etc. It is also possible to adopt a method of simultaneously performing drying and granulation.

The obtained granulated product has at least one dispersant selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less on at least a part of the surface, and having an average particle size of The particles of 50 nm to 500 nm of Cox-2 inhibitor and at least one excipient selected from mannitol, sucrose, inositol, and maltose.
The content of the excipient is preferably 10 parts by mass to 500 parts by mass, more preferably 20 parts by mass to 400 parts by mass, and further 50 parts by mass to 300 parts by mass with respect to 100 parts by mass of Cox-2 inhibitor particles. preferable.
Within the above range of the content of the excipient, good granules can be obtained.

The obtained granulated product can be used as it is as a granular pharmaceutical composition. In addition, the granulate can also be used to form tablets comprising Cox-2 inhibitor particles.
That is, the second embodiment of the production method of the present disclosure can further include the step of tableting the granulated product obtained in the step (II) described above to obtain a solid preparation.

In forming a tablet, first, the granulated product of the present disclosure obtained by the second embodiment of the manufacturing method of the present disclosure, an excipient for forming a tablet formulation, and a lubricant are mixed. To prepare a mixture.
Tablet forming excipients include mannitol, corn starch, lactose hydrate, anhydrous lactose, microcrystalline cellulose, sorbitol, erythritol, and mixtures thereof.
As a commercial item of the excipient for tableting formulation shaping, there may be mentioned Pearitor Flash manufactured by Rocket Japan Co., Ltd. and the like.

Lubricants that can be used at the time of tablet formation improve the flowability of the raw material powder so that a fixed amount is filled in the die of a tableting machine, and at the same time capping, sticking, binding and the like during tableting It is an ingredient that prevents and gives a gloss to the surface of the tablet.
For example, as the lubricant, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerin monostearate, hydrogenated oil, talc, light anhydrous silicic acid and the like can be mentioned.
The lubricant may be used alone or in combination of two or more.
The lubricant may be a commercially available product. Commercially available products include Partek MST (trade name: magnesium stearate) manufactured by Merck and the like.

The content of the excipient for forming a tableting preparation is preferably 10 parts by mass to 500 parts by mass, and more preferably 20 parts by mass to 300 parts by mass with respect to 100 parts by mass of the already-described granulated product. Preferably, it is 50 parts by mass to 200 parts by mass.
When preparing the mixture, in addition to the granulated material and the binder for forming a solid preparation, the pharmaceutical additives described in the section of other components may be appropriately mixed.

The mixing method is not particularly limited as long as the respective components can be mixed.
Examples of the mixing method include mixing using a known mixer such as a V-type mixer (manufactured by Tsutsui Rikagaku Kiki Co., Ltd.).
The mixing conditions such as the time required for mixing can be appropriately adjusted according to the amount, type, etc. of the granulated material and the binder.

A tablet can be formed by compressing the mixture obtained above.
As a method for tableting the obtained mixture as it is, a method generally applied as a tableting method may be applied as it is, and there is no particular limitation.
Although the tableting pressure at the time of tableting is not particularly limited, it is preferable to tablet the mixture at a tableting pressure of 300 N / mm ² or less, more preferably 200 N / mm ² or less, 150 N It is further more preferable that it is / mm < ² > or less.
Further, a compression pressure (N / mm ²⁾ and the absolute hardness of the tablet obtained by the second embodiment of the manufacturing method of the present disclosure (N / mm ^2), but compression pressure / absolute hardness 15 or less Is preferred.
There is no restriction | limiting in particular as temperature at the time of tableting of a mixture, For example, normal temperature conditions, such as 20 degreeC-40 degreeC, can be applied.

  As a compression molding machine applicable to tableting, for example, a rotary tableting machine (product name HT-P18A, manufactured by Hata Iron Works Co., Ltd.), a high-speed rotary tablet machine (product name: AQUARIUS G, Kikusui Seisakusho (stock) Made).

  The size and shape of the tablet obtained by the second embodiment of the manufacturing method of the present disclosure is not particularly limited as long as it is pharmaceutically acceptable. In the case of a circular tablet, a diameter of 7 mm to 12 mm, a thickness of 3.0 mm to 7.0 mm, preferably a diameter of 8 mm to 11 mm, a thickness of 3.5 mm to 6.5 mm, etc. 4 mm to 8 mm, long diameter 8 mm to 18 mm, preferably short diameter: 4 mm to 6.5 mm, long diameter: 8 mm to 15 mm, etc., thickness 3.0 mm to 7.0 mm, preferably 3.5 mm to 6.5 mm Etc.

The hardness of the tablet is not particularly limited.
The hardness (N) measured with a tablet hardness tester is preferably 50N to 150N, more preferably 70N to 130N, and more preferably 80N from the viewpoint of disintegration, transportation stability, availability of an automatic packing machine, etc. It is further preferable that it is -120N.
In the present specification, the hardness of the tablet was measured using a tablet hardness tester Model 8M manufactured by Schleuniger.

(Redispersibility)
When the pharmaceutical composition of the present disclosure is in the form of a solid preparation such as a granulated product or a tablet, Cox-2 is rapidly redispersed when the solid preparation is immersed in water or simulated gastric fluid; The inhibitor particles maintain a particle size of 50 nm to 500 nm.
Therefore, the Cox-2 inhibitor particles are redispersed into nano-sized dispersed particles both when taking essential dissolution and taking orally and reaching, for example, gastric juice.
For this reason, even in the case of a solid preparation, since it is redispersed in a state containing stable nanosized Cox-2 inhibitor particles, good absorbability can be expected.
As described above, it is also possible to use a pharmaceutical composition in the form of a tablet or powder, which is a solid preparation, as a "preparable preparation" pharmaceutical composition, which is taken by dissolving it in a solvent such as water if necessary. it can.
The Cox-2 inhibitor is finely dispersed in a solvent by mixing a powdered or tablet pharmaceutical composition with a solvent such as water or an aqueous solution, and dissolving or dispersing the solid preparation pharmaceutical composition in the solvent. The Cox-2 inhibitor re-dispersed in the form of dispersed particles and reconstituted is also a fine dispersed particle, and the dispersibility and dispersion stability of the dispersed particle are good. Furthermore, good absorbability can be expected.

  The average particle size of the redispersed Cox-2 inhibitor particles is also 50 nm to 500 nm, preferably 50 nm to 400 nm, more preferably 50 nm to 300 nm, particularly preferably 50 nm to 200 nm. preferable.

<Method of treatment>
Another embodiment of the present disclosure also encompasses a method of treatment comprising orally administering the pharmaceutical composition of the present disclosure containing Cox-2 inhibitor particles as an active ingredient to a subject to be treated.

  Hereinafter, the present invention will be more specifically described by way of examples. However, the present invention is not limited to the following examples as long as the gist thereof is not exceeded. In addition, unless otherwise indicated, "part" is a mass reference | standard.

Example 1
[Preparation of particle dispersion]
10 mg of hydroxypropyl cellulose (NISSO HPC-SSL (manufactured by Nippon Soda Co., Ltd.)) as a dispersant was dissolved in 0.89 mL (milliliter) of water to obtain an aqueous solution of hydroxypropyl cellulose (HPC). 100 mg of celecoxib as a Cox-2 inhibitor and 3 g of zirconia beads having a diameter of 0.1 mm as a medium, the mixture is subjected to media dispersion treatment at an external temperature of 5 ° C. for 30 hours, and crushed celecoxib particles The resulting dispersion was obtained.
The average particle size of celecoxib particles in the obtained particle dispersion is measured by a dynamic light scattering method using a concentrated particle size analyzer FPAR-1000 (trade name, manufactured by Otsuka Electronics Co., Ltd.), and D ₅₀ Asked as. The results are shown in Table 1 below.

(Examples 2 to 14 and Comparative Examples 1 to 6)
A particle dispersion was obtained in the same manner as in Example 1 except that the type of Cox-2 inhibitor and the type and content of the dispersant were changed as described in Tables 1 and 2 below.
The average particle size of the particles of Cox-2 inhibitor in the obtained particle dispersion was measured in the same manner as in Example 1. The results are shown in Table 1 below.

The details of the components used in Table 1 are as follows. The molecular weight of the following dispersant is a catalog value.
(Cox-2 inhibitor)
Celecoxib (from Jiangsu Chiatai Qingjiang Pharmaceutica I Co., Ltd.)
Etodolac (Wako Pure Chemical Industries, Ltd.)
Meloxicam (made by Tokyo Chemical Industry Co., Ltd.)

(Specific dispersant)
Hydroxypropyl cellulose (NISSO HPC-SSL, manufactured by Nippon Soda Co., Ltd., molecular weight: 40,000)
Hydroxypropyl cellulose (NISSO HPC-SL, manufactured by Nippon Soda Co., Ltd., molecular weight: 100,000)
Polyvinyl pyrrolidone (Kollidon 25, manufactured by BASF, molecular weight: 28,000 to 34,000)
Polyvinyl pyrrolidone (Kollidon 30, manufactured by BASF, molecular weight: 44,000 to 54,000)

(Comparative dispersant)
Hydroxypropyl cellulose (NISSO HPC-L, manufactured by Nippon Soda Co., Ltd., molecular weight: 140,000)
Polyvinyl pyrrolidone (Kollidon 90F, manufactured by BASF, molecular weight: 1,000,000 to 1.5,000,000)
Methylcellulose (MC SM-15, manufactured by Shin-Etsu Chemical Co., Ltd.)
Polyvinyl alcohol (Gorcenol (registered trademark) EG-30P, manufactured by Japan Synthetic Chemical Industry Co., Ltd.)
Hydroxypropyl methylcellulose ester (HPMC 2910 TC-5M, Shin-Etsu Chemical Co., Ltd. product, molecular weight: 22,000)

From the description of Table 1, the particle dispersions of Examples 1 to 14 are all dispersions of nano-sized particles in which the average particle diameter of Cox-2 inhibitor is in the range of 50 nm to 500 nm. confirmed. The particles of the nanosized Cox-2 inhibitor can be expected to have good in vivo absorbability of the Cox-2 inhibitor as a pharmaceutical composition.
On the other hand, in the particle dispersions of Comparative Examples 1 to 6, the dispersion is inferior, the particles of Cox-2 inhibitor exceed 500 nm, and the formation of aggregates is suppressed even if the content of the dispersant is increased. No stable and fine particle dispersion was obtained.

(Example 15)
[Preparation of granulated material]
The 5 g dispersion (Celecoxib content 100 mg) of the Cox-2 inhibitor (celecoxib) obtained in Example 2 above contains 500 mg of d-mannitol (manufactured by Merck) as an excipient, and the excipient is The mixture was dissolved to obtain a mixed solution containing an excipient.
The obtained mixed solution was spray-dried with a spray drier (manufactured by Buchi) at an inlet temperature of 110 ° C., an outlet temperature of 50 ° C., and a liquid velocity of 3 g / min to obtain celecoxib-containing granules.

[Evaluation of redispersibility of granulated material in water]
90 μL of water was added to 10 mg of the obtained granules, and the mixture was stirred at 37 ° C. and 125 rpm (rotation / minute) for 30 minutes to prepare a redispersion liquid in which celecoxib was redispersed in water.
Re dispersion prepared, the average particle size of celecoxib particles, using a concentrated system particle size analyzer FPAR-1000 (manufactured by Otsuka Electronics Co.), was measured by a dynamic light scattering method, it was determined as D _50. The results are shown in Table 2.

(Examples 16 to 18)
A structure containing celecoxib particles is prepared in the same manner as in Example 15, except that the content of the dispersing agent is the amount described in Table 2 and the excipient d-mannitol is changed to the excipient described in Table 2. Granules were prepared.
The prepared granules are re-dispersed in water to prepare a re-dispersion in the same manner as in Example 15. The average particle size of celecoxib particles in the obtained re-dispersion is obtained in the same manner as in Example 15. It was measured. The results are shown in Table 2.

The details of the components used in Table 2 are as follows. Other components are the same as the components in Table 1.
(Excipient)
d-mannitol (trade name: Parteck M-100, manufactured by Merck Millipore)
Sucrose (refined white sugar, trade name: Schuklein SR 80/100, manufactured by Saline Port Seishoku Co., Ltd.)
Maltose (maltose, hydrate, manufactured by Wako Pure Chemical Industries, Ltd.)
Inositol (manufactured by Wako Pure Chemical Industries, Ltd.)

  From the results of Table 2, the granulated products of Examples 15 to 18 prepared using the dispersion obtained in Example 2 are mixed with water to re-disperse celecoxib, it is in the re-dispersion. The average particle size of celecoxib particles is 350 nm or less in any case, and it is understood that excellent redispersibility is exhibited.

(Example 19)
[Preparation of granulated material]
A dispersion was obtained in the same manner as in Example 2 except that the contents of celecoxib, the specific dispersant and the excipient were as described in Table 3. To 10 parts by mass (Celecoxib content 100 mg) of the obtained Cox-2 inhibitor (celecoxib) dispersion, 1 part by mass d-mannitol (product of Merck) 200 mg content of d-mannitol as an excipient It was contained and the excipient was dissolved to obtain a mixed solution A containing the excipient. 10 parts by mass of an aqueous solution containing 1 part by mass of MC2910 TC-5E (manufactured by Shin-Etsu Chemical Co., Ltd.), which is a water-soluble polymer, was further added to the mixed solution A to obtain a mixed solution B.
The obtained mixed solution B was spray-dried with a spray drier (manufactured by Buchi) at an inlet temperature of 110 ° C., an outlet temperature of 50 ° C., and a liquid velocity of 3 g / min to obtain celecoxib-containing granules.

[Evaluation of redispersibility of granulated material in simulated gastric fluid]
To 13 mg of the obtained granulated product, 1.25 mL of dissolution test first solution (according to Japanese Pharmacopoeia, manufactured by Kanto Chemical Co., Ltd.) as a simulated gastric fluid was added and stirred at 37 ° C., 125 rpm for 30 minutes. A redispersion was prepared in which celecoxib was redispersed in simulated gastric fluid.
The average particle size of celecoxib particles in the prepared redispersion was measured in the same manner as in Example 15. The results are shown in Table 3 below.
Dissolution test 1st solution used as simulated gastric fluid is a solution in which 2.0 g of sodium chloride was dissolved in 7.0 mL (milliliter) of hydrochloric acid and water to make 1000 mL, and it was colorless and clear, and the pH was about 1.2. is there.

Example 20
A mixed solution B was prepared in the same manner as in Example 19 except that sodium lauryl sulfate (SLS) was further contained as another additive in the preparation of the mixed solution B in Example 19. A redispersion of celecoxib particles in simulated gastric fluid was prepared in the same manner as in Example 19 except the above.
The average particle size of celecoxib particles in the prepared redispersion was measured in the same manner as in Example 19. The results are shown in Table 3.

(Example 21)
A mixed solution B was prepared in the same manner as in Example 19 except that the water-soluble polymer HPMC 2910 TC-5E used in Example 19 was changed to the compounds described in Table 3. A redispersion of celecoxib particles in simulated gastric fluid was prepared in the same manner as in Example 19 except the above.
The average particle size of celecoxib particles in the prepared redispersion was measured in the same manner as in Example 19. The results are shown in Table 3.

(Example 22)
Granules were obtained in the same manner as in Example 19, except that the water-soluble polymer HPMC 2910 TC-5E was changed to the compounds described in Table 3.
The obtained granulated product (6 mg) was added to 1.25 mL of Dissolution Test Liquid 1 to prepare a redispersion solution of celecoxib particles in a simulated gastric fluid in the same manner as in Example 19. The average particle size of celecoxib particles in the prepared redispersion was measured in the same manner as in Example 15. The results are shown in Table 3 below.

(Example 23)
10 mg of the granulated product obtained in Example 22 was added to 0.09 mL of Dissolution Test Liquid 1, and in the same manner as Example 19, a redispersion solution of celecoxib particles in a simulated gastric fluid was prepared. The average particle size of celecoxib particles in the prepared redispersion was measured in the same manner as in Example 15. The results are shown in Table 3 below.

(Example 24)
In the same manner as in Example 19 except that HPMC 2910 TC-5E, which is a water-soluble polymer used in Example 19 above, is changed to the compound described in Table 3, and further SLS is contained as another additive. , Obtained granulated material.
13 mg of the obtained granulated product was added to 1.25 mL of Dissolution Test Liquid 1 to prepare a redispersion solution of celecoxib particles in a simulated gastric fluid in the same manner as in Example 19. The average particle size of celecoxib particles in the prepared redispersion was measured in the same manner as in Example 15. The results are shown in Table 3 below.

The details of the components used in Table 3 are as follows. The other components are the same as the components in Tables 1 and 2.
(Water soluble polymer)
HPC 2910 TC-5E and HPC-SSL are the same as the compounds used as dispersants in Table 1.
Polyvinyl alcohol (PVA: Gohsenol (registered trademark) EG-05P, manufactured by Japan Synthetic Chemical Industry Co., Ltd.)
Gohsenol EG-05PW (manufactured by Japan Synthetic Chemical Industry Co., Ltd.)
(Other additives)
Sodium lauryl sulfate (SLS, trade name: Emar OS, manufactured by Kao Corporation)

  From the results in Table 3, when the granulated products of Example 19 to Example 24 are mixed with simulated gastric fluid and redispersed celecoxib, the average particle size of the celecoxib particles in the redispersion solution is 300 nm or less It can be seen that it exhibits excellent redispersion even in simulated gastric fluid.

(Example 25)
A dispersion was obtained in the same manner as in Example 2 except that the contents of celecoxib, the specific dispersant and the excipient were as described in Table 3. The obtained dispersion was spray-dried with a spray drier (manufactured by Buchi) at an inlet temperature of 110 ° C., an outlet temperature of 50 ° C., and a liquid velocity of 3 g / min to obtain a granulated product.
Paritol flush (mixture of mannitol and corn starch: 1050 mg of Rocket Japan Co., Ltd.) as an excipient for forming a tablet formulation into 350 mg of the obtained granulated product, and Partek MST (magnesium stearate, manufactured by Merck Millipore) 7 mg was added, and tableted with 5 kN using a 10 mm diameter die and tablets were obtained.
The hardness of the obtained tablet was measured with a load cell type tablet photometer (manufactured by Okada Seiko Co., Ltd.). The results are shown in Table 4 below.
In addition, since the dispersion prepared in the same manner as in Example 2 is used, the celecoxib particles contained in Example 25 have an average particle diameter of 154 nm in the dispersion, and in Examples 25 to 29, Even when re-dispersed in water, the average particle size was 350 nm or less. Thus, it was confirmed that the particles were celecoxib particles having an average particle diameter in the present disclosure.

(Example 26)
Granules were obtained in the same manner as in Example 15 except that the types and contents of celecoxib, specific dispersant and excipient were as shown in Table 4. To 700 mg of the obtained granulated product, 700 mg of Paritol flash and 7 mg of Partek MST were added to form a tablet in the same manner as in Example 25, and the hardness of the obtained tablet was measured in the same manner as in Example 25. .

(Example 27)
The granulated material obtained in the same manner as in Example 15 used in Example 26 is changed to the amount and content of celecoxib, a specific dispersant and an excipient described in Table 4 except Granules were obtained in the same manner as in Example 16 above. A tablet was formed in the same manner as in Example 25 except that the obtained granulated product was used, and the hardness of the obtained tablet was measured in the same manner as in Example 25.

(Example 28)
The granulated material obtained in the same manner as in Example 15 used in Example 26 is changed to the amount and content of celecoxib, a specific dispersant and an excipient described in Table 4 except Granules were obtained in the same manner as in Example 17 above. A tablet was formed in the same manner as in Example 25 except that the obtained granulated product was used, and the hardness of the obtained tablet was measured in the same manner as in Example 25.

(Example 29)
In a dispersion obtained in the same manner as in Example 26, 500 mg of lactose is dissolved instead of d-mannitol as an excipient, and the obtained mixture is treated with a spray drier (manufactured by Buchi) at an inlet temperature of 110 ° C. The mixture was spray-dried at an outlet temperature of 50 ° C. and a liquid velocity of 3 g / min to obtain a granulated product. Using the obtained granulated product, a tablet was formed in the same manner as in Example 25, and the hardness of the obtained tablet was measured in the same manner as in Example 25.

(Comparative example 7)
To 294 mg of celecoxib with an average particle size of 13 μm, 1106 mg of Paritol flash and 7 mg of Partek MST were added to form tablets in the same manner as in Example 25, and the hardness of the obtained tablets was measured in the same manner as in Example 25. .

  From the results of Table 4, it can be seen that the pharmaceutical compositions of Example 25 to Example 29 can obtain sufficient tablet hardness when made into a tableting preparation. On the other hand, in Comparative Example 7 using celecoxib particles having an average particle size of micron level, the hardness of the tablet obtained for the example was low, and a tablet having practically sufficient hardness was not obtained.

(Example 30)
5 mL of water was added to 6 mg of the granulated product obtained in Example 22 and redispersed at 37 ° C., 125 rpm for 15 minutes. In Table 5, the excipient is described as PVA.
The average particle size of celecoxib particles in the redispersion was measured in the same manner as in Example 15.
The obtained granulated product was suspended in water in an amount of 10 mg / kg as celecoxib at a concentration of 1 mg / mL and orally administered to male rats (five rats in one group) under fasting conditions.
Blood was collected sequentially at 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration, and celecoxib plasma concentration was measured by LC-MS / MS.
The results are shown in Table 5 below.

(Example 31)
Re-dispersion, administration, and measurement of plasma concentration were performed in the same manner as in Example 30 using the granulated product obtained in Example 21. The particle size of the celecoxib particles was measured in the same manner as in Example 15.
The results are shown in Table 5 below.

(Comparative example 8)
Using a celecoxib commercial preparation, administration was performed in the same manner as in Example 30, and in the same manner as in Example 30, plasma concentration was measured. The average particle size of celecoxib particles was determined using a laser diffraction particle size distribution analyzer (manufactured by Horiba, Ltd.).
In addition, the commercially available preparation used in Comparative Example 8 was administered with mass adjusted so that the content of celecoxib would be the same as in Example 26, Example 27 and Comparative Example 9.
The results are shown in Table 5 below.

(Comparative example 9)
0.5 w / v% methylcellulose 400 solution · 100 g of sterile (Wako Pure Chemical Industries, Ltd.) polysorbate 80 (nonionic surfactant: polyoxyethylene (20) sorbitan oleate, NOF (stock 100 mg was added and mixed well to obtain a mixed solution. A celecoxib drug substance was added to the obtained mixture, and 10 mg / kg of celecoxib was added in an amount of 1 mg / mL to be suspended to obtain a dispersion. The resulting dispersion was administered in the same manner as in Example 30, and the plasma concentration was measured.
The average particle size of celecoxib particles in the dispersion was measured in the same manner as in Comparative Example 8.
The results are shown in Table 5 below.

  It can be seen from Table 5 that the pharmaceutical compositions of Example 30 to Example 31 have Tmax extremely smaller than that of the comparative example, and the active ingredient is absorbed into the blood more quickly. Furthermore, the values of Cmax and AUC are larger than those of the comparative example, and it can be expected that the function of the active ingredient is effectively exhibited. It is considered that this is because the average particle size of celecoxib particles, which are active ingredients, is small and the absorbability into the body is good.

Claims (11)

Cox-2 inhibitor particles having an average particle size of 50 nm to 500 nm,
A pharmaceutical composition comprising at least one dispersant selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less.   The pharmaceutical composition according to claim 1, wherein the dispersing agent contains hydroxypropyl cellulose having a molecular weight of 50,000 or less.   The pharmaceutical composition according to claim 1 or 2, wherein the particles of the Cox-2 inhibitor have an average particle size of 50 nm to 200 nm.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the Cox-2 inhibitor is celecoxib.   The pharmaceutical composition according to any one of claims 1 to 4, which is a solid preparation.   The pharmaceutical composition according to claim 5, further comprising at least one excipient selected from the group consisting of mannitol, sucrose, inositol, and maltose.   7. The pharmaceutical composition according to claim 5, further comprising at least one water-soluble polymer selected from polyvinyl alcohol and hydroxypropyl methylcellulose.   The pharmaceutical composition according to any one of claims 5 to 7, which is a tablet.   A mixed solution containing particles of Cox-2 inhibitor, and at least one dispersant selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less is subjected to media dispersion treatment to obtain an average particle size A method of manufacturing a pharmaceutical composition comprising the step of obtaining particles of Cox-2 inhibitor with a diameter of 50 nm to 500 nm. A mixed solution containing particles of Cox-2 inhibitor, and at least one dispersant selected from hydroxypropyl cellulose having a molecular weight of 100,000 or less and polyvinyl pyrrolidone having a molecular weight of 100,000 or less is subjected to media dispersion treatment to obtain an average particle size Obtaining a liquid composition comprising particles of Cox-2 inhibitor having a diameter of 50 nm to 500 nm;
A step of drying the mixture obtained by mixing the obtained liquid composition and at least one excipient selected from mannitol, sucrose, inositol and maltose by a spray drying method to obtain a granulated product And a method of producing a pharmaceutical composition comprising   The method for producing a pharmaceutical composition according to claim 10, further comprising the step of tableting the obtained granulated product to obtain a solid preparation.