WO2019208725A1 - Pharmaceutical composition, and method for producing pharmaceutical composition - Google Patents

Abstract

A pharmaceutical composition comprising abiraterone acetate ester particles having an average particle diameter of 50 to 200 nm and hydroxypropyl cellulose in an amount of 10 to 150% by mass relative to the content of abiraterone acetate ester; and a method for producing the pharmaceutical composition.

Description

Pharmaceutical composition and method for producing pharmaceutical composition

The present disclosure relates to a pharmaceutical composition and a method for producing the pharmaceutical composition.

Abiraterone exhibits irreversible and selective inhibitory action of CYP17 (17α-hydroxylase / C17,20-lyase) and has been reported to inhibit androgen synthesis in testis, adrenal gland and prostate tumor tissue.
Abiraterone has been reported to be useful as an oral prostate cancer therapeutic agent in the form of abiraterone acetate, a prodrug.
Abiraterone acetate is hydrophobic and has low water solubility. A pharmaceutical composition that is administered orally has low solubility in water, so it does not have solubility that can be quickly absorbed in the digestive tract, and is discharged outside the body before it is completely absorbed into the circulating blood. It may become. Various studies have been made for the purpose of formulating abiraterone acetate having good absorbability when orally administered.

For example, abiraterone acetate, contain additives and surfactants such as hydroxypropylmethyl cellulose, having the following _{D 50} size 1000 .mu.m, high abiraterone acetate dispersion of dissolution rate has been proposed (WO 2014/009436 Issue).
In addition, a pharmaceutical composition (see US Patent Publication No. 2016/0151392) in which an additive such as abiraterone acetate and hydroxypropylmethylcellulose is heated and dissolved in a solvent to prepare a self-emulsifying preparation, Solplus (a product) And the like (see US Patent Publication No. 2016/0331763) for dispersing abiraterone acetate into fine particles by a solvent precipitation method.
A method has been proposed in which abiraterone acetate is dry pulverized in the presence of lactose and an ionic surfactant to obtain a fine particle preparation of 100 nm to 300 nm (see JP-T-2017-528457).

As described above, when applying abiraterone acetate, which is sparingly soluble in water, to pharmaceutical compositions, various proposals have been made for a dispersion of fine particles.
In International Publication No. 2014/009436, various dispersants are described in parallel. In particular, it is described that a dispersion having dispersed particles having an initial particle size of about 130 nm is obtained using hydroxypropylmethylcellulose. However, the stability of the dispersion in the digestive tract has not been studied. Moreover, although the hydroxypropyl cellulose is illustrated as an example, the specific aspect combined with abiraterone acetate is not described.
The pharmaceutical composition described in U.S. Patent Publication No. 2016/0151392 is refined by adding a solubilizing agent and a surfactant more than 8 times the amount of abiraterone acetate, so that the formulation size increases, There is concern about the burden on the recipient.
The dispersion described in U.S. Patent Publication No. 2016/0331763 is obtained by a solvent precipitation method. However, the powdering method in which the solvent is removed from the organic solvent system has low formulation efficiency and there is a concern about the residual solvent. There are problems such as.
In the method described in JP-T-2017-528457, since an ionic surfactant is used for dispersion, there is a concern that, for example, aggregation and precipitation may occur in an acidic atmosphere such as gastric juice, resulting in a decrease in absorbability.
Further, in each of the above-mentioned documents, the dispersions, powders, and the like containing the obtained abiraterone acetate are fine in initial particle diameter, but are considered to be able to improve the absorbability when taken orally, for example. At present, no detailed examination has been made as to whether or not the order particle size can be stably maintained even in the digestive tract.

The problem to be solved by one embodiment of the present invention is to provide a pharmaceutical composition containing fine particles of abiraterone acetate which is stable even in the digestive tract.
The subject of another one Embodiment of this invention is providing the manufacturing method of the pharmaceutical composition containing the fine particle of abiraterone acetate stable also in a digestive tract.

Means for solving the above problems include the following embodiments.
<1> A pharmaceutical composition comprising abiraterone acetate particles having an average particle diameter of 50 nm to 200 nm, and 10% by mass to 150% by mass of hydroxypropylcellulose with respect to the content of abiraterone acetate particles.
<2> The pharmaceutical composition according to <1>, wherein the hydroxypropylcellulose has a weight average molecular weight of 140,000 or less.

<3> The pharmaceutical composition according to <1> or <2>, further comprising a surfactant.
<4> The surfactant is selected from the group consisting of polyoxyethylene polyoxypropylene glycol, lauromacrogol, sodium deoxycholate, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydroxystearate, polysorbate 20, and polysorbate 80. The pharmaceutical composition according to <3>, which is at least one kind.
<5> The pharmaceutical composition according to <3> or <4>, wherein the content of the surfactant is 0.1% by mass to 40% by mass with respect to the content of abiraterone acetate.
<6> The pharmaceutical composition according to any one of <3> to <5>, wherein the content of the surfactant is more than 0% by mass and 100% by mass or less with respect to the content of hydroxypropylcellulose.

<7> The pharmaceutical composition according to any one of <1> to <6>, which is a solid preparation.
<8> The pharmaceutical composition according to <7>, which is a powder formulation.
<9> Furthermore, it contains a pharmaceutically acceptable additive for molding a solid preparation containing at least one selected from the group consisting of an excipient, a disintegrant, and a lubricant, and <7> is a tablet The pharmaceutical composition as described.
<10> The pharmaceutical composition according to <9>, wherein the total content of the pharmaceutically acceptable additive for solid preparation molding is 10% by mass to 80% by mass with respect to the total mass of the pharmaceutical composition. .
<11> The pharmaceutical composition according to any one of <1> to <10>, which is used for oral administration.

<12> A dispersion to be dispersed containing 10% by mass to 150% by mass of hydroxypropyl cellulose and a dispersion medium with respect to the content of abiraterone acetate and abiraterone acetate is dispersed by a wet pulverization method to obtain an average. A method for producing a pharmaceutical composition, comprising a step of obtaining a dispersion containing particles of abiraterone acetate having a particle diameter of 50 nm to 200 nm.
<13> The method for producing a pharmaceutical composition according to <12>, wherein the wet pulverization method includes a pulverization dispersion method using a medium.
<14> Furthermore, the manufacturing method of the pharmaceutical composition as described in <12> or <13> including the process of removing a dispersion medium from a dispersion and obtaining a powder formulation.

According to one embodiment of the present invention, it is possible to provide a pharmaceutical composition containing fine particles of abiraterone acetate that are stable even in the digestive tract.
According to another embodiment of the present invention, it is possible to provide a method for producing a pharmaceutical composition containing fine particles of abiraterone acetate that is stable even in the digestive tract.

Hereinafter, the pharmaceutical composition of the present disclosure and the method for producing the pharmaceutical composition will be described in detail.
The constituent elements described below may be described based on typical embodiments of the present disclosure, but the present disclosure is not limited to such embodiments.
In the present disclosure, “to” indicating a numerical range is used in a sense including numerical values described before and after the numerical value as a lower limit value and an upper limit value.
In the numerical ranges described stepwise in the present disclosure, the upper limit value or the lower limit value described in one numerical range may be replaced with the upper limit value or the lower limit value of another numerical description. . Further, in the numerical ranges described in the present disclosure, the upper limit value or the lower limit value of the numerical range may be replaced with the values shown in the examples.
In the present disclosure, a 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 there is a specific indication when there are a plurality of substances corresponding to each component in the composition. means.
In the present disclosure, the term “step” is not limited to an independent step, and is included in the term if the intended purpose of the step is achieved even when it cannot be clearly distinguished from other steps.

<Pharmaceutical composition>
The pharmaceutical composition of the present disclosure includes abiraterone acetate particles having an average particle diameter of 50 nm to 200 nm, and 10% by mass to 150% by mass of hydroxypropylcellulose with respect to the content of the abiraterone acetate particles. .
Hereinafter, in the present disclosure, abiraterone acetate may be abbreviated as “ABR” and hydroxypropylcellulose may be abbreviated as “HPC”, respectively.
Hereinafter, each component contained in the pharmaceutical composition will be sequentially described.

(Abiraterone acetate: ABR)
ABR is rapidly hydrolyzed to abiraterone in vivo and develops an inhibitory effect on CYP17.
ABR used in the pharmaceutical composition of the present disclosure is a compound in which the hydroxyl group of abiraterone is converted to acetate, and is also referred to as 17- (pyridin-3-yl) androst-5,16-dien-3β-yl acetate. The
There is no restriction | limiting in particular in ABR, A commercial item, a synthetic product, etc. can be used suitably.

ABR is included in the pharmaceutical composition of the present disclosure in the form of particles having an average particle size of 50 nm to 200 nm. The average particle size of the ABR particles is more preferably 50 nm to 180 nm, and further preferably 50 nm to 150 nm.
In the present disclosure, the average particle diameter of the ABR particles is determined by measuring the particle diameter in the dispersion by a dynamic light scattering method, and adopting the median diameter of the obtained scattering intensity distribution as the particle diameter. Examples of commercially available particle size measuring devices using the dynamic light scattering method include Nanotrac UPA (Nikkiso Co., Ltd.), dynamic light scattering type particle size distribution measuring device LB-550 (Horiba Ltd.), A dense particle size analyzer FPAR-1000 (trade name: manufactured by Otsuka Electronics Co., Ltd.) or the like can be used.
When the average particle size of the ABR particles is within the above range, the solubility of ABR, which is a medicinal component, in the digestive tract is improved, and high absorption into the body can be expected.

The average particle size of the ABR particles can be appropriately adjusted by controlling the type, content, dispersion conditions, and the like of the HPC as a dispersant described later.

The average particle size of the ABR particles is the particle size in the pharmaceutical composition. The particle size of the ABR raw material used for preparing the pharmaceutical composition is not necessarily in the above range.

The content of ABR in the pharmaceutical composition of the present disclosure can be appropriately selected depending on the purpose of treatment or prevention within a pharmaceutically acceptable range.
In general, a single dose of ABR contained in a pharmaceutical composition can be in the range of 5 mg to 1000 mg.

<Hydroxypropyl cellulose: HPC>
The pharmaceutical composition of the present disclosure contains at least one of 10% by mass to 150% by mass of HPC with respect to the content of ABR particles. In the pharmaceutical composition, the HPC functions as a dispersant for the ABR particles.
By coexisting 10% by mass to 150% by mass of HPC with respect to the content of ABR particles, ABR particles are in the form of nano-sized particles having an average particle diameter in the range of 50 nm to 200 nm in the pharmaceutical composition. It exists stably.

HPC is preferably HPC having a weight average molecular weight of 140,000 or less.
The weight average molecular weight of HPC is more preferably 100,000 or less, and further preferably 50,000 or less.
Although there is no restriction | limiting in particular in the lower limit of the molecular weight of HPC, From the viewpoint of an effect, it can be set to 10,000 or more.
As the weight average molecular weight of HPC, when using a commercially available product, the catalog value of the commercially available product may be adopted.
Examples of the method for directly measuring the weight average molecular weight of HPC include a method using gel permeation chromatography (GPC) or size exclusion chromatography (SEC).
For example, the weight average molecular weight of HPC that is a water-soluble polymer can be determined as a value of weight average molecular weight in terms of polystyrene (PST) or pullulan using GPC.
When measuring the weight average molecular weight by applying the GPC method, if PST is dissolved in the eluent for measurement, measure it in PST conversion. If pullulan is dissolved in the eluent, measure it in pullulan conversion. That's fine.

A commercially available product can be used as the HPC.
Commercially available products of HPC include NISSO HPC-SSL (trade name, molecular weight: 40,000), NISSO HPC-SL (trade name, molecular weight: 100,000), NISSO HPC-L (trade name, molecular weight: 140,000), NISSO. HPC-LM (trade name, molecular weight: 180,000, manufactured by Nippon Soda Co., Ltd.), 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), Klucel JF Pharm (trade name, molecular weight: 140,000, manufactured by Ashland) and the like.

The content of HPC is 10% by mass to 150% by mass, preferably 20% by mass to 100% by mass, and preferably 30% by mass to 80% by mass with respect to the total mass of the ABR particles contained in the pharmaceutical composition. More preferably, it is mass%.
That is, the HPC content is in the range of 10 to 150 parts by weight, preferably in the range of 20 to 100 parts by weight, with respect to 100 parts by weight of the ABR particles contained in the pharmaceutical composition. More preferably, it is 30 to 80 parts by mass.
When the HPC content is in the above range, the ABR particles in the obtained pharmaceutical composition are more stably dispersed and the aggregation of the particles is more effectively suppressed. As a result, the average particle size of the ABR particles is 50 nm to 200 nm. Easy to be in range.

(Surfactant)
The pharmaceutical composition of the present disclosure may further contain a surfactant in addition to the aforementioned HPC.
The surfactant can be used as a dispersion aid or a dispersion stabilizer.
Examples of the surfactant include polyoxyethylene hydrogenated castor oil (for example, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.), polysorbate 80, polysorbate 65, polysorbate 40, polysorbate 20, poly Oxyethylene sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene lauryl ether (eg Lauromacrogol BL-9, Lauromacrogol BL-25), polyoxyethylene polyoxypropylene glycol (poloxamer, pluronics, eg Poloxamer 188, poloxamer 407), polyoxyethylene hydroxystearate, sodium lauryl sulfate, sodium deoxycholate, etc. It is below.
Among them, the surfactant is selected from the group consisting of polyoxyethylene polyoxypropylene glycol, lauromacrogol, sodium deoxycholate, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydroxystearate, polysorbate 20, and polysorbate 80. It is preferable to include at least one, and it is more preferable to include at least one selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil.

When the pharmaceutical composition of the present disclosure contains a surfactant, the content of the surfactant is preferably 0.1% by mass to 40% by mass with respect to the content of ABR in the pharmaceutical composition. More preferably, the content is from 30% by mass to 30% by mass.
Further, the content of the surfactant when the pharmaceutical composition of the present disclosure contains a surfactant is preferably more than 0% by mass and 100% by mass or less with respect to the content of HPC in the pharmaceutical composition, It is more preferably 5% by mass to 100% by mass, and further preferably 7.5% by mass to 75% by mass.
When the content of the surfactant in the pharmaceutical composition is in the above range, the surfactant can sufficiently improve the dispersion stability of the ABR particles in the digestive tract, and the surfactant can be contained. There is no concern that the ABR absorbability decreases when the amount is too large, and that the surfactant has an effect on the living body.

As a method for producing a pharmaceutical composition, there may be mentioned a method in which ABR is added to a solution in which HPC is dissolved and subjected to a dispersion treatment. However, the manufacturing method is not limited to the above method. In addition, the detail of the preferable manufacturing method of a pharmaceutical composition is mentioned later.

(Form of pharmaceutical composition, administration method)
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.
The pharmaceutical composition of the present disclosure is preferably provided for oral administration.
Examples of the dosage form include tablets, granules, powders, fine granules, capsules, liquids, syrups and the like as oral dosage forms.
Tablets include tablets, sugar-coated tablets, etc., chewable tablets, troches, drops, solubilized or disintegrated rapidly in the oral cavity, and so-called oral cavity prepared with granular materials that can be taken without water Includes disintegrating tablets, and further includes redissolved tablets such as effervescent tablets that are used after dissolution.
Granules, powders, and fine granules include dry syrups that are dissolved at the time of use, and also include granules that dissolve or disintegrate rapidly in the oral cavity and can be taken without water.
The liquid preparation and syrup preparation may further contain various pharmaceutically acceptable dispersion media.

The pharmaceutical composition of the present disclosure is preferably a solid preparation.
Since the pharmaceutical composition of the present disclosure has good stability of ABR particles in the digestive tract, that is, in the stomach and intestines, the powder formulation, the tablet obtained by compressing the powder formulation, and the powder formulation are encapsulated. It can also be suitably used as a solid preparation such as a capsule.
The solid preparation in the present disclosure includes a powder preparation (powder), a granule containing the powder preparation and an excipient, a tablet obtained by tableting the powder preparation, a coated tablet coated with the obtained tablet, It includes forms such as capsules in which powder preparations are encapsulated. By making the pharmaceutical composition of the present disclosure into a solid preparation, the manufacturability and storage stability of the pharmaceutical composition become better, and it can be easily carried and also has the advantage that it is easy to take the required amount.

When the pharmaceutical composition of the present disclosure is used as a powder formulation, granule, capsule, and tablet as a solid formulation, the total mass of the formulation administered orally per day is 2400 mg or less from the viewpoint of ease of taking. Is preferable, and 2000 mg or less is more preferable. For example, when the pharmaceutical composition of the present disclosure is orally administered as 4 tablets per day, the mass per tablet is preferably 600 mg or less, more preferably 500 mg or less. Moreover, when it is orally administered by 2 tablets a day, it is preferable that the mass per tablet is 1200 mg or less, and it is further more preferable that it is 1000 mg or less.

(Formulation additives)
The pharmaceutical composition of the present disclosure may contain various pharmaceutical additives that are generally used and pharmaceutically acceptable as long as the effects are not hindered.
Examples of the formulation additive include an excipient, a disintegrant, a binder, a lubricant, a colorant, a flavoring agent, a sweetener, a corrigent, and a pH adjuster.
In addition, the solid formulation molding additive in the present disclosure is an additive used to mold a pharmaceutical composition containing ABR into a solid formulation, for example, a powder formulation, a granule, a capsule, a tablet, or the like. Point to.

(Excipient)
When the pharmaceutical composition of the present disclosure is a solid preparation including a powder preparation and a tablet, it is preferable to include an excipient for forming a solid preparation in order to maintain a stable dosage form.
Examples of excipients include sugars (eg, glucose, lactose, sucrose, maltose, trehalose, dextrin, cyclodextrin, etc.), sugar alcohols (eg, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, inositol, etc.) , Starch (eg, corn starch, potato starch, rice starch, wheat starch, etc.), crystalline cellulose, light anhydrous silicic acid / crystalline cellulose, calcium salt (eg, anhydrous calcium phosphate, light anhydrous calcium silicate, calcium silicate, calcium sulfate) , Calcium carbonate, calcium lactate), light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminate metasilicate, silicic anhydride, amino acids (eg glycine, alanine, asthma Ragin, include the tryptophan, etc.) and the like.
Mannitol is an optically active substance, and there are d-form, l-form, racemate, and the like, and naturally-occurring d-mannitol is suitable as an excipient.
As the excipient, saccharides or sugar alcohols are preferable from the viewpoints of disintegration and aggregation suppression of ABR particles. When the pharmaceutical composition of the present disclosure is used as a powder formulation, granule, capsule or tablet, light anhydrous silicic acid / crystalline cellulose, d-mannitol, sucrose, lactose, trehalose, erythritol, maltitol, and It is preferable to include at least one excipient selected from the group consisting of maltose.

(Water-soluble polymer)
The pharmaceutical composition of the present disclosure may further contain a water-soluble polymer other than HPC (hereinafter sometimes referred to as other water-soluble polymer).
By including other water-soluble polymers, the dispersion stability of ABR particles can be improved in combination with HPC. In addition, when used in powder formulations including tablets, it functions as a binder, enhances the stability of solid formulations such as powder formulations, and dissolves rapidly when solid formulations are taken orally. The components contained in the composition can be redispersed.
Examples of the water-soluble polymer include cellulose derivatives other than HPC (for example, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxypropyl methyl cellulose, etc.), hydroxypropyl starch, dextrin, carbomer (cosmetic raw material name: crosslinked) Polyacrylic acid), vinylpyrrolidone polymers (for example, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, etc.), polyvinyl alcohol, polyethylene glycol and the like.

(Disintegrant)
The pharmaceutical composition may contain a disintegrant. When the pharmaceutical composition is in the form of a tablet, granule or the like, the pharmaceutical composition contains a disintegrating agent, so that the preparation taken orally disintegrates more quickly and improves the solubility in the digestive tract faster. The effect can be expected.
Examples of disintegrants include carmellose, crospovidone, carmellose calcium, croscarmellose sodium, sodium starch glycolate, partially pregelatinized starch, pregelatinized starch, hydroxypropyl starch, low-substituted hydroxypropylcellulose, and processed corn starch. Crospovidone, sodium starch glycolate, partially pregelatinized starch, croscarmellose sodium, and carmellose calcium are preferred.

(PH adjuster)
The pharmaceutical composition can contain a pH adjuster as necessary during production. As the pH adjuster, any biocompatible acid or alkali agent can be used without particular limitation.
Examples of the known pH adjuster include sodium hydroxide (NaOH), hydrochloric acid (HCl) and the like.

(Other formulation additives)
The pharmaceutical composition may contain a lubricant, a coloring agent, a flavoring agent, a sweetening agent, a corrigent, and the like for the purpose of improving the appearance and feel when ingested orally.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, and sucrose fatty acid ester.
Examples of the colorant include edible colorants such as edible yellow No. 5 dye, edible red No. 2 dye, edible blue No. 2 dye, edible lake dye, yellow ferric oxide, and titanium oxide.
Examples of flavoring agents include orange flavor, lemon flavor, and other various flavors that can be taken orally.

Examples of the sweetening agent include aspartame, stevia, thaumatin, sodium saccharin, dipotassium glycyrrhizinate and the like.
Examples of the corrigent include L-menthol, camphor, mint, sodium L-glutamate, disodium inosinate, magnesium chloride and the like.

The preparation additives described above may be appropriately added at an appropriate step 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 mentioned above, It can manufacture by a well-known method.
Especially, it is preferable to manufacture by the manufacturing method of the pharmaceutical composition of this indication described below.
A method for producing a pharmaceutical composition of the present disclosure (hereinafter sometimes simply referred to as a production method of the present disclosure) includes ABR and HPC having a content of 10% to 150% by mass with respect to the content of ABR in the pharmaceutical composition. And a dispersion medium containing a dispersion medium is dispersed by a wet pulverization method to obtain a dispersion containing ABR particles having an average particle diameter of 50 nm to 200 nm (step (I)).

(Process (I))
The dispersion by the wet pulverization method in the production method of the present disclosure will be described in detail.
The average particle diameter of the ABR particles used as the raw material is arbitrary. Commercially available ABR may be used as a raw material as it is.
Preferably, HPC is first dissolved in a solvent. The solvent is selected according to the purpose. Among these, it is preferable to use water as the solvent in view of the better solubility of HPC and the higher degree of freedom of formulation of the resulting pharmaceutical composition.
Here, the solvent which dissolves HPC can function as a dispersion medium for the dispersion as it is.
The water used for dissolving HPC is preferably ion-exchanged water, pure water, ultrapure water, water for injection, purified water or the like from the viewpoint that there are few impurities.

ABR as a raw material is added to the obtained HPC solution to prepare a dispersion.
The ABR particles in the obtained dispersion are dispersed by a wet pulverization method. More specifically, the dispersion is subjected to mechanical dispersion using a solid disperser, and solid ABR is pulverized in a dispersion medium to prepare a dispersion containing fine ABR particles.

Known solid dispersers used for the preparation of dispersions include a tribological shear force type disperser that applies a shear force directly to dispersed particles using a drive unit and a medium, and a shear force applied to dispersed particles via a liquid medium There is a rheological shear type disperser.
The tribology shear force type disperser includes a roll mill that disperses a slurry containing a solid dispersion through a plurality of rolls, a kneader that applies shear force to the slurry with a stirring blade, and beads in the slurry. The media mill etc. which coexist media, such as these, and give a shearing force through media are mentioned.
Examples of the rheological shear force type disperser include various stirring type dispersers, high pressure dispersers, ultrasonic dispersers, and the like.

In the manufacturing method of the present disclosure, a high-shearing force is directly applied to solid ABR, and a mechanical disperser that pulverizes and disperses ABR forms fine and stable dispersion particles. From the viewpoint that it is easy to do. Therefore, in the step (I), it is more preferable to include a wet pulverization method using a tribological shear force type disperser suitable for the wet pulverization method, including a wet dispersion treatment method using a medium represented by a media mill. More preferably.
Examples of the wet dispersion method using media include a method of dispersing media by mixing a material to be dispersed containing ABR particles, a material selected according to the purpose, and a media having a particle size. When step (I) includes a wet dispersion treatment method using media, a dispersion in which fine ABR particles are stably dispersed can be obtained.

The medium can be appropriately selected from media such as balls and beads according to the particle size of the target dispersed particles. From the viewpoint that finer dispersed particles can be obtained, the beads are used as the media. Is preferably used.
Media materials used for dispersion include zirconia, alumina, steatite, silicon carbide, silicon nitride, silica, sand, menor, steel balls, stainless steel, glass and other inorganic compounds, polystyrene, polymethyl methacrylate, polytetrafluoroethylene, Examples thereof include polymer resins such as polyamide, polyethylene, polypropylene, polyetheretherketone (PEEK), and polyimide.
Among these, zirconia beads are preferable as the media from the viewpoint of dispersion power, durability, and the absence of fear of contamination due to the media.

Various media dispersers that add kinetic force to the media are known depending on the agitation method, media separation mechanism, vertical or horizontal type, cooling method, etc. A bead mill equipped with a separation mechanism is preferable.
As commercial products of bead mill dispersers having a microbead separation mechanism such as 0.1 mmφ or less, Ultra Apex Mill (trade name: Kotobuki Kogyo), Star Mill (trade name: Ashizawa Finetech), Pearl Mill (trade name: Buhler), OB mill (trade name: Freund Sangyo), dyno mill (trade name: WAB) and the like can be mentioned, and any of them can be used in the method for producing a pharmaceutical composition of the present disclosure. Note that the dispersing device that can be used for the distributed processing is not limited to the above-described example.

Even a dispersion apparatus that does not include a bead separation mechanism can be used in the manufacturing method of the present disclosure by adding a post-bead filtration step after the dispersion treatment.
Examples of a disperser that does not include a bead separation mechanism that can be used in the manufacturing method of the present disclosure include a ball mill, a sand grinder mill, and a planetary ball mill.
The ball mill is a dispersing device that places and rotates a pot formed of a material selected from magnetic, nylon, polymer, stainless steel, and the like in which slurry and beads are placed on a rotating table.
As the sand grinder mill, there are many devices that can change the shape of the agitator into a pin type or a disk type according to the viscosity of the slurry, and a ready mill (trade name: Imex) is known.
The planetary ball mill has a structure in which a vessel containing slurry and balls revolves while rotating, and has better dispersion efficiency than ordinary ball mills. An example of a planetary ball mill is a planetary ball mill (trade name: Fritsch). Rotating / revolving nano-pulverizer NP-100 (trade name: Sinky) and the like.

In the dispersion treatment by the wet pulverization method, when media dispersion treatment using zirconia beads is performed in preparation of dispersion particles containing ABR particles, multistage dispersion treatment in two or more stages can be performed, and multistage dispersion treatment in three or more stages. May be performed.
Especially, it is preferable to perform a two-stage dispersion process from a viewpoint of an effect and the simplicity of a process.
Taking the two-stage dispersion process as an example, the first stage dispersion process involves a step of pulverizing relatively coarse raw material particles of ABR to a certain size, for example, about 1 μm to 10 μm. A method of performing second-stage dispersion to obtain particles is mentioned.
In the first stage dispersion process when performing multistage dispersion, the wet pulverization method is not necessarily applied. That is, it is not necessary to use a wet disperser using a medium, and for example, a rheological shear force type disperser such as a high-speed stirring method may be used. However, from the viewpoint of dispersion efficiency, it is preferable to use a relatively large bead of 0.5 mmφ or more and perform coarse dispersion with a media disperser. In the case of the two-stage dispersion process following the first-stage dispersion process (hereinafter sometimes referred to as the coarse dispersion process), the second-stage dispersion, that is, the main dispersion is performed. In the second stage dispersion treatment, it is preferable to carry out a pulverization dispersion treatment method using media, to which a media dispersion machine using fine beads of 0.3 mmφ or less is applied as the media.
In the second stage dispersion treatment, a dispersion is obtained in which the ABR particles are finely dispersed to an average particle size of about 50 nm to 200 nm, which is the target particle size.

As described above, when performing multi-stage dispersion, it is preferable to include a pulverization / dispersion method using a medium at any stage, and in the final stage of the dispersion process, a pulverization / dispersion process using a medium may be performed. More preferred.

In the mechanical dispersion process, when performing multi-stage dispersion processing, the dispersion machine other than the media dispersion machine that can be used as an auxiliary to the coarse dispersion process, which is the first stage dispersion process, is a rheological shear force type dispersion machine. Stirrers such as homomixers, disper mixers, ultramixers, and CLEARMIX (trade name: M Technique), ultrasonic homogenizers, high-pressure homogenizers, and the like can be used. High-pressure homogenizers include microfluidizer (trade name: microfluidics), nanomizer (trade name: Yoshida Kikai Kogyo), starburst (trade name: Sugino Machine), gorin homogenizer (trade name: APV), and Ranie homogenizer (product) Name: Lanier), high-pressure homogenizer (product name: Niro Soabi), homogenizer (product name: Sanwa Machinery), high-pressure homogenizer (product name: Izumi Food Machinery), ultra-high pressure homogenizer (product name: squid), etc. .
The mechanical distributed process may be a multistage distributed process having three or more stages.

When dispersing by the wet pulverization method, HPC is adsorbed on at least a part of the pulverized surface of the pulverized ABR particles by preparing a dispersion by coexisting ABR particles and HPC as raw materials. Then, HPC is further adsorbed on the new crushing surface, and the refined ABR particles become particles having a so-called protective layer. In the dispersion medium containing water, reaggregation between adjacent dispersed particles It is effectively suppressed by the presence of HPC adsorbed on at least a part of the surface. Therefore, the obtained dispersion containing ABR particles has an average particle diameter of ABR particles of nano-order of 200 nm or less, and is excellent in particle dispersibility and dispersion stability.
Therefore, preferably, the particles of ABR in the pharmaceutical composition of the present disclosure have HPC on at least a part of the particle surface.

By carrying out the dispersion treatment by the wet pulverization method, the average particle diameter of the obtained ABR particles can be set to 50 nm to 200 nm as described above. The average particle diameter of the dispersed particles is more preferably 50 nm to 180 nm, and further preferably 50 nm to 150 nm.

The pharmaceutical composition obtained by the production method of the present disclosure described above is a dispersion in which fine ABR particles are stably dispersed in a dispersion medium containing water.
The surfactant may be added after the dispersion treatment by the wet pulverization method, or may be added simultaneously with the HPC added as a dispersant during the dispersion treatment.
The ABR particles obtained by the wet pulverization method maintain a particle size of preferably 300 nm or less, more preferably 200 nm or less even in an environment in the digestive tract such as simulated gastric fluid and simulated intestinal fluid, and good absorbability can be expected.
The dispersion may be used as it is as a liquid, syrup, or lotion. Further, it may be diluted with various pharmaceutically acceptable dispersion media, solvents containing water, etc., and adjusted to appropriate physical properties for drinking. Furthermore, in order to adjust the taste and appearance suitable for drinking, the above-mentioned coloring agents, flavoring agents, sweetening agents, flavoring agents and the like may be added as appropriate. By performing at least one of the adjustments described above, a pharmaceutical composition more suitable for drinking can be obtained.

The method for producing the pharmaceutical composition of the present disclosure further comprises removing the dispersion medium from the dispersion containing ABR particles having an average particle diameter of 50 nm to 200 nm obtained in the above-described step (I), to obtain a solid preparation (Step (II)).
The method for removing the dispersion medium from the dispersion is not particularly limited, and a known method can be applied. In the present disclosure, “removing the dispersion medium” does not necessarily mean that the dispersion medium is completely removed to make it completely dry, but the dispersion medium is maintained to the extent that the dosage form as a solid preparation can be maintained. Reducing the content of.

(Process (II))
Step (II) is a step in which the dispersion of ABR particles having an average particle diameter of 50 nm to 200 nm obtained in the above-described step (I) is used as a pharmaceutical composition as a solid preparation.
Specifically, the dispersion medium obtained in the step (I), preferably a mixture of the dispersion and an excipient for solid preparation molding, is removed by a drying means such as spray drying to remove powder. A solid formulation may be used. Hereinafter, the powdery solid preparation is also referred to as a powder preparation.

The excipient for forming a solid preparation is preferably at least one selected from mannitol, sucrose, lactose, trehalose, erythritol, maltitol, and maltose, and more preferably at least one selected from mannitol, lactose, and trehalose.
When the dispersion medium is removed, a powder preparation that hardly aggregates after drying can be obtained by using an excipient. The obtained powder formulation can be directly subjected to a tableting process to produce a tablet, for example. Further, as will be described later, the powder preparation can be further granulated, and the resulting granulated product can be subjected to a tableting process to produce a tablet.

As a means for removing the dispersion medium (hereinafter sometimes referred to as a drying means), a known drying means can be used. For example, natural drying, heat drying, hot air drying, high frequency drying, ultrasonic drying, reduced pressure drying, Examples include vacuum drying, freeze drying, and spray drying. Although a drying means may be used independently, it can also be used in combination of 2 or more types of drying means.

As the drying means, freeze-drying in which water is removed by sublimating ice from a frozen material can also be applied.
Examples of commercially available freeze dryers that can be used for freeze drying include freeze dryer VD-800F (trade name: Taitec Co., Ltd.), Flexi Dry MP (trade name: FTS Systems), Duratop Durastop ( Product name: FTS Systems Co., Ltd.), Takara vacuum freeze dryer A type (product name: Takara ATM), desktop 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.

Further, as a drying means, spray drying is a preferable means from the viewpoint of achieving both production efficiency and quality. In the case of applying the spray drying method, a powder preparation as a solid preparation by removing moisture while spraying a mixture containing a liquid composition, which is a dispersion of ABR particles obtained in step (I), and an excipient. May be prepared.
Examples of commercially available spray dryers that can be used for spray drying include spray dryer SD-1000 (trade name: Tokyo Rika Kikai Co., Ltd.), spray dryer L-8i (trade name: Okawara Kako Co., Ltd.) ), Closed spray dryer CL-12 (trade name: Okawara Chemical Co., Ltd.), spray dryer ADL310 (trade name: Yamato Kagaku Co., Ltd.), mini spray dryer B-290 (trade name: BUCHI) , PJ-MiniMax (trade name: Powdering Japan Co., Ltd.), PHARMASD (trade name: Niro Co., Ltd.) and the like.
Further, for example, the above-described apparatus is used, for example, a treatment using a fluidized bed granulator / dryer MP-01 (trade name: POWREC Co., Ltd.), a fluidized bed built-in spray dryer FSD (trade name: Niro). It is also possible to use a method of simultaneously performing drying and granulation.

The obtained powder formulation contains ABR particles having HPC and an average particle diameter of 50 nm to 200 nm, and preferably at least one excipient, on at least a part of the surface.
The content of the excipient is preferably 10 parts by weight to 500 parts by weight, more preferably 20 parts by weight to 300 parts by weight, and more preferably 50 parts by weight to 200 parts by weight with respect to 100 parts by weight of the ABR particles contained in the powder preparation. Is more preferable.
When the content of the excipient is in the above range, a good powder formulation can be obtained.

The obtained powder formulation can be directly used as a granular pharmaceutical composition. Further, a granulated product containing ABR particles, a tablet containing ABR particles, and the like can be formed using the powder preparation.
That is, the production method of the present disclosure can further include a step (step (III)) of tableting the powder formulation obtained in the above-described step (II) to obtain a tablet as a solid formulation.

(Process (II-2))
Step (II-2) is a step of granulating the powder preparation obtained in the above-mentioned step (II). It is preferable to granulate the powder preparation in advance to produce a granulated product, and to tablet the obtained granulated product to obtain a tablet as a solid preparation (step (III)). That is, when producing a tablet by the step (III), the method for producing a pharmaceutical composition of the present disclosure preferably further includes a step (II-2) for preparing a granulated product.
Granulation includes dry granulation and wet granulation, both of which can be used, but dry granulation is preferred from the viewpoint of suppressing aggregation of nano-order ABR particles.
For wet granulation, known wet granulation methods such as fluidized bed granulation method, high speed stirring granulation method, extrusion granulation method and the like can be applied.

In the step (II-2) of preparing the granulated product, at least one pharmaceutically acceptable additive for solid preparation is added to the powder formulation obtained in the step (II), followed by dry granulation. It is preferable to prepare a dry granulated product.
Dry granulation refers to forming a dry granulated product (ie, a granular product) from a mixed powder without using a solution.

Examples of the dry granulation method include a compacting method and a slagging method, and the compacting method is preferable.
Examples of the compacting method include a method of producing a compression-molded product using a roller compactor and crushing it to obtain a dry granulated product. For the compacting method, an apparatus such as a roller compactor TF-LABO or TF-MINI (Freund Sangyo Co., Ltd.) can be used.

In the method for producing a pharmaceutical composition of the present disclosure, if the production scale is small, a tableting machine may be used for dry granulation, and a granulated product as a compression molded product is produced using the tableting machine. can do.
The granulated product can be produced by the tableting machine as follows.
First, at least one pharmaceutically acceptable additive for solid preparation molding is added to the obtained powder preparation to obtain a mixed powder, and then compression molding is performed with a tableting machine to obtain a compression molding. Thereafter, the obtained compression-molded product is crushed in a mortar, and the pulverized product is sized with a test sieve, whereby dry granulation can be performed. By granulating with a test sieve, a granulated product of a desired size can be obtained.

Examples of the pharmaceutically acceptable additive for forming a solid preparation used in the step (II-2) for preparing the granulated product include a disintegrant, an excipient, and a lubricant described in the above-mentioned preparation additive. Agents, binders, granulating agents, fluidization accelerators and the like can be mentioned, and one or more of these additives can be selected and used according to the target addition amount.
In the step (II-2) of preparing the dry granulated product, it is preferable to use at least one selected from the group consisting of a disintegrant, an excipient, and a lubricant as an additive.

(Step (III))
Step (III) is a step in which the powder mixture obtained in step (II) or the granulated product obtained in step (II-2) is compressed and tableted to form tablets.
That is, the pharmaceutical composition as a tablet can be prepared by compressing and compressing the powder mixture obtained in the step (II) or the granulated product obtained in the step (II).
When forming a tablet, the powder mixture or the granulated product is added with at least a pharmaceutically acceptable additive for solid pharmaceutical preparation such as a disintegrant, an excipient, a lubricant, and a binder as necessary. Mixing with one type, the mixture obtained may be introduced into a mold of a tableting machine and compressed into tablets to obtain tablets.
As a tableting method in the step (III), a generally applied tableting method may be applied as it is, and there is no particular limitation.
Examples of the apparatus used for tableting include a rotary tablet making machine HT-AP series (Hatabe Laboratories), a tabletop rotary tableting machine PICCOLA (RIVA), a tabletop simple tablet molding machine HANDTAB-jr, HANDTAB-100 (Ichibashi Seiki Co., Ltd.).
The tableting pressure, tablet size, and the like are appropriately selected according to the purpose of use of the tablet.

If an example of the process (process (III)) which forms a tablet is given, first, at least 1 chosen from the group which consists of a powder formulation obtained by process (II), an excipient | filler, a disintegrating agent, and a lubricant. Examples include a step of mixing a pharmaceutically acceptable additive for solid pharmaceutical preparation containing a seed to prepare a powder mixture and tableting the obtained powder mixture.
The additive used for the preparation of the powder mixture preferably contains at least an excipient and a lubricant.

The solid formulation excipients that can be used during tablet formation include mannitol, corn starch, lactose hydrate, anhydrous lactose, crystalline cellulose, sorbitol, erythritol, light anhydrous silicic acid / crystalline cellulose, light anhydrous silicic acid, water containing Examples include silicon dioxide, calcium silicate, and mixtures thereof.
Examples of commercially available excipients for forming solid preparations include Pearitol Flash manufactured by Rocket Japan Co., Ltd.

A lubricant, which is an additive for forming a solid preparation that can be used during tablet formation, has the function of improving the fluidity of the raw material powder and facilitating filling a fixed amount into the die of a tableting machine. It is a component that prevents capping, sticking, binding, and the like at the time of tableting and gives gloss to the surface of the tablet.
For example, examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, glyceryl monostearate, hydrogenated oil, talc, and light anhydrous silicic acid.
One type of lubricant may be used alone, or two or more types may be used in combination.
A commercially available product may be used as the lubricant. Examples of commercially available products include Partek MST (trade name: magnesium stearate) manufactured by Merck.

The mixing method for preparing the powder mixture is not particularly limited as long as each component can be mixed.
As a mixing method, for example, a method of mixing using a known mixer such as a V-type mixer (manufactured by Tsutsui Chemical Co., Ltd.) can be mentioned.
Mixing conditions such as the time required for mixing can be appropriately adjusted depending on the amount and type of the powder preparation and the binder.

Another example of the step (III) is a step of tableting the granulated product obtained in the step (II-2) as described above. When tableting the granulated product, if necessary, at least one pharmaceutically acceptable additive for solid preparation molding is mixed in advance to prepare a mixture, and the resulting mixture is compressed and compressed. Can be locked.
When tableting the granulated product, it is possible to mix at least one of the above-mentioned additives for molding a solid preparation with the granulated product as necessary, obtain a mixture, and then compress and compress the tablet. it can.
In the production of the pharmaceutical composition that is a tablet in the present disclosure, the step (III) is preferably a step of tableting the mixture containing the granulated product obtained in the step (II-2).

(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, the solid preparation is rapidly redispersed when immersed in water. Maintain a particle size of ~ 200 nm.
Even when the pharmaceutical composition of the present disclosure is in the form of a powder preparation, good resorbability can be expected because it is redispersed in a state containing ABR particles having a target average particle size.
As described above, the pharmaceutical composition of the present disclosure in the form of a powder preparation or a tablet obtained by compressing the powder preparation is dissolved in a solvent such as water as needed, and is used for “preparation for use” pharmaceutical composition It can also be used as a product.
A powdered or tableted pharmaceutical composition and a solvent such as water or an aqueous solution are mixed, and the pharmaceutical composition, which is a solid preparation, is dissolved or dispersed in the solvent, so that the ABR particles are finely dispersed in the solvent. It can be redispersed into a good shape and good absorption can be expected.

The particles of ABR redispersed in water can be 50 nm to 200 nm, preferably 50 nm to 180 nm, and more preferably 50 nm to 150 nm.

<Treatment method>
Other embodiments of the present disclosure also encompass a method of treatment comprising orally administering a pharmaceutical composition of the present disclosure comprising ABR particles as an active ingredient to an application subject to be treated.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist thereof.
Unless otherwise specified, “%” and “part” are based on mass.
In the following examples, abiraterone acetate (ABR) particles may be referred to as ABR particles.

Example 1
[Preparation of particle dispersion]
Dissolve 300 mg of hydroxypropylcellulose (NISSO HPC-SSL, molecular weight: 40,000, manufactured by Nippon Soda Co., Ltd.) as a dispersant in 8 g of water, and add a pH adjuster (0.1 mol / L NaOH or HCl). After adjusting the pH to 6.8 to 7.2, an amount of water of a total amount of 9.25 g was added to obtain an HPC solution.
925 mg of the obtained HPC solution was added to 75 mg of abiraterone acetate (ABR) to obtain a dispersion.
The obtained dispersion was mixed with 3 g of zirconia beads having a diameter of 0.1 mm as a medium, and the mixture was dispersed by a wet pulverization method using a medium at an external temperature of 5 ° C. for 20 hours, and pulverized ABR particles A dispersion liquid containing was obtained (step (I)).

[Average particle size of ABR particles immediately after preparation]
The average particle size of the ABR particles in the obtained dispersion was measured by a dynamic light scattering method using a dense particle size analyzer FPAR-1000 (trade name: manufactured by Otsuka Electronics Co., Ltd.), and D ₅₀ Asked. The results are shown in Table 1 below.

[Average particle size of ABR particles in simulated gastrointestinal fluid]
The following test was conducted for the purpose of confirming the behavior of orally administered ABR particles in the digestive fluid.
(1) Mixing with simulated gastric fluid For the obtained dispersion (ABR particle content equivalent to 20 mg), 1 mL of dissolution test 1st liquid as simulated gastric fluid (compliant with Japanese Pharmacopoeia, manufactured by Kanto Chemical Co., Ltd.) ) Was added, mixed, and allowed to stand at 37 ° C. for 30 minutes. The average particle size of the ABR particles after standing for 30 minutes was measured in the same manner as described above. The results are shown in Table 1 below.

(2) Mixing with simulated intestinal fluid Mixing with simulated gastric fluid in (1) above, adding 0.2 mL of FaSSIF (milliliter) as simulated intestinal fluid to 0.2 mL of test solution after standing for 30 minutes And left at 37 ° C. for 60 minutes. The average particle size of the ABR particles after standing for 60 minutes was measured in the same manner as described above. The results are shown in Table 1 below.

The first dissolution test used as a simulated gastric juice is a solution obtained by dissolving 2.0 g of sodium chloride in 7.0 mL (milliliter) of hydrochloric acid and water to make 1000 mL, is colorless and clear, and has a pH of about 1.2. is there.
FaSSIF (Fasted State Simulated Intestinal Fluid) used as simulated intestinal fluid was 2.18 g of an artificial intestinal fluid preparation reagent (Celeste Co., Ltd.), 6.19 g of sodium chloride and sodium dihydrogen phosphate dihydrate. A solution prepared by dissolving 4.47 g of the product in water to 1000 mL, and a pH adjusted to 8.0 using 1 mol / L sodium hydroxide.

(Examples 2 to 3, Comparative Examples 1 to 16)
A dispersion of ABR particles was obtained in the same manner as in Example 1 except that the type of HPC or comparative dispersant was changed as shown in Table 1 below.
For the obtained dispersion, the average particle size was measured immediately after preparation, after mixing with simulated gastric juice, and after mixing with simulated intestinal fluid in the same manner as in Example 1. The results are shown in Table 1 below.

In addition, the detail of the component used in each Example is as follows. The molecular weight of HPC is a catalog value.
(ABR)
Abiraterone acetate (manufactured by Teva Pharmaceuticals)

(HPC)
Hydroxypropylcellulose (NISSO HPC-SSL, Nippon Soda Co., Ltd., molecular weight: 40,000)
Hydroxypropyl cellulose (NISSO HPC-SL, Nippon Soda Co., Ltd., molecular weight: 100,000)
Hydroxypropyl cellulose (NISSO HPC-L, Nippon Soda Co., Ltd., molecular weight: 140,000)

(Comparison dispersant)
Methylcellulose (METOLOSE (registered trademark) SM-4, manufactured by Shin-Etsu Chemical Co., Ltd.)
Hydroxyethyl cellulose (Natrosol 250 (trade name), manufactured by ASHLAND Co., Ltd.)
Polyvinylpyrrolidone (PVP K30, manufactured by BASF Corporation)
Polyoxyethylene (196) polyoxypropylene (67) glycol (Kolliphor (registered trademark) P407, manufactured by BASF Corporation)
Polyoxyethylene (160) polyoxypropylene (30) glycol (Kolliphor (registered trademark) P188, manufactured by BASF Corporation)
Polyoxyethylene castor oil (Kolliphor (registered trademark) EL, manufactured by BASF Corporation)
Polyoxyethylene hydroxystearate (Solutol HS15, manufactured by BASF Corporation)
Polysorbate 20 (Fujifilm Wako Pure Chemical Industries, Ltd.)
Polysorbate 80 (manufactured by NOF Corporation)
Lauro Macrogol BL-25 (Nikko Chemicals Co., Ltd.)
Polyoxyethylene hydrogenated castor oil 50 (NIKKOL (registered trademark) HCO-50, manufactured by Nikko Chemicals Co., Ltd.)
Sodium deoxycholate (manufactured by Tokyo Chemical Industry Co., Ltd.)
Sodium lauryl sulfate (SLS, trade name: Emar OS, manufactured by Kao Corporation)
Doxert sodium (manufactured by Tokyo Chemical Industry Co., Ltd.)
Carmellose sodium (Serogen PR-S, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.)
Hydroxypropyl methylcellulose (HPMC2910 TC-5M, manufactured by Shin-Etsu Chemical Co., Ltd., molecular weight: 22,000)

As shown in Table 1, in the pharmaceutical compositions of Examples 1 to 3, the average particle size immediately after the preparation of the dispersion of ABR particles is 200 nm or less, and it is a dispersion of nano-order ABR particles. It was. Further, even after mixing with the simulated gastric fluid and further with the simulated intestinal fluid and allowing to stand, a significant increase in the average particle size of the ABR particles is suppressed, and after mixing with the simulated gastric fluid, the maximum average particle size is 221 nm. The maximum value of the average particle size after mixing with the simulated intestinal fluid was 265 nm, and it was confirmed that the ABR particles were maintained at an average particle size of nano order.

On the other hand, in the dispersion (pharmaceutical composition) obtained using the comparative dispersant, the average particle diameter of the ABR particles immediately after preparation was 200 nm or less in some cases, but the average particle diameter was significantly increased in the simulated gastric fluid. An example was found. Further, as in Comparative Examples 12 to 13, when an ionic surfactant was used as a comparative dispersant, solidification was caused by gastrointestinal fluid, and generation and precipitation of coarse particles were observed.
For example, in Comparative Example 16 using hydroxypropyl methylcellulose having a structure similar to HPC as a comparative dispersant, the average particle diameter immediately after preparation exceeds 200 nm, and after mixing with simulated intestinal fluid, the average particle diameter is greatly increased. Although there was no increase, the generation of coarse particles that could be visually confirmed was observed.
From the above results, in the pharmaceutical compositions of the examples, the average particle size of the ABR particles is maintained not only immediately after the preparation but also in the nano-order by mixing with simulated gastric fluid and further simulated intestinal fluid. As a product, it can be expected that the absorbability of ABR in the body is good.

(Examples 4 to 8)
[Preparation of particle dispersion]
In the same manner as in Example 1 except that the content of ABR, the type of HPC, the content of HPC, and the dispersion treatment time of the dispersion used in Example 1 were changed as shown in Table 2 below. A dispersion of particles was obtained.
The average particle diameter of the ABR particles immediately after preparation was measured in the same manner as in Example 1 for the obtained dispersion. The results are shown in Table 2 below.

 

From the results shown in Table 2, the average particle diameters of the ABR particles in the pharmaceutical compositions of Examples 4 to 8 were all 200 nm or less, and fine particle dispersion was achieved.
When the weight average molecular weight of HPC was in the range of 40,000 to 140,000, Example 4 having a weight average molecular weight of 40,000 was slightly good from the viewpoint of particle diameter, but no significant difference was observed. Further, as compared with Examples 4, 5, and 6 and Examples 7 and 8, there is a tendency that the average particle diameter of the dispersed particles tends to be reduced by increasing the dispersion treatment time, and the weight average molecular weight is 4 It can be seen that ten thousand examples obtain fine particles in a shorter time.

(Examples 9 to 15, Comparative Examples 17 to 19)
The HPC-SSL having a weight average molecular weight of 40,000 was used as the HPC, and the ABR content, the HPC content and the dispersion treatment time used in Example 1 were changed as shown in Table 3 below. Except for the above, a dispersion of ABR particles was obtained in the same manner as in Example 1.
The average particle diameter of the ABR particles immediately after preparation was measured in the same manner as in Example 1 for the obtained dispersion. The results are shown in Table 3 below.

 

From the results shown in Table 3, the pharmaceutical compositions of Examples 9 to 15 and Example 4 described in Table 2 containing 10% to 150% of HPC with respect to the content of ABR in the pharmaceutical composition are as follows: The average particle size of the ABR particles contained was 200 nm or less.
On the other hand, in Comparative Example 17 in which the content of HPC with respect to the content of ABR is 200%, the average particle size becomes 200 nm or less by increasing the dispersion treatment time, but coarse particles that can be visually confirmed in the dispersion There was a problem in dispersibility. Further, in Comparative Example 18 in which the HPC content is less than 10% relative to the ABR content, the average particle diameter of the obtained ABR particles exceeds 200 nm, and in Comparative Example 19, the amount of HPC as the dispersant is too small. In the dispersion treatment under the same conditions as in Examples 10 to 15, uniform dispersion could not be achieved.

(Example 16 to Example 30)
(Preparation of dispersion)
Using HPC-SSL having a weight average molecular weight of 40,000 as HPC, a dispersion of ABR particles was obtained in the same manner as in Example 1. Next, an aqueous solution containing the excipients shown in Table 4 was prepared, and an amount of ABR and HPC contents shown in Table 4 was added to the resulting dispersion to prepare a mixed solution. Further, in Examples 22 to 28, when preparing an aqueous solution containing the excipients shown in Table 4, Kolliphor P407, which is a surfactant, was added and added to the dispersion to obtain a mixed solution. . (Step (I)).
The average particle diameter of the ABR particles immediately after preparation was measured in the same manner as in Example 1 for the obtained mixed solution. The results are shown in Table 4 below.

(Preparation of powder formulation)
The mixture obtained in the step (I) is spray-dried with a spray dryer (spray dryer, manufactured by BUCHI Co., Ltd.) at an inlet temperature of 100 ° C., an outlet temperature of 50 ° C., and a liquid speed of 3 g / min. Was obtained (step (II)).

(Excipient)
Sucrose (refined white sugar, trade name: Sukurene SR80 / 100, manufactured by Shimizu Minato Sugar Co., Ltd.)
d-Mannitol (trade name: Mannit P, manufactured by Mitsubishi Corporation Foodtech)
Lactose (Lactose monohydrate, trade name: Granitol R, manufactured by Freund Sangyo Co., Ltd.)
Trehalose (manufactured by Hayashibara)
Maltose (Maltose monohydrate, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.)
Erythritol (Mitsubishi Chemical Foods Co., Ltd.)
Maltitol (Amalti (registered trademark), manufactured by Mitsubishi Corporation Foodtech)

[Redispersibility of powder formulations]
The obtained powder formulation was added to purified water at 25 ° C. in such an amount that the ABR was 0.5 mg / mL, and gently stirred until the solid content disappeared visually to redisperse the powder formulation in purified water.
The average particle size of the ABR particles contained in the obtained redispersed liquid was measured in the same manner as the method for measuring the average particle size of the ABR particles immediately after preparation in Example 1. The results are shown in Table 4 below.
In Table 4, “-” indicates that the component is not contained.

As shown in the results of Table 4, in all of the dispersions of Examples 16 to 30, the average particle size of the ABR particles contained in the dispersion was 150 nm or less. Even when the dispersion is made into a powder preparation and redispersed in purified water, the average particle diameter of the ABR particles is 200 nm or less, indicating that the redispersibility of the powder preparation is excellent. For this reason, all of the pharmaceutical compositions of the Examples are pharmaceutical compositions that have good absorbability because they are rapidly re-dispersed nano-order ABR particles when administered orally even when powdered. Can be expected.
From the comparison between Example 20 and Example 22, it can be seen that the average particle diameter of the ABR particles is smaller due to the coexistence of the surfactant, and the surfactant contributes to the redispersibility.

(Example 31 to Example 40)
HPC-SSL having a weight average molecular weight of 40,000 was used as HPC. The content of ABR used and the content of HPC were the amounts shown in Table 5 below. Furthermore, surfactants listed in Table 5 were included as dispersion aids.
As a method for adding the surfactant, the surfactant was initially added to the dispersion, and the dispersion containing the surfactant was subjected to the same dispersion treatment as in Example 1. Table 5 It was described as “dispersed substance” in the addition method. In addition, after a dispersion treatment was performed without adding a surfactant to the dispersion, a dispersion was obtained, and the obtained dispersion was allowed to contain a surfactant. "After".
The average particle diameter of the ABR particles immediately after preparation was measured in the same manner as in Example 1 for the obtained dispersion. The results are shown in Table 5 below. As a control, the evaluation results of Example 1 not containing a surfactant are also shown in Table 5.

Thereafter, in the same manner as in Example 1, the average particle diameter of ABR particles in the simulated gastrointestinal fluid was measured. The results are shown in Table 5 below.
As a control, the evaluation results of Example 1 not containing a surfactant are also shown in Table 5.

 

As described in the results of Table 5, it can be seen that the inclusion of the surfactant keeps the average particle diameter of the ABR particles smaller.
The surfactant is added to the material to be dispersed, and then dispersed in a wet pulverization method using a medium, and when added to a dispersion treated by a wet pulverization method. The dispersibility of ABR particles is improved by the addition of the agent, and both the average particle size of the obtained ABR particles and the average particle size of the ABR particles in the simulated gastrointestinal fluid are compared with the case where no surfactant is added. It can be seen that it can be kept smaller and more stable.

(Examples 41 to 48)
A dispersion containing ABR particles was prepared in the same manner as in Example 35 except that at least one of the type and content of the surfactant was changed as shown in Table 6. That is, in each Example described in Table 6, the surfactant was added to a dispersion obtained by dispersing ABR by a wet pulverization method.
The average particle size of the ABR particles in the dispersion and the average particle size of the ABR particles after mixing with the simulated gastrointestinal fluid were measured in the same manner as in Example 1. The results are shown in Table 6. In addition, as a control example, the evaluation results of Example 1 not containing a surfactant, Example 35 and Example 36 having different HPC contents are shown in Table 6.

 

From the results in Table 6, it can be seen that the inclusion of a surfactant as a dispersion aid can keep the average particle size of ABR particles smaller not only in the dispersion but also in the simulated digestive fluid. In particular, when Kolliphor P407 is used as the surfactant, 4% to 40% of the ABR content is obtained, and 10% to 100% of the HPC is more effective. When HCO-50 was used as the surfactant, a better effect was obtained at 30% to 40% with respect to the ABR content and 75% to 100% with respect to HPC. From this, it is expected that the average particle size of the ABR particles can be made smaller and more stable by appropriately selecting and using the type and content of the surfactant.

(Example 49 to Example 53)
[Preparation of tablets]
For the powder formulation obtained in Example 29 obtained through the steps (I) and (II), a disintegrant for forming a solid formulation, light anhydrous silicic acid / crystalline cellulose as an excipient, stearin as a lubricant Magnesium acid was mixed according to the formulation ratio used in the granulated product preparation step shown in Table 7 to obtain a powder mixture. Mixing was carried out using a V-type mixer (VM-2 type Tsutsui Rika Kikai Co., Ltd.).
Subsequently, the obtained powder mixture was compression-molded with a tabletop simple tablet molding machine (HANDTAB-jr Ichihashi Seiki Co., Ltd.), and then the compacted product was crushed in a mortar and sized with a test sieve. Dry granulation was performed to obtain a granular dry granulated product. (Process II-2)

Then, to the obtained dry granulated product, the disintegrant for solid preparation molding, the excipient, and the lubricant described in Table 7 were mixed in an amount corresponding to the content described in Table 7, A mixture containing the ABR particle-containing granulated product was obtained.
In Table 7, “-” indicates that the component is not contained.
115 mg of the obtained mixed powder was introduced into a mortar (size: 10 mm × 5 mm oval type), and tableted with a tabletop simple tablet press (HANDTAB-jr Ichihashi Seiki Co., Ltd.) to obtain tablets. (Step (III))

The following additives were used for molding solid preparations described in Tables 7 to 9.
Sodium starch glycolate (trade name primojel: manufactured by DFE Pharma)
Carmellose calcium (trade name ECG-505: Gotoku Pharmaceutical Co., Ltd.)
Croscarmellose Na (croscarmellose sodium) (trade name primellose: manufactured by DFE Pharma)
Partially pregelatinized starch (trade name: PCS PC10: manufactured by Asahi Kasei Corporation)
Crospovidone (Polyplasmone XL-10: manufactured by Ashland)
Light anhydrous silicic acid / crystalline cellulose (trade name prosolv SMCC90: manufactured by Kimura Sangyo Co., Ltd.)
Spray-dried lactose (trade name supertab 11SD: manufactured by DFE Pharma)
D-mannitol (trade name Granitol F: manufactured by Freund Corporation)
Calcium silicate (trade name: FLORITE (registered trademark) R: Eisai Food Chemical Co., Ltd.)
Light anhydrous silicic acid (trade name Adsolider (registered trademark) 102, Freund Sangyo Co., Ltd.)
Hydrous anhydrous silica (trade name Carplex # 67, Degussa)
Hydrous anhydrous silica (trade name Carplex # 80, Degussa)
Hydrous Anhydrous Silicic Acid (trade name Cycilia 350, Fuji Silysia Chemical Ltd.)

[Tablet evaluation]
The obtained tablets were evaluated by the following methods.
[1. Evaluation of redispersibility of tablets]
The obtained tablet is pulverized in a mortar, and a part of the tablet is added to purified water at 25 ° C. in an amount such that the ABR contained in the pulverized product is 0.5 mg / mL, and is slowly gradually until there is no solid content visually. Stir and redisperse in purified water to prepare a redispersion.
The average particle size of the ABR particles contained in the obtained redispersed liquid was measured in the same manner as the method for measuring the average particle size of the ABR particles immediately after preparation in Example 1. The results are also shown in Table 7.

 

From the results of Table 7, it can be seen that all the tablets produced using pharmaceutically acceptable additives for solid preparation molding have good redispersibility. From the results of the redispersed particle size, it is understood that sodium starch glycolate and croscarmellose sodium are more preferable as the disintegrant.

(Example 54 to Example 61)
[Preparation of tablets]
The content of the powder preparation obtained in Example 29 obtained through the steps (I) and (II), and the contents of the disintegrant, excipient, and lubricant were changed to the ratios shown in Table 8. Except for the above, the same operation as in Example 49 was performed to obtain a mixed powder containing an ABR granulated product.
An amount of mixed powder containing 100 mg of ABR was introduced into a mortar and the same operation as in Example 49 was performed to obtain tablets.

[Tablet evaluation]
[1. Evaluation of redispersibility of tablets]
The tablet of each Example obtained was subjected to the same operation as Example 49, and the redispersibility of the tablet was evaluated. The evaluation results of Examples 54 to 61 are shown in Table 8. The evaluation results of Example 49 are also shown in Table 8.

[2. Tablet disintegration evaluation)
The obtained tablet was applied to the disintegration test method described in the Japanese Pharmacopoeia, and the time until the tablet disintegrated completely was measured.
Test conditions are shown below.
Test device: Disintegration tester (HM-41D Miyamoto Riken Co., Ltd.)
Test solution: 0.1 mol / L hydrochloric acid aqueous solution Test temperature: 37 ° C
Reciprocating speed: 30 times / 1 minute It is estimated that the shorter the disintegration time, the faster the drug is released from the tablet in the digestive tract and the better absorbability can be expected. The results are also shown in Table 8.

From the results in Table 8, it can be seen that the tablets of Example 54 to Example 61 are all excellent in redispersibility and tablet disintegration. In addition, the tablets of Example 49 and Examples 56 to 61 in which the content of the additive for solid preparation molding in the tablet is in the range of 28% by mass to 70% by mass have better disintegration, It can be seen that the tablets of Examples 57 to 61, in which the content of the solid formulation-forming additive in the tablet is 37% by mass to 70% by mass, have even better disintegration.

(Example 62 to Example 71)
Except for changing the types and contents of the ABR particle-containing granulated product, the disintegrant for forming a solid preparation to be used together, the excipient, and the lubricant as shown in Table 9, the procedure was the same as in Example 49. Thus, a mixed powder containing the ABR granulated product was obtained.
120 mg of the mixed powder was introduced into a mortar, and the same operation as in Example 49 was performed to obtain tablets of Examples 62 to 71. The redispersibility and disintegration of the tablets were evaluated in the same manner as in Example 49 with respect to the obtained tablets of each Example. The results are also shown in Table 9.

In Examples 62 to 71, in addition to the above evaluation, the stability of the tablet was also evaluated.
[3. Tablet stability evaluation)
The obtained tablet was put in a vial bottle containing silica gel and sealed, and stored at 70 ° C. for 6 days. After storage, the tablet was taken out, and the amount of analog of abiraterone acetate in the tablet was measured using a high performance liquid chromatography method.
As an indicator of analogs of abiraterone acetate, the amount of 7-keto-abiraterone (described as “7-keto abiraterone” in the table) was measured.
In the high performance liquid chromatography method, an HPLC system (product of Shimadzu Corporation) was used, and the evaluation was performed under the following conditions.
(Measurement condition)
Column: Inert Sustain C18 3.0 μm, 3.0 * 150 mm
Eluent A: 10 mM ammonium acetate aqueous solution / ethanol = 7/3 (vol / vol)
Eluent B: acetonitrile / ethanol = 7/3 (vol / vol)
Elution conditions: Separation by gradient according to the following time.
Time 0 minute → 35 minutes Eluent B = 30% by volume → 65% by volume
Time 35 minutes → 45 minutes Eluent B = 65% by volume → 100% by volume
Time 45 minutes → 55 minutes Eluent B = 100 volume% → 100 volume%
Flow rate: 0.45 mL / min Column temperature: 25 ° C
Detection wavelength: 254 nm

It can be evaluated that the smaller the amount of the produced analog, the more stable the tablet with excellent storage stability. The results are also shown in Table 9.

From the results of Table 9, it can be seen that the tablets of Examples 62 to 71 are all excellent in redispersibility, disintegration, and stability. From the results of disintegration and stability, it can be seen that as the excipient, Carplex # 80 and spray-dried lactose are more preferable, and Adsolider 102 and D-mannitol are more preferable.

The disclosure of Japanese Patent Application No. 2018-084321 filed on Apr. 25, 2018 is incorporated into this disclosure by reference.
All documents, patent applications, and technical standards mentioned in this disclosure are as if they were specifically and individually stated that each individual document, patent application, and technical standard was incorporated by reference. Incorporated by reference in the disclosure.

Claims (14)

1. Abiraterone acetate particles having an average particle size of 50 nm to 200 nm;
   A pharmaceutical composition comprising 10% by mass to 150% by mass of hydroxypropylcellulose with respect to the content of the abiraterone acetate particles.
2. The pharmaceutical composition according to claim 1, wherein the hydroxypropylcellulose has a weight average molecular weight of 140,000 or less.
3. The pharmaceutical composition according to claim 1 or 2, further comprising a surfactant.
4. The surfactant is at least one selected from the group consisting of polyoxyethylene polyoxypropylene glycol, lauromacrogol, sodium deoxycholate, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydroxystearate, polysorbate 20, and polysorbate 80. The pharmaceutical composition according to claim 3, which is a seed.
5. The pharmaceutical composition according to claim 3 or 4, wherein a content of the surfactant is 0.1% by mass to 40% by mass with respect to a content of the abiraterone acetate.
6. The pharmaceutical composition according to any one of claims 3 to 5, wherein a content of the surfactant is more than 0% by mass and 100% by mass or less with respect to a content of the hydroxypropylcellulose.
7. The pharmaceutical composition according to any one of claims 1 to 6, which is a solid preparation.
8. The pharmaceutical composition according to claim 7, which is a powder preparation.
9. The pharmaceutical according to claim 7, which further comprises a pharmaceutically acceptable additive for molding a solid preparation containing at least one selected from the group consisting of an excipient, a disintegrant, and a lubricant, and is a tablet. Composition.
10. The pharmaceutical composition according to claim 9, wherein the total content of the pharmaceutically acceptable additive for solid preparation molding is 10% by mass to 80% by mass with respect to the total mass of the pharmaceutical composition.
11. The pharmaceutical composition according to any one of claims 1 to 10, which is used for oral administration.
12. A dispersion to be dispersed containing abiraterone acetate, 10% by mass to 150% by mass of hydroxypropyl cellulose, and a dispersion medium with respect to the content of abiraterone acetate is dispersed by a wet pulverization method to obtain an average particle size. A method for producing a pharmaceutical composition comprising the step of obtaining a dispersion comprising particles of abiraterone acetate having a particle size of 50 nm to 200 nm.
13. The method for producing a pharmaceutical composition according to claim 12, wherein the wet pulverization method includes a pulverization dispersion method using a medium.
14. Furthermore, the manufacturing method of the pharmaceutical composition of Claim 12 or Claim 13 including the process of removing a dispersion medium from the said dispersion, and obtaining a powder formulation.