WO2022210829A1 - Abiraterone acetate-containing tablet - Google Patents

Abiraterone acetate-containing tablet Download PDF

Info

Publication number
WO2022210829A1
WO2022210829A1 PCT/JP2022/015807 JP2022015807W WO2022210829A1 WO 2022210829 A1 WO2022210829 A1 WO 2022210829A1 JP 2022015807 W JP2022015807 W JP 2022015807W WO 2022210829 A1 WO2022210829 A1 WO 2022210829A1
Authority
WO
WIPO (PCT)
Prior art keywords
tablet
mass
abiraterone acetate
content
solubilizer
Prior art date
Application number
PCT/JP2022/015807
Other languages
French (fr)
Japanese (ja)
Inventor
遼 松田
琢哉 角野
尭彬 城
Original Assignee
ニプロ株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ニプロ株式会社 filed Critical ニプロ株式会社
Priority to JP2023511455A priority Critical patent/JPWO2022210829A1/ja
Publication of WO2022210829A1 publication Critical patent/WO2022210829A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to tablets containing abiraterone acetate. More specifically, it relates to small tablets containing abiraterone acetate with an improved abiraterone acetate content.
  • Abiraterone acetate has the formula: is rapidly hydrolyzed to abiraterone in vivo, inhibits the activity of androgen synthase 17 ⁇ -hydroxylase/C17,20-lyase (CYP17), castration-resistant prostate cancer, testis, adrenal glands and In prostate tumor tissue, it reduces testosterone and dihydrotestosterone content and suppresses tumor growth.
  • Tablets containing abiraterone acetate as an active ingredient are marketed under names such as "Zytiga (registered trademark) tablet 250 mg" as a therapeutic agent for castration-resistant prostate cancer (Non-Patent Document 1).
  • abiraterone acetate When abiraterone acetate is used as an active ingredient in a therapeutic agent for castration-resistant prostate cancer, 1,000 mg of abiraterone acetate should be orally administered to adults once daily under fasting conditions in combination with prednisolone.
  • tablets containing 250 mg of abiraterone acetate per tablet are used, and 4 tablets are taken daily.
  • This tablet has a low abiraterone acetate content of about 35% by mass, and is a large tablet with a major axis of 16 mm, a minor axis of 9.6 mm, a thickness of 6.3 mm, and a total mass of 736 mg.
  • Abiraterone acetate is a poorly soluble drug with low oral availability.
  • the use of nanoparticles has been disclosed (Patent Document 1).
  • the content of abiraterone acetate in the tablet, which is specifically described in Patent Document 1 is about 15% by mass, which is even lower than that of the commercially available tablet. nothing has been done.
  • Non-Patent Document 1 has a problem of ease of administration due to its large size as described above, and also has a problem that it is difficult to obtain patient compliance because four tablets must be taken a day.
  • small tablets with a high content of abiraterone acetate also have a high content of a solubilizer, which causes gelation and affects the dissolution rate.
  • an object of the present disclosure is to provide a small tablet with a higher content of abiraterone acetate and exhibiting good dissolution characteristics in order to improve ease of administration.
  • the present disclosure [1] 55 to 95 mass%, preferably 55 to 90 mass%, 65 to 95 mass%, 65 to 90 mass%, 75 to 95 mass% of abiraterone acetate as an active ingredient relative to the mass of the whole tablet; or a tablet containing 75-90% by mass, a solubilizer and an aluminometasilicate, [2]
  • the active ingredient abiraterone acetate and the solubilizer together with the metasilicate aluminate as a fluidizing agent, it has good dissolution characteristics, and the active ingredient abiraterone acetate is tableted. It is possible to provide small tablets containing 55 to 95% by mass of the total mass of abiraterone acetate at a high content rate, and improve patient compliance.
  • FIG. 1 is a graph showing the elution rate (%) of abiraterone acetate in Examples 1-3.
  • the tablet of the present disclosure contains 55 to 95% by mass of abiraterone acetate as an active ingredient relative to the mass of the entire tablet, a solubilizer, and a metasilicate aluminate.
  • abiraterone acetate as an active ingredient relative to the mass of the entire tablet
  • a solubilizer and a metasilicate aluminate.
  • metasilicate aluminate as a glidant, gelation during dissolution, which is thought to be caused by the increased content of abiraterone acetate and the solubilizer due to the downsizing of tablets, is suppressed, resulting in good dissolution characteristics.
  • Alumina metasilicate is porous and has the property of drawing water into the tablet.
  • the good dissolution characteristics of the resulting tablet are preferably the same as those of tablets containing abiraterone acetate which are already on the market.
  • the dissolution time was 30 minutes. is preferably 30 to 65%, more preferably 35 to 60%, and an elution time of 60 minutes is preferably 70 to 95%, more preferably 75 to 95%.
  • the content of abiraterone acetate in the tablet is 55% by mass or more, preferably 65% by mass or more, more preferably 75% by mass or more, relative to the mass of the entire tablet. If the content of abiraterone acetate is less than 55% by mass relative to the mass of the entire tablet, the tablet cannot be sufficiently miniaturized, and it tends to be difficult to improve the ease of administration.
  • the content of abiraterone acetate in the tablet is 95% by mass or less, preferably 90% by mass or less, relative to the mass of the entire tablet. When the content of abiraterone acetate is more than 95% by mass relative to the mass of the entire tablet, the dissolution rate tends to be delayed due to the high density of abiraterone acetate.
  • the tablet of the present disclosure preferably has a mass of 420 mg or less, more preferably 260 to 420 mg, from the viewpoint of ease of administration.
  • the metasilicate aluminate is not particularly limited, but magnesium aluminometasilicate and the like are used, and Neusilin (registered trademark) manufactured by Fuji Chemical Industry Co., Ltd. can be used as a commercially available product.
  • the content of the metasilicate aluminate in the tablet is not particularly limited, but is generally preferably 0.1% by mass or more, preferably 0.5% by mass, based on the total mass of the tablet from the viewpoint of disintegration. The above is more preferable, and 1.0% by mass or more is even more preferable.
  • the content of metasilicate aluminate in the tablet is usually preferably 20% by mass or less, more preferably 10% by mass or less, and further preferably 5% by mass or less from the viewpoint of fluidity, relative to the total mass of the tablet. preferable.
  • solubilizers include, but are not limited to, anionic surfactants such as sodium lauryl sulfate and sodium dioctylsulfosuccinate, polyoxyethylene glycol sorbitan alkyl esters (eg, polysorbate 80), and polyethylene glycols. and other nonionic surfactants, and various other surfactants.
  • anionic surfactants such as sodium lauryl sulfate are preferred, and sodium lauryl sulfate is more preferred, because they generally have a relatively high solubilizing ability and the active ingredient is a basic drug.
  • the solubilizers may be used alone or in combination of two or more.
  • the content of the solubilizing agent in the tablet varies depending on the content of abiraterone acetate and metasilicate aluminate in the tablet, and is not particularly limited. From the viewpoint of , the content is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, still more preferably 1% by mass or more, and particularly preferably 3% by mass or more. In addition, the content of the solubilizer in the tablet is usually preferably 30% by mass or less, more preferably 20% by mass or less, and further preferably 15% by mass or less from the viewpoint of disintegration, relative to the total mass of the tablet. 10% by mass or less is particularly preferred, and 7% by mass or less is even more preferred.
  • the tablet of the present disclosure contains, in addition to the active ingredients abiraterone acetate, solubilizer, and metasilicate aluminate, for example, disintegrants, binders, excipients, sweeteners, flavors, and metasilicate aluminate. Additives commonly used in this field, such as fluidizing agents, lubricants, flavoring agents, coloring agents, and surfactants, may be included. Tablets of the present disclosure may also be film-coated tablets. When the tablet of the present disclosure is a film-coated tablet, the tablet of the present disclosure can further contain a film coating base that forms a film coating layer in addition to the above excipients.
  • Disintegrants are roughly classified into Swelling type disintegrants and Wicking type disintegrants.
  • Swelling-type disintegrants are insoluble in water, but the disintegrant itself swells by taking in a larger amount of water than the voids of the disintegrant, and the swelling force destroys the structure of the tablet. Since water permeates between the particles one after another, it is thought that the tablet disperses and disintegrates while pulverizing like an eruption.
  • Wicking-type disintegrants have a small contact angle, so water permeates quickly through the surface of the disintegrant and penetrates into the inside of the tablet. thought to collapse.
  • the tablet of the present disclosure is characterized by the use of metasilicate aluminate, and in addition, both Swelling type disintegrant and Wicking type disintegrant can be used, and are not particularly limited.
  • Swelling-type disintegrants include croscarmellose sodium, carmellose calcium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl starch, and the like. Among them, it is preferably selected from croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose.
  • Wicking-type disintegrants include partially pregelatinized starch, carmellose, corn starch, microcrystalline cellulose, and the like. These disintegrants may be used alone or in combination of two or more.
  • Content in the tablet when using a disintegrant is not particularly limited, relative to the total weight of the tablet, preferably 0.01 wt% or more, more preferably 0.1 wt% or more, 1 % by mass or more is more preferable, and 10% by mass or more is particularly preferable.
  • the disintegrant is preferably 30% by mass or less, more preferably 25% by mass or less, and even more preferably 20% by mass or less, relative to the total mass of the tablet.
  • Binders include, but are not limited to, hydroxypropyl cellulose, povidone, polyvinyl alcohol, hypromellose, methyl cellulose, hydroxyethyl cellulose, gelatin, agar, sodium alginate, dextrin, xanthan gum, gum arabic powder, partially saponified polyvinyl alcohol and and pullulan. Among them, it is preferably at least one selected from the group consisting of hydroxypropyl cellulose, povidone, polyvinyl alcohol and hypromellose, and at least one selected from hydroxypropyl cellulose, povidone and polyvinyl alcohol. Hydroxypropylcellulose is more preferred, and hydroxypropylcellulose is particularly preferred. These may be used independently and may use 2 or more types together.
  • the content in the tablet is not particularly limited, but is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, based on the total mass of the tablet. 1 mass % or more is more preferable.
  • the content of the binder in the tablet is not particularly limited, but is preferably 20% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less, relative to the total mass of the tablet. .
  • excipients include, but are not limited to, celluloses (crystalline cellulose, ethyl cellulose, etc.) and derivatives thereof, sugars (glucose, lactose, sucrose, refined sucrose, powdered sugar, trehalose, dextran, dextrin, and others). hydrate, etc.), sugar alcohol (D-mannitol, xylitol, sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (synthetic hydrotalcite), anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, hydrogen phosphate Inorganic salts such as calcium hydrate and sodium bicarbonate are included. Celluloses such as crystalline cellulose and sugars such as lactose and lactose hydrate are particularly preferred. Excipients may be used alone or in combination of two or more.
  • the content in the tablet varies depending on the content of abiraterone acetate and other additives in the tablet, and is not particularly limited. .1 to 30% by mass is preferred, and 0.5 to 20% by mass is more preferred.
  • Fluidizing agents other than aluminate metasilicate are not particularly limited, and examples include silicates such as calcium silicate, silicic anhydride such as light anhydrous silicic acid, hydrated silicon dioxide, talc, and titanium oxide. , stearic acid, magnesium stearate, calcium stearate and the like. These may be used alone or in combination of two or more.
  • the content in the tablet varies depending on the content of the aluminate metasilicate, but the above-mentioned powder or abiraterone contained in the granules
  • Acetic acid esters and various additives may be added in an amount that allows smooth flow in the production of tablets, and this varies depending on the type of glidant used, so it is not particularly limited, but usually , with respect to the total weight of the tablet, preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight.
  • lubricants include, but are not limited to, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, hydrogenated oil, glycerol fatty acid esters, and talc. be done.
  • magnesium stearate is preferable because of its high lubricity. These may be used alone or in combination of two or more.
  • the content in the tablet is an amount that can suppress adhesion of the above-mentioned abiraterone acetate and various additives to the tablet manufacturing equipment (punches and dies).
  • the content in the tablet is an amount that can suppress adhesion of the above-mentioned abiraterone acetate and various additives to the tablet manufacturing equipment (punches and dies).
  • it is not particularly limited because it varies depending on the type of lubricant used, it is usually preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, based on the total mass of the tablet. preferable.
  • the tablet of the present disclosure uses a film-coating base, and can be a film-coated tablet in which a film is applied to the surface of the tablet, thereby masking bitterness and malodor, and protecting against external conditions such as moisture, light, or oxygen. It can be expected to have effects such as improved stability of the main drug, improved appearance, and increased commercial value.
  • Film coating bases include, but are not limited to, hydroxypropyl cellulose, hypromellose, carmellose sodium, ethyl acrylate/methyl methacrylate copolymer dispersion, polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol. Polymers such as can be used. Film coating bases may optionally contain plasticizers such as polyethylene glycol, propylene glycol, triacetin and triethyl citrate, colorants such as titanium oxide, iron sesquioxide and aluminum lake, and brightening agents such as carnauba wax. can be added.
  • plasticizers such as polyethylene glycol, propylene glycol, triacetin and triethyl citrate, colorants such as titanium oxide, iron sesquioxide and aluminum lake, and brightening agents such as carnauba wax. can be added.
  • the mass of the film-coating layer is not particularly limited as long as it is an amount that can cover the entire tablet. From the viewpoint of quickly eluting, when the mass of the portion other than the film coating layer in the tablet is 100 parts by mass, it is preferably 0.1 to 5 parts by mass, and 1 to 5 parts by mass. is more preferred.
  • the tablet of the present disclosure is useful for treatment of castration-resistant prostate cancer and endocrine therapy-naive prostate cancer with high-risk prognostic factors.
  • the dose of the tablet of the present disclosure is not particularly limited as long as it is within the scope of common knowledge in the technical field.
  • it is, for example, 1000 mg, and can be administered in 1 to 4 divided doses per day.
  • Tablet manufacturing method As a method for producing tablets, a general method in this technical field can be used, and there is no particular limitation. For example, it can be produced by mixing and granulating abiraterone acetate and a solubilizer, mixing the resulting granules with aluminate metasilicate, and compressing into tablets. At this time, it is preferable to granulate a binder and a disintegrant together with the abiraterone acetate and the solubilizer, and furthermore, it is preferable to mix a lubricant together with the aluminate metasilicate.
  • the granulation method is not particularly limited, and granulation methods commonly used in the pharmaceutical field, such as dry granulation and wet granulation, can be used.
  • the tableting method is not particularly limited. For example, using a tableting die, upper and lower tableting punches, a hydraulic hand press machine, a single-shot tableting machine, a rotary tableting machine, etc. and the like can be used. Tableting may be performed at a tableting pressure such that the resulting tablet has an appropriate hardness, and the tableting pressure is appropriately adjusted according to the tableting method, the equipment used for tableting, the size of the tablet, and the like. .
  • the shape of the tablet to be obtained is not particularly limited, and may be, for example, disk-shaped, doughnut-shaped, polygonal plate-shaped, spherical, elliptical, or caplet-shaped.
  • the size is preferably small.
  • the long axis is about 8 to 15 mm
  • the short axis is about 5 to 12 mm
  • the thickness is about 3 to 8 mm.
  • the diameter is about 5 to 15 mm and the thickness is about 2.5 to 6 mm.
  • a film-coating method As a film-coating method, a conventional film-coated tablet production method used in this technical field can be used. For example, a tablet (uncoated tablet) containing abiraterone acetate is charged into a film coating machine, and the film coating agent and additives are added to an organic solvent such as water or ethanol, or a mixed solution thereof (e.g., water / ethanol mixture). Tablets can be coated by spraying a coating liquid dissolved or dispersed in an appropriate solvent and drying the tablets.
  • an organic solvent such as water or ethanol, or a mixed solution thereof (e.g., water / ethanol mixture). Tablets can be coated by spraying a coating liquid dissolved or dispersed in an appropriate solvent and drying the tablets.
  • Japanese Pharmacopoeia XVII represents the 17th revision of the Japanese Pharmacopoeia.
  • Examples 1-3 According to the formulation in Table 1, abiraterone acetate and low-substituted hydroxypropyl cellulose were put into a stirring granulator (FM-VG-05, manufactured by Powrex Co., Ltd.) to mix the powders. Granulation was carried out by adding a granulation liquid obtained by mixing sodium lauryl sulfate, hydroxypropylcellulose-SL and water. After drying the obtained granules with a fluid bed granulator dryer (FD-MINI, manufactured by Powrex Co., Ltd.) at an air supply temperature of 80 ° C.
  • FD-MINI fluid bed granulator dryer
  • a granule sizing machine (Comil, Powrex Co., Ltd.) (1397 ⁇ m)) to obtain regulated granules.
  • Magnesium aluminometasilicate and magnesium stearate were added to the obtained sized granules, mixed in a plastic bag, and compressed with a rotary tableting machine (VIRG0512SS2AZ, manufactured by Kikusui Seisakusho Co., Ltd.) to give a tablet having a major diameter of 12.8 mm and a minor diameter of 7. It was compressed to 0.7 mm and 5.3 mm thick to give tablets.
  • Test Example 1 Dissolution property test The tablets immediately after production in Examples 1 to 3 were dissolved in a dissolution tester (trade name: NTR-6000 series, manufactured by Toyama Sangyo Co., Ltd.) according to the dissolution test method of the Japanese Pharmacopoeia. The paddle method was used using the Japanese Pharmacopoeia dissolution test liquid 1 (pH 1.2) as the test liquid.
  • the test conditions were a volume of dissolution medium of 900 mL, a temperature of 37 ⁇ 0.5° C., and a paddle speed of 75 rpm. The results are shown in Figure 1 and Table 2 as mean values.
  • the abiraterone acetate tablets containing metasilicate aluminate together with the solubilizer were in the range of 30-65% and 70-95% at the dissolution times of 30 minutes and 60 minutes, respectively, indicating good results. It can be seen that it exhibits excellent elution characteristics.

Abstract

Provided is a tablet: containing 55-95 mass% abiraterone acetate, as an active ingredient, to the total mass of the tablet, a solubilizing agent, and an aluminate metasilicate; being a small tablet having the content of abiraterone acetate further increased in order to improve dosing properties; and exhibiting good dissolution characteristics.

Description

アビラテロン酢酸エステル含有錠剤Tablets containing abiraterone acetate
　本開示は、アビラテロン酢酸エステルを含む錠剤に関する。より詳細には、アビラテロン酢酸エステルの含有率を向上させたアビラテロン酢酸エステル含有小型錠剤に関する。 The present disclosure relates to tablets containing abiraterone acetate. More specifically, it relates to small tablets containing abiraterone acetate with an improved abiraterone acetate content.
　アビラテロン酢酸エステルは、つぎの式：
Figure JPOXMLDOC01-appb-C000001
 で表され、生体内で速やかにアビラテロンへ加水分解され、アンドロゲン合成酵素である１７α－ヒドロキシラーゼ／Ｃ１７，２０－リアーゼ（ＣＹＰ１７）の活性を阻害し、去勢抵抗性前立腺癌など、精巣、副腎および前立腺腫瘍組織において、テストステロンやジヒドロテストステロン含量を低下させ、腫瘍の増殖を抑制する。アビラテロン酢酸エステルを有効成分とする錠剤が、去勢抵抗性前立腺癌治療剤として「ザイティガ（登録商標）錠２５０ｍｇ」などの名称で販売されている（非特許文献１）。 Abiraterone acetate has the formula:
Figure JPOXMLDOC01-appb-C000001
 is rapidly hydrolyzed to abiraterone in vivo, inhibits the activity of androgen synthase 17α-hydroxylase/C17,20-lyase (CYP17), castration-resistant prostate cancer, testis, adrenal glands and In prostate tumor tissue, it reduces testosterone and dihydrotestosterone content and suppresses tumor growth. Tablets containing abiraterone acetate as an active ingredient are marketed under names such as "Zytiga (registered trademark) tablet 250 mg" as a therapeutic agent for castration-resistant prostate cancer (Non-Patent Document 1).
　アビラテロン酢酸エステルを有効成分として去勢抵抗性前立腺癌治療剤に用いる場合、通常、成人にはプレドニゾロンとの併用において、アビラテロン酢酸エステルとして１日１回１，０００ｍｇを空腹時に経口投与することとされており、現在は、上述のとおり、１錠中にアビラテロン酢酸エステルを２５０ｍｇ含有する錠剤が用いられ、１日４錠服用されている。この錠剤はアビラテロン酢酸エステルの含有量が、約３５質量％と低く、長径１６ｍｍ、短径９．６ｍｍ、厚さ６．３ｍｍ、総質量７３６ｍｇの大きな錠剤である。 When abiraterone acetate is used as an active ingredient in a therapeutic agent for castration-resistant prostate cancer, 1,000 mg of abiraterone acetate should be orally administered to adults once daily under fasting conditions in combination with prednisolone. Currently, as described above, tablets containing 250 mg of abiraterone acetate per tablet are used, and 4 tablets are taken daily. This tablet has a low abiraterone acetate content of about 35% by mass, and is a large tablet with a major axis of 16 mm, a minor axis of 9.6 mm, a thickness of 6.3 mm, and a total mass of 736 mg.
　アビラテロン酢酸エステルについては、経口アベイラビリティーの低い難溶性の薬剤であることから、薬剤の溶解速度を高めるために、所定の粉砕化合物や促進剤と共にアビラテロン酢酸エステルを粉砕して得られるアビラテロン酢酸エステルのナノ微粒子を用いることが開示されている（特許文献１）。また、特許文献１においても具体的に記載されている錠剤中のアビラテロン酢酸エステルの含有量は、約１５質量％と市販の錠剤よりもさらに低く、有効成分の含有率や錠剤のサイズについての議論は一切なされていない。 Abiraterone acetate is a poorly soluble drug with low oral availability. The use of nanoparticles has been disclosed (Patent Document 1). In addition, the content of abiraterone acetate in the tablet, which is specifically described in Patent Document 1, is about 15% by mass, which is even lower than that of the commercially available tablet. nothing has been done.
特開２０１８－１３５３５１号公報JP 2018-135351 A
　しかし、非特許文献１記載の錠剤では、上述したとおりサイズが大きく服用性に問題があり、また、１日４錠も服用しなければならないため、患者のコンプライアンスが得られ難いという問題がある。 However, the tablet described in Non-Patent Document 1 has a problem of ease of administration due to its large size as described above, and also has a problem that it is difficult to obtain patient compliance because four tablets must be taken a day.
　また、本発明者らの研究により、アビラテロン酢酸エステルの含有率を高めた小型の錠剤では、可溶化剤の含有率も上昇し、これによりゲル化が生じ、溶出率に影響を及ぼすという問題が見出された。 In addition, according to the studies of the present inventors, small tablets with a high content of abiraterone acetate also have a high content of a solubilizer, which causes gelation and affects the dissolution rate. Found.
　そこで、本開示においては、服用性を向上させるために、よりアビラテロン酢酸エステルの含有率を高めた小型の錠剤であって、良好な溶出特性を示す錠剤を提供することを課題とする。 Therefore, an object of the present disclosure is to provide a small tablet with a higher content of abiraterone acetate and exhibiting good dissolution characteristics in order to improve ease of administration.
　本発明者らが、上記課題を検討した結果、メタケイ酸アルミン酸塩を流動化剤として加えることにより、良好な溶出特性を有するアビラテロン酢酸エステルの含有率の高い小型の錠剤を提供できること見出した。 As a result of examining the above problems, the present inventors found that small tablets with a high abiraterone acetate content and good dissolution properties can be provided by adding an aluminate metasilicate as a fluidizing agent.
　すなわち、本開示は、
［１］有効成分としてのアビラテロン酢酸エステルを錠剤全体の質量に対して５５～９５質量％、好ましくは５５～９０質量％、６５～９５質量％、６５～９０質量％、７５～９５質量％、または７５～９０質量％と、可溶化剤と、メタケイ酸アルミン酸塩とを含む錠剤、
［２］錠剤全体の質量が４２０ｍｇ以下、好ましくは２６０～４２０ｍｇである上記［１］記載の錠剤、
［３］可溶化剤を錠剤全体の質量に対して０．１～３０質量％、好ましくは０．１～２０質量％、０．１～１５質量％、０．１～１０質量％、０．１～７質量％、０．５～３０質量％、０．５～２０質量％、０．５～１５質量％、０．５～１０質量％、０．５～７質量％、１～３０質量％、１～２０質量％、より好ましくは１～１５質量％、１～１０質量％、１～７質量％、さらに好ましくは３～３０質量％、３～２０質量％、３～１５質量％、３～１０質量％、または３～７質量％含む上記［１］または［２］記載の錠剤、ならびに
［４］メタケイ酸アルミン酸塩が、アビラテロン酢酸エステルおよび可溶化剤を含有する造粒物の外部に存在する上記［１］～［３］のいずれかに記載の錠剤
に関する。 That is, the present disclosure
[1] 55 to 95 mass%, preferably 55 to 90 mass%, 65 to 95 mass%, 65 to 90 mass%, 75 to 95 mass% of abiraterone acetate as an active ingredient relative to the mass of the whole tablet; or a tablet containing 75-90% by mass, a solubilizer and an aluminometasilicate,
[2] The tablet according to [1] above, wherein the mass of the entire tablet is 420 mg or less, preferably 260 to 420 mg,
[3] 0.1 to 30% by mass, preferably 0.1 to 20% by mass, 0.1 to 15% by mass, 0.1 to 10% by mass, 0.1 to 10% by mass of a solubilizer based on the mass of the whole tablet 1-7% by mass, 0.5-30% by mass, 0.5-20% by mass, 0.5-15% by mass, 0.5-10% by mass, 0.5-7% by mass, 1-30% by mass %, 1 to 20% by mass, more preferably 1 to 15% by mass, 1 to 10% by mass, 1 to 7% by mass, more preferably 3 to 30% by mass, 3 to 20% by mass, 3 to 15% by mass, The tablet according to [1] or [2] above containing 3 to 10% by mass, or 3 to 7% by mass, and [4] granulated product containing metasilicate aluminate containing abiraterone acetate and a solubilizer It relates to the tablet according to any one of [1] to [3], which exists externally.
　本開示によれば、有効成分であるアビラテロン酢酸エステルと可溶化剤とともに、流動化剤としてメタケイ酸アルミン酸塩を用いることにより、良好な溶出特性を有し、有効成分であるアビラテロン酢酸エステルを錠剤全体の質量に対して５５～９５質量％含有させたアビラテロン酢酸エステルの含有率の高い小型の錠剤を提供することができ、患者の服用性を向上させることができる。 According to the present disclosure, by using the active ingredient abiraterone acetate and the solubilizer together with the metasilicate aluminate as a fluidizing agent, it has good dissolution characteristics, and the active ingredient abiraterone acetate is tableted. It is possible to provide small tablets containing 55 to 95% by mass of the total mass of abiraterone acetate at a high content rate, and improve patient compliance.
実施例１～３のアビラテロン酢酸エステルの溶出率（％）を示すグラフである。1 is a graph showing the elution rate (%) of abiraterone acetate in Examples 1-3.
　本開示の錠剤は、有効成分としてのアビラテロン酢酸エステルを錠剤全体の質量に対して５５～９５質量％と、可溶化剤と、メタケイ酸アルミン酸塩とを含むものである。流動化剤としてメタケイ酸アルミン酸塩を用いることにより、錠剤の小型化により含有率の上昇したアビラテロン酢酸エステルおよび可溶化剤に起因すると考えられる溶出時のゲル化が抑制され、良好な溶出特性を得ることができる。メタケイ酸アルミン酸塩は、多孔性で錠剤中に水を引き込む性質を有し、メタケイ酸アルミン酸塩を含有させることでゲル化が抑制され、錠剤の崩壊・溶出特性が維持されて良好な溶出特性が得られるものと考えられる。得られる錠剤の良好な溶出特性は、既に市販されているアビラテロン酢酸エステルを含有する錠剤と同様であることが好ましく、具体的には、日本薬局方溶出試験法に従い、溶出試験液として日本薬局方溶出試験第一液（ｐＨ１．２）を用いてパドル法により、溶出溶媒の容積９００ｍＬ、温度３７±０．５℃、パドル速度７５ｒｐｍの条件下で溶出試験を行った場合に、溶出時間３０分で好ましくは３０～６５％、より好ましくは３５～６０％、溶出時間６０分で好ましくは７０～９５％、より好ましくは７５～９５％となる溶出特性であることが望ましい。 The tablet of the present disclosure contains 55 to 95% by mass of abiraterone acetate as an active ingredient relative to the mass of the entire tablet, a solubilizer, and a metasilicate aluminate. By using metasilicate aluminate as a glidant, gelation during dissolution, which is thought to be caused by the increased content of abiraterone acetate and the solubilizer due to the downsizing of tablets, is suppressed, resulting in good dissolution characteristics. Obtainable. Alumina metasilicate is porous and has the property of drawing water into the tablet. By containing aluminate metasilicate, gelation is suppressed and disintegration and dissolution properties of the tablet are maintained, resulting in good dissolution. It is considered that the characteristics can be obtained. The good dissolution characteristics of the resulting tablet are preferably the same as those of tablets containing abiraterone acetate which are already on the market. When the dissolution test was conducted by the paddle method using the dissolution test first solution (pH 1.2) under the conditions of a dissolution solvent volume of 900 mL, a temperature of 37 ± 0.5 ° C, and a paddle speed of 75 rpm, the dissolution time was 30 minutes. is preferably 30 to 65%, more preferably 35 to 60%, and an elution time of 60 minutes is preferably 70 to 95%, more preferably 75 to 95%.
　錠剤中のアビラテロン酢酸エステルの含有量は、錠剤全体の質量に対して５５質量％以上であり、６５質量％以上が好ましく、７５質量％以上がより好ましい。アビラテロン酢酸エステルの含有量が、錠剤全体の質量に対して５５質量％未満であると、十分に錠剤を小型化することができず、服用性を向上し難い傾向がある。また、錠剤中のアビラテロン酢酸エステルの含有量は、錠剤全体の質量に対して９５質量％以下であり、９０質量％以下が好ましい。アビラテロン酢酸エステルの含有量が、錠剤全体の質量に対して９５質量％より多いと、アビラテロン酢酸エステルの密度が高いために溶解速度が遅延する傾向がある。 The content of abiraterone acetate in the tablet is 55% by mass or more, preferably 65% by mass or more, more preferably 75% by mass or more, relative to the mass of the entire tablet. If the content of abiraterone acetate is less than 55% by mass relative to the mass of the entire tablet, the tablet cannot be sufficiently miniaturized, and it tends to be difficult to improve the ease of administration. The content of abiraterone acetate in the tablet is 95% by mass or less, preferably 90% by mass or less, relative to the mass of the entire tablet. When the content of abiraterone acetate is more than 95% by mass relative to the mass of the entire tablet, the dissolution rate tends to be delayed due to the high density of abiraterone acetate.
　本開示の錠剤は、服用性の観点から錠剤全体の質量が４２０ｍｇ以下であることが好ましく、２６０～４２０ｍｇであることがより好ましい。 The tablet of the present disclosure preferably has a mass of 420 mg or less, more preferably 260 to 420 mg, from the viewpoint of ease of administration.
　メタケイ酸アルミン酸塩は、特に限定されるものではないが、メタケイ酸アルミン酸マグネシウムなどが用いられ、市販品としては富士化学工業（株）製のノイシリン（登録商標）などを用いることができる。メタケイ酸アルミン酸塩の錠剤中の含有量は、特に限定されるものではないが、通常、錠剤の全質量に対し、崩壊性の観点から０．１質量％以上が好ましく、０．５質量％以上がより好ましく、１．０質量％以上がさらに好ましい。また、錠剤中のメタケイ酸アルミン酸塩の含有量は、通常、錠剤の全質量に対し、流動性の観点から２０質量％以下が好ましく、１０質量％以下がより好ましく、５質量％以下がさらに好ましい。 The metasilicate aluminate is not particularly limited, but magnesium aluminometasilicate and the like are used, and Neusilin (registered trademark) manufactured by Fuji Chemical Industry Co., Ltd. can be used as a commercially available product. The content of the metasilicate aluminate in the tablet is not particularly limited, but is generally preferably 0.1% by mass or more, preferably 0.5% by mass, based on the total mass of the tablet from the viewpoint of disintegration. The above is more preferable, and 1.0% by mass or more is even more preferable. In addition, the content of metasilicate aluminate in the tablet is usually preferably 20% by mass or less, more preferably 10% by mass or less, and further preferably 5% by mass or less from the viewpoint of fluidity, relative to the total mass of the tablet. preferable.
　可溶化剤としては、特に限定されるものではないが、例えばラウリル硫酸ナトリウム、ジオクチルスルホコハク酸ナトリウムなどのアニオン系界面活性剤、ポリオキシエチレングリコールソルビタンアルキルエステル類（例えばポリソルベート８０等）、ポリエチレングリコール類などのノニオン系界面活性剤、その他各種界面活性剤などが挙げられる。なかでも一般的に可溶化能が比較的高い点、また有効成分が塩基性薬物である点からラウリル硫酸ナトリウムなどのアニオン系界面活性剤が好ましく、ラウリル硫酸ナトリウムがより好ましい。可溶化剤は、単独で使用してもよく、２種以上混合して用いてもよい。 Examples of solubilizers include, but are not limited to, anionic surfactants such as sodium lauryl sulfate and sodium dioctylsulfosuccinate, polyoxyethylene glycol sorbitan alkyl esters (eg, polysorbate 80), and polyethylene glycols. and other nonionic surfactants, and various other surfactants. Among them, anionic surfactants such as sodium lauryl sulfate are preferred, and sodium lauryl sulfate is more preferred, because they generally have a relatively high solubilizing ability and the active ingredient is a basic drug. The solubilizers may be used alone or in combination of two or more.
　可溶化剤の錠剤中の含有量は、錠剤におけるアビラテロン酢酸エステルやメタケイ酸アルミン酸塩の含有量に応じて異なり、特に限定されるものではないが、通常、錠剤の全質量に対し、溶解性の観点から０．１質量％以上が好ましく、０．５質量％以上がより好ましく、１質量％以上がさらに好ましく、３質量％以上が特に好ましい。また、可溶化剤の錠剤中の含有量は、通常、錠剤の全質量に対し、崩壊性の観点から３０質量％以下が好ましく、２０質量％以下がより好ましく、１５質量％以下がさらに好ましく、１０質量％以下が特に好ましく、７質量％以下がなおさらに好ましい。 The content of the solubilizing agent in the tablet varies depending on the content of abiraterone acetate and metasilicate aluminate in the tablet, and is not particularly limited. From the viewpoint of , the content is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, still more preferably 1% by mass or more, and particularly preferably 3% by mass or more. In addition, the content of the solubilizer in the tablet is usually preferably 30% by mass or less, more preferably 20% by mass or less, and further preferably 15% by mass or less from the viewpoint of disintegration, relative to the total mass of the tablet. 10% by mass or less is particularly preferred, and 7% by mass or less is even more preferred.
　本開示の錠剤には、有効成分であるアビラテロン酢酸エステル、可溶化剤、およびメタケイ酸アルミン酸塩以外に、例えば、崩壊剤、結合剤、賦形剤、甘味剤、香料、メタケイ酸アルミン酸塩以外の流動化剤、滑沢剤、矯味剤、着色剤、界面活性剤など、この分野で通常使用される添加剤を含むことができる。また、本開示の錠剤は、フィルムコーティング錠であってもよい。本開示の錠剤をフィルムコーティング錠とする場合、本開示の錠剤には、上記添加剤に加えてさらにフィルムコーティング層を形成するフィルムコーティング基剤などを含むことができる。 The tablet of the present disclosure contains, in addition to the active ingredients abiraterone acetate, solubilizer, and metasilicate aluminate, for example, disintegrants, binders, excipients, sweeteners, flavors, and metasilicate aluminate. Additives commonly used in this field, such as fluidizing agents, lubricants, flavoring agents, coloring agents, and surfactants, may be included. Tablets of the present disclosure may also be film-coated tablets. When the tablet of the present disclosure is a film-coated tablet, the tablet of the present disclosure can further contain a film coating base that forms a film coating layer in addition to the above excipients.
　崩壊剤は、Ｓｗｅｌｌｉｎｇタイプの崩壊剤とＷｉｃｋｉｎｇタイプの崩壊剤とに大別される。Ｓｗｅｌｌｉｎｇタイプの崩壊剤は、崩壊剤自体は水に不溶であるが崩壊剤の内部に崩壊剤が有する空隙よりも大量の水を取り込んで膨潤し、その膨潤力で錠剤の構造を破壊し、さらに水が次々に粒子間に浸透するため、錠剤は噴火するように微粉化しながら分散崩壊すると考えられる。Ｗｉｃｋｉｎｇタイプの崩壊剤は、接触角が小さいため水の浸潤速度が速く、水が崩壊剤の表面を伝わって錠剤内部に浸透し、粒子間の結合力を低下させることで、錠剤はひび割れ状に崩壊すると考えられる。本開示の錠剤では、メタケイ酸アルミン酸塩を用いることが特徴であり、加えてＳｗｅｌｌｉｎｇタイプの崩壊剤とＷｉｃｋｉｎｇタイプの崩壊剤のいずれも使用することができ、特に限定されるものではない。 Disintegrants are roughly classified into Swelling type disintegrants and Wicking type disintegrants. Swelling-type disintegrants are insoluble in water, but the disintegrant itself swells by taking in a larger amount of water than the voids of the disintegrant, and the swelling force destroys the structure of the tablet. Since water permeates between the particles one after another, it is thought that the tablet disperses and disintegrates while pulverizing like an eruption. Wicking-type disintegrants have a small contact angle, so water permeates quickly through the surface of the disintegrant and penetrates into the inside of the tablet. thought to collapse. The tablet of the present disclosure is characterized by the use of metasilicate aluminate, and in addition, both Swelling type disintegrant and Wicking type disintegrant can be used, and are not particularly limited.
　Ｓｗｅｌｌｉｎｇタイプの崩壊剤としては、クロスカルメロースナトリウム、カルメロースカルシウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、カルボキシメチルスターチナトリウム、ヒドロキシプロピルスターチなどが挙げられる。なかでも、クロスカルメロースナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロースから選択されることが好ましい。Ｗｉｃｋｉｎｇタイプの崩壊剤としては、部分α化デンプン、カルメロース、トウモロコシデンプン、結晶セルロースなどが挙げられる。これら崩壊剤は単独で用いてもよいし、２種以上を併用してもよい。 Swelling-type disintegrants include croscarmellose sodium, carmellose calcium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl starch, and the like. Among them, it is preferably selected from croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose. Wicking-type disintegrants include partially pregelatinized starch, carmellose, corn starch, microcrystalline cellulose, and the like. These disintegrants may be used alone or in combination of two or more.
　崩壊剤を使用する場合の錠剤中の含有量は、特に限定されるものではないが、錠剤の全質量に対し、０．０１質量％以上が好ましく、０．１質量％以上がより好ましく、１質量％以上がさらに好ましく、１０質量％以上が特に好ましい。崩壊剤の錠剤の全質量に対し、３０質量％以下が好ましく、２５質量％以下がより好ましく、２０質量％以下がさらに好ましい。 Content in the tablet when using a disintegrant is not particularly limited, relative to the total weight of the tablet, preferably 0.01 wt% or more, more preferably 0.1 wt% or more, 1 % by mass or more is more preferable, and 10% by mass or more is particularly preferable. The disintegrant is preferably 30% by mass or less, more preferably 25% by mass or less, and even more preferably 20% by mass or less, relative to the total mass of the tablet.
　結合剤としては、特に限定されるものではないが、ヒドロキシプロピルセルロース、ポビドン、ポリビニルアルコール、ヒプロメロース、メチルセルロース、ヒドロキシエチルセルロース、ゼラチン、寒天、アルギン酸ナトリウム、デキストリン、キサンタンガム、アラビアゴム末、部分けん化ポリビニルアルコールおよびプルランなどが挙げられる。なかでも、ヒドロキシプロピルセルロース、ポビドン、ポリビニルアルコールおよびヒプロメロースからなる群より選択される少なくとも１種のものであることが好ましく、ヒドロキシプロピルセルロース、ポビドンおよびポリビニルアルコールから選択される少なくとも１種であることがより好ましく、特にヒドロキシプロピルセルロースが好ましい。これらは単独で用いてもよいし、２種以上を併用してもよい。 Binders include, but are not limited to, hydroxypropyl cellulose, povidone, polyvinyl alcohol, hypromellose, methyl cellulose, hydroxyethyl cellulose, gelatin, agar, sodium alginate, dextrin, xanthan gum, gum arabic powder, partially saponified polyvinyl alcohol and and pullulan. Among them, it is preferably at least one selected from the group consisting of hydroxypropyl cellulose, povidone, polyvinyl alcohol and hypromellose, and at least one selected from hydroxypropyl cellulose, povidone and polyvinyl alcohol. Hydroxypropylcellulose is more preferred, and hydroxypropylcellulose is particularly preferred. These may be used independently and may use 2 or more types together.
　結合剤を併用する場合、その錠剤中の含有量は、特に限定されるものではないが、錠剤の全質量に対し、０．０１質量％以上が好ましく、０．１質量％以上がより好ましく、１質量％以上がさらに好ましい。また、錠剤中の結合剤の含有量は、特に限定されるものではないが、錠剤の全質量に対し、２０質量％以下が好ましく、１０質量％以下がより好ましく、５質量％以下がさらに好ましい。 When a binder is used in combination, the content in the tablet is not particularly limited, but is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, based on the total mass of the tablet. 1 mass % or more is more preferable. The content of the binder in the tablet is not particularly limited, but is preferably 20% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less, relative to the total mass of the tablet. .
　賦形剤としては、特に限定されるものではないが、例えばセルロース類（結晶セルロース、エチルセルロースなど）およびその誘導体、糖（ブドウ糖、乳糖、白糖、精製白糖、粉糖、トレハロース、デキストラン、デキストリンやそれらの水和物など）、糖アルコール（Ｄ－マンニトール、キシリトール、ソルビトール、エリスリトールなど）、グリセリン脂肪酸エステル、無機粉体（合成ヒドロタルサイト）、無水リン酸カルシウム、沈降炭酸カルシウム、ケイ酸カルシウム、リン酸水素カルシウム水和物、炭酸水素ナトリウムなどの無機塩が挙げられる。なかでも結晶セルロースなどのセルロース類、乳糖や乳糖水和物などの糖が好ましい。賦形剤は、単独で使用してもよく、２種以上混合して用いてもよい。 Examples of excipients include, but are not limited to, celluloses (crystalline cellulose, ethyl cellulose, etc.) and derivatives thereof, sugars (glucose, lactose, sucrose, refined sucrose, powdered sugar, trehalose, dextran, dextrin, and others). hydrate, etc.), sugar alcohol (D-mannitol, xylitol, sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (synthetic hydrotalcite), anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, hydrogen phosphate Inorganic salts such as calcium hydrate and sodium bicarbonate are included. Celluloses such as crystalline cellulose and sugars such as lactose and lactose hydrate are particularly preferred. Excipients may be used alone or in combination of two or more.
　賦形剤を使用する場合の錠剤中の含有量は、錠剤におけるアビラテロン酢酸エステルやその他の添加剤の含有量に応じて異なり、特に限定されるものではないが、錠剤の全質量に対し、０．１～３０質量％が好ましく、０．５～２０質量％がより好ましい。 When using excipients, the content in the tablet varies depending on the content of abiraterone acetate and other additives in the tablet, and is not particularly limited. .1 to 30% by mass is preferred, and 0.5 to 20% by mass is more preferred.
　メタケイ酸アルミン酸塩以外の流動化剤としては、特に限定されるものではないが、例えばケイ酸カルシウムなどのケイ酸塩、軽質無水ケイ酸などの無水ケイ酸、含水二酸化ケイ素、タルク、酸化チタン、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウムなどが挙げられる。これらは単独で使用してもよく、２種以上混合して用いてもよい。 Fluidizing agents other than aluminate metasilicate are not particularly limited, and examples include silicates such as calcium silicate, silicic anhydride such as light anhydrous silicic acid, hydrated silicon dioxide, talc, and titanium oxide. , stearic acid, magnesium stearate, calcium stearate and the like. These may be used alone or in combination of two or more.
　メタケイ酸アルミン酸塩以外の流動化剤を使用する場合の錠剤中の含有量は、メタケイ酸アルミン酸塩の含有量によっても異なるが、上述の粉体である又は造粒物中に含まれるアビラテロン酢酸エステルや種々の添加剤が、錠剤の製造においてスムーズに流動できる程度の添加量であればよく、これは用いる流動化剤の種類に応じて異なるため、特に限定されるものではないが、通常、錠剤の全質量に対し、０．１～１０質量％が好ましく、０．５～５質量％がより好ましい。 When using a glidant other than aluminate metasilicate, the content in the tablet varies depending on the content of the aluminate metasilicate, but the above-mentioned powder or abiraterone contained in the granules Acetic acid esters and various additives may be added in an amount that allows smooth flow in the production of tablets, and this varies depending on the type of glidant used, so it is not particularly limited, but usually , with respect to the total weight of the tablet, preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight.
　滑沢剤としては、特に限定されるものではないが、例えばステアリン酸、フマル酸ステアリルナトリウム、ステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステル、ポリエチレングリコール、硬化油、グリセリン脂肪酸エステル、タルクなどが挙げられる。なかでも滑沢性が高い点からステアリン酸マグネシウムが好ましい。これらは単独で使用してもよく、２種以上混合して用いてもよい。 Examples of lubricants include, but are not limited to, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, hydrogenated oil, glycerol fatty acid esters, and talc. be done. Among them, magnesium stearate is preferable because of its high lubricity. These may be used alone or in combination of two or more.
　滑沢剤を使用する場合の錠剤中の含有量は、上述のアビラテロン酢酸エステルや種々の添加剤が錠剤を製造する装置（杵や臼）に付着することが抑制できる程度の量であり、これは用いる滑沢剤の種類に応じて異なるため、特に限定されるものではないが、通常、錠剤の全質量に対し、０．１～１０質量％が好ましく、０．５～５質量％がより好ましい。 When a lubricant is used, the content in the tablet is an amount that can suppress adhesion of the above-mentioned abiraterone acetate and various additives to the tablet manufacturing equipment (punches and dies). Although it is not particularly limited because it varies depending on the type of lubricant used, it is usually preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, based on the total mass of the tablet. preferable.
　本開示の錠剤はフィルムコーティング基剤を使用し、錠剤の表面に被膜を施したフィルムコーティング錠とすることができ、それにより、苦みや悪臭のマスキング、水分、光または酸素などの外的条件からの主薬の安定性向上、外観の改善と商品価値の増加などの効果を期待することができる。 The tablet of the present disclosure uses a film-coating base, and can be a film-coated tablet in which a film is applied to the surface of the tablet, thereby masking bitterness and malodor, and protecting against external conditions such as moisture, light, or oxygen. It can be expected to have effects such as improved stability of the main drug, improved appearance, and increased commercial value.
　フィルムコーティング基剤としては、特に限定されるものではないが、ヒドロキシプロピルセルロース、ヒプロメロース、カルメロースナトリウム、アクリル酸エチル・メタクリル酸メチルコポリマー分散液、ポリビニルピロリドン、ポリビニルアルコール、ポリオキシエチレンポリオキシプロピレングリコールなどの高分子を用いることができる。フィルムコーティング基剤には、必要に応じてポリエチレングリコール、プロピレングリコール、トリアセチン、クエン酸トリエチルなどの可塑剤、酸化チタン、三二酸化鉄、アルミニウムレーキなどの着色剤、カルナウバロウなどの光沢化剤などを適宜添加することができる。 Film coating bases include, but are not limited to, hydroxypropyl cellulose, hypromellose, carmellose sodium, ethyl acrylate/methyl methacrylate copolymer dispersion, polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol. Polymers such as can be used. Film coating bases may optionally contain plasticizers such as polyethylene glycol, propylene glycol, triacetin and triethyl citrate, colorants such as titanium oxide, iron sesquioxide and aluminum lake, and brightening agents such as carnauba wax. can be added.
　本開示の錠剤をフィルムコーティング錠とする場合のフィルムコーティング層の質量は、錠剤全体を被覆できる程度の量であれば、特に限定されるものではないが、通常、服用後に錠剤中のアビラテロン酢酸エステルを速やかに溶出させる点から、錠剤中のフィルムコーティング層以外の部分の質量を１００質量部とした場合、その０．１～５質量部とすることが好ましく、その１～５質量部とすることがより好ましい。 When the tablet of the present disclosure is a film-coated tablet, the mass of the film-coating layer is not particularly limited as long as it is an amount that can cover the entire tablet. From the viewpoint of quickly eluting, when the mass of the portion other than the film coating layer in the tablet is 100 parts by mass, it is preferably 0.1 to 5 parts by mass, and 1 to 5 parts by mass. is more preferred.
　本開示の錠剤は、去勢抵抗性前立腺癌および内分泌療法未治療のハイリスクの予後因子を有する前立腺癌などの治療に有用である。 The tablet of the present disclosure is useful for treatment of castration-resistant prostate cancer and endocrine therapy-naive prostate cancer with high-risk prognostic factors.
　本開示の錠剤の服用量は、本技術分野の常識の範囲内であれば特に限定されるものではなく、例えば去勢抵抗性前立腺癌治療については、成人１日当たりアビラテロン酢酸エステル換算で５００ｍｇ～１０００ｍｇ、特に例えば１０００ｍｇであり、１日当たりの服用量を１～４回に分けて服用することができる。 The dose of the tablet of the present disclosure is not particularly limited as long as it is within the scope of common knowledge in the technical field. In particular, it is, for example, 1000 mg, and can be administered in 1 to 4 divided doses per day.
（錠剤の製造方法）
　錠剤の製造方法としては、本技術分野において一般的な方法を用いることができ、特に限定されるものではない。例えば、アビラテロン酢酸エステルおよび可溶化剤を混合造粒し、得られた造粒物にメタケイ酸アルミン酸塩を混合し、打錠することにより製造することができる。この際、アビラテロン酢酸エステルおよび可溶化剤とともに、結合剤及び崩壊剤もあわせて造粒することが好ましく、さらにメタケイ酸アルミン酸塩とともに滑沢剤を混合することが好ましい。造粒方法は、特に限定されるものではなく、乾式造粒および湿式造粒など、製剤分野において通常使用される造粒法を用いることができる。打錠方法は、特に限定されるものではなく、例えば、打錠用臼、打錠用上杵および下杵を用いて、油圧式ハンドプレス機、単発式打錠機、ロータリー式打錠機などにより行う方法などを用いることができる。打錠は、得られる錠剤が適度な硬度を有するような打錠圧で行えばよく、打錠圧は、打錠方法、打錠に用いる機器、錠剤の大きさなどに応じて適宜調整される。 (Tablet manufacturing method)
As a method for producing tablets, a general method in this technical field can be used, and there is no particular limitation. For example, it can be produced by mixing and granulating abiraterone acetate and a solubilizer, mixing the resulting granules with aluminate metasilicate, and compressing into tablets. At this time, it is preferable to granulate a binder and a disintegrant together with the abiraterone acetate and the solubilizer, and furthermore, it is preferable to mix a lubricant together with the aluminate metasilicate. The granulation method is not particularly limited, and granulation methods commonly used in the pharmaceutical field, such as dry granulation and wet granulation, can be used. The tableting method is not particularly limited. For example, using a tableting die, upper and lower tableting punches, a hydraulic hand press machine, a single-shot tableting machine, a rotary tableting machine, etc. and the like can be used. Tableting may be performed at a tableting pressure such that the resulting tablet has an appropriate hardness, and the tableting pressure is appropriately adjusted according to the tableting method, the equipment used for tableting, the size of the tablet, and the like. .
　得られる錠剤の形状は、特に限定されるものではなく、例えば、円盤状、ドーナツ状、多角形板状、球状、楕円状、カプレット状などの形状とすることができる。大きさは、小型である方が好ましく、例えば楕円状の場合は、長径が８～１５ｍｍ程度、短径が５～１２ｍｍ程度、厚みが３～８ｍｍ程度であることが好ましい。また、円形の場合は、直径が５～１５ｍｍ程度、厚みが２．５～６ｍｍ程度であることが好ましい。 The shape of the tablet to be obtained is not particularly limited, and may be, for example, disk-shaped, doughnut-shaped, polygonal plate-shaped, spherical, elliptical, or caplet-shaped. The size is preferably small. For example, in the case of an elliptical shape, it is preferable that the long axis is about 8 to 15 mm, the short axis is about 5 to 12 mm, and the thickness is about 3 to 8 mm. In the case of a circular shape, it is preferable that the diameter is about 5 to 15 mm and the thickness is about 2.5 to 6 mm.
（フィルムコーティング方法）
　フィルムコーティング方法としては、本技術分野において使用されている通常のフィルムコーティング錠剤の製造方法を用いることができる。例えば、アビラテロン酢酸エステルを含む錠剤（素錠）をフィルムコーティング機に仕込み、上記フィルムコーティング剤や添加物を水やエタノールなどの有機溶媒、またはそれらの混合溶液（例えば、水／エタノール混液）などの適切な溶媒に溶解または分散したコーティング液を錠剤に噴霧し、乾燥することによりコーティングすることができる。 (Film coating method)
As a film-coating method, a conventional film-coated tablet production method used in this technical field can be used. For example, a tablet (uncoated tablet) containing abiraterone acetate is charged into a film coating machine, and the film coating agent and additives are added to an organic solvent such as water or ethanol, or a mixed solution thereof (e.g., water / ethanol mixture). Tablets can be coated by spraying a coating liquid dissolved or dispersed in an appropriate solvent and drying the tablets.
　以下、本開示を実施例にもとづき具体的に説明するが、本開示はこれらの実施例に限定されることを意図するものではない。 The present disclosure will be specifically described below based on examples, but the present disclosure is not intended to be limited to these examples.
　実施例において使用した試薬の詳細を以下に記載する。
アビラテロン酢酸エステル
ラウリル硫酸ナトリウム：日局ＸＶＩＩ
ヒドロキシプロピルセルロース（ＨＰＣ）ＳＬ（数平均分子量：１０×１０4）：日局ＸＶＩＩ
低置換度ヒドロキシプロピルセルロース（Ｌ－ＨＰＣ）：日局ＸＶＩＩ
ステアリン酸マグネシウム：日局ＸＶＩＩ
メタケイ酸アルミン酸マグネシウム：日局ＸＶＩＩ　ノイシリン（登録商標）富士化学工業（株）製 Details of the reagents used in the examples are described below.
Abiraterone acetate Sodium lauryl sulfate: JP XVII
Hydroxypropyl cellulose (HPC) SL (number average molecular weight: 10×10 4 ): JP XVII
Low-substituted hydroxypropyl cellulose (L-HPC): JP XVII
Magnesium stearate: JP XVII
Magnesium aluminometasilicate: Nissho XVII Neusilin (registered trademark) manufactured by Fuji Chemical Industry Co., Ltd.
　上記において、日局ＸＶＩＩとは第十七改正日本薬局方を表す。 In the above, the Japanese Pharmacopoeia XVII represents the 17th revision of the Japanese Pharmacopoeia.
実施例１～３
　表１の処方に従い、アビラテロン酢酸エステルおよび低置換度ヒドロキシプロピルセルロースを撹拌造粒機（ＦＭ－ＶＧ－０５、（株）パウレック製）に投入し、粉末を混合した。ラウリル硫酸ナトリウム、ヒドロキシプロピルセルロース－ＳＬおよび水を混合した造粒液を加えて造粒した。得られた造粒顆粒を流動層造粒乾燥機（ＦＤ－ＭＩＮＩ、（株）パウレック製）で給気温度８０℃にて排気温度３４℃まで乾燥後、整粒機（コーミル、（株）パウレック製（１３９７μｍ））で整粒し整粒顆粒を得た。得られた整粒顆粒にメタケイ酸アルミン酸マグネシウムおよびステアリン酸マグネシウムを加え、ポリ袋で混合し、ロータリー打錠機（ＶＩＲＧ０５１２ＳＳ２ＡＺ、（株）菊水製作所製）にて、長径１２．８ｍｍ、短径７．７ｍｍ、厚さ５．３ｍｍに圧縮成型し、錠剤を得た。 Examples 1-3
According to the formulation in Table 1, abiraterone acetate and low-substituted hydroxypropyl cellulose were put into a stirring granulator (FM-VG-05, manufactured by Powrex Co., Ltd.) to mix the powders. Granulation was carried out by adding a granulation liquid obtained by mixing sodium lauryl sulfate, hydroxypropylcellulose-SL and water. After drying the obtained granules with a fluid bed granulator dryer (FD-MINI, manufactured by Powrex Co., Ltd.) at an air supply temperature of 80 ° C. and an exhaust temperature of 34 ° C., a granule sizing machine (Comil, Powrex Co., Ltd.) (1397 μm)) to obtain regulated granules. Magnesium aluminometasilicate and magnesium stearate were added to the obtained sized granules, mixed in a plastic bag, and compressed with a rotary tableting machine (VIRG0512SS2AZ, manufactured by Kikusui Seisakusho Co., Ltd.) to give a tablet having a major diameter of 12.8 mm and a minor diameter of 7. It was compressed to 0.7 mm and 5.3 mm thick to give tablets.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
試験例１：溶出特性試験
　実施例１～３で製造した直後の錠剤について、日本薬局方溶出試験法に従い、溶出試験機（商品名：ＮＴＲ－６０００シリーズ、富山産業（株）製）において、溶出試験液として日本薬局方溶出試験第一液（ｐＨ１．２）を用いてパドル法により実施した。試験条件は、溶出溶媒の容積９００ｍＬ、温度３７±０．５℃、パドル速度７５ｒｐｍとした。結果は、図１および表２に平均値で示す。 Test Example 1: Dissolution property test The tablets immediately after production in Examples 1 to 3 were dissolved in a dissolution tester (trade name: NTR-6000 series, manufactured by Toyama Sangyo Co., Ltd.) according to the dissolution test method of the Japanese Pharmacopoeia. The paddle method was used using the Japanese Pharmacopoeia dissolution test liquid 1 (pH 1.2) as the test liquid. The test conditions were a volume of dissolution medium of 900 mL, a temperature of 37±0.5° C., and a paddle speed of 75 rpm. The results are shown in Figure 1 and Table 2 as mean values.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　図１および表２より、メタケイ酸アルミン酸塩を可溶化剤と共に含有するアビラテロン酢酸エステル錠剤は、溶出時間３０分および６０分でそれぞれ３０～６５％および７０～９５％の範囲内であり、良好な溶出特性を示すことがわかる。 From FIG. 1 and Table 2, the abiraterone acetate tablets containing metasilicate aluminate together with the solubilizer were in the range of 30-65% and 70-95% at the dissolution times of 30 minutes and 60 minutes, respectively, indicating good results. It can be seen that it exhibits excellent elution characteristics.

Claims (4)

  1. 有効成分としてのアビラテロン酢酸エステルを錠剤全体の質量に対して５５～９５質量％と、可溶化剤と、メタケイ酸アルミン酸塩とを含む錠剤。 A tablet containing abiraterone acetate as an active ingredient in an amount of 55 to 95% by mass relative to the total mass of the tablet, a solubilizer, and an aluminate metasilicate.
  2. 錠剤全体の質量が４２０ｍｇ以下である請求項１記載の錠剤。 2. The tablet according to claim 1, wherein the weight of the whole tablet is 420 mg or less.
  3. 可溶化剤を錠剤全体の質量に対して０．１～３０質量％含む請求項１または２記載の錠剤。 3. The tablet according to claim 1 or 2, which contains 0.1 to 30% by mass of the solubilizer relative to the total mass of the tablet.
  4. メタケイ酸アルミン酸塩が、アビラテロン酢酸エステルおよび可溶化剤を含有する造粒物の外部に存在する請求項１～３のいずれか１項に記載の錠剤。 The tablet according to any one of claims 1 to 3, wherein the aluminometasilicate is present outside the granules containing abiraterone acetate and solubilizer.
PCT/JP2022/015807 2021-04-01 2022-03-30 Abiraterone acetate-containing tablet WO2022210829A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2023511455A JPWO2022210829A1 (en) 2021-04-01 2022-03-30

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021-062993 2021-04-01
JP2021062993 2021-04-01

Publications (1)

Publication Number Publication Date
WO2022210829A1 true WO2022210829A1 (en) 2022-10-06

Family

ID=83456526

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/015807 WO2022210829A1 (en) 2021-04-01 2022-03-30 Abiraterone acetate-containing tablet

Country Status (2)

Country Link
JP (1) JPWO2022210829A1 (en)
WO (1) WO2022210829A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005139168A (en) * 2003-10-15 2005-06-02 Fuji Chem Ind Co Ltd Composition for tablet quickly disintegrating in oral cavity
WO2020004630A1 (en) * 2018-06-29 2020-01-02 中外製薬株式会社 Pharmaceutical composition containing poorly-soluble basic medicine
JP2020169143A (en) * 2019-04-04 2020-10-15 ニプロ株式会社 Tablets containing azilsartan
JP2021024865A (en) * 2019-08-07 2021-02-22 沢井製薬株式会社 Abiraterone acetate-containing preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005139168A (en) * 2003-10-15 2005-06-02 Fuji Chem Ind Co Ltd Composition for tablet quickly disintegrating in oral cavity
WO2020004630A1 (en) * 2018-06-29 2020-01-02 中外製薬株式会社 Pharmaceutical composition containing poorly-soluble basic medicine
JP2020169143A (en) * 2019-04-04 2020-10-15 ニプロ株式会社 Tablets containing azilsartan
JP2021024865A (en) * 2019-08-07 2021-02-22 沢井製薬株式会社 Abiraterone acetate-containing preparation

Also Published As

Publication number Publication date
JPWO2022210829A1 (en) 2022-10-06

Similar Documents

Publication Publication Date Title
JP6092936B2 (en) Method for producing orally disintegrating tablets
JP4757872B2 (en) Tablet formulation with extended release comprising pramipexole or a pharmaceutically acceptable salt thereof, process for its production and use thereof
JP5680898B2 (en) Fast disintegrating tablets with reduced bitterness
JP5401327B2 (en) Tablets with improved dissolution
JP2008214334A (en) Coated medicine-containing particle and solid preparation containing particle
EP2754438B2 (en) Coating composition, drug-containing particle, solid preparation and method for preparing drug-containing particle
JP6915258B2 (en) Pharmaceutical composition particles, orally disintegrating preparation containing them, method for producing pharmaceutical composition particles
JP5511663B2 (en) Method for producing spherical fine particles containing tamsulosin hydrochloride
JP2023036924A (en) Pharmaceutical composition containing lenalidomide
JP2023071921A (en) Lenalidomide oral tablet composition in various doses
WO2022210829A1 (en) Abiraterone acetate-containing tablet
JP6924177B2 (en) Pharmaceutical composition particles and orally disintegrating preparation containing them
US20100172982A1 (en) Sustained release formulations of divalproex sodium
JP4716063B2 (en) Unpleasant taste masking particles and oral preparations containing the same
CA3145459A1 (en) Pharmaceutical composition of darolutamide
JP2010001242A (en) Rebamipide solid preparation, and method for producing the same
JP2022042886A (en) Pharmaceutical preparation comprising abiraterone acetate
JP6920564B1 (en) Solid formulation
JP2021070658A (en) Abiraterone acetate-containing preparation
JP2021070659A (en) Abiraterone acetate-containing preparation
JP6077459B2 (en) Solid preparation
JP5919173B2 (en) Sustained release ambroxol hydrochloride orally disintegrating tablets
JP2017075138A (en) Dienogest-containing tablet
JP2022103591A (en) Timed-releasable granules and applications thereof
EP3545951A1 (en) Oral tablet composition comprising dexlansoprazole, oral tablet comprising same and method for manufacturing same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22781040

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2023511455

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22781040

Country of ref document: EP

Kind code of ref document: A1