JP2018502130A - Dutasteride composition in tablet form with improved stability - Google Patents
Dutasteride composition in tablet form with improved stability Download PDFInfo
- Publication number
- JP2018502130A JP2018502130A JP2017537224A JP2017537224A JP2018502130A JP 2018502130 A JP2018502130 A JP 2018502130A JP 2017537224 A JP2017537224 A JP 2017537224A JP 2017537224 A JP2017537224 A JP 2017537224A JP 2018502130 A JP2018502130 A JP 2018502130A
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- Prior art keywords
- dutasteride
- pharmaceutical composition
- solid pharmaceutical
- producing
- propylene glycol
- Prior art date
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- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940080350 sodium stearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- -1 sucrose ester Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 229920001221 xylan Polymers 0.000 description 1
- 150000004823 xylans Chemical class 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
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- 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
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- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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Abstract
本発明は、安定性が改善された錠剤形態のデュタステリド組成物に関する。より詳しくは、本発明に係る錠剤形態のデュタステリド組成物は、安定化剤として硬質無水ケイ酸を含み、デュタステリド製剤の製造工程中に類縁物質の発生を防止することにより、優れた安定性を示すデュタステリド錠剤に関する。【選択図】図１The present invention relates to a dutasteride composition in tablet form with improved stability. More specifically, the tablet-form dutasteride composition according to the present invention includes hard silicic acid as a stabilizer and exhibits excellent stability by preventing the generation of related substances during the manufacturing process of the dutasteride preparation. It relates to dutasteride tablets. [Selection] Figure 1
Description
本発明は、デュタステリドを含有する錠剤形態の組成物に関する。 The present invention relates to a composition in tablet form containing dutasteride.
デュタステリド（Ｄｕｔａｓｔｅｒｉｄｅ）は、下記化学式１で表示される化合物であって、命名法によると、１７β−Ｎ−［２，５−ビス（トリフルオロメチル）］フェニルカルバモイル−４−アザ−５α−アンドロスト−１−エン−３−オン化合物と呼ばれる。
デュタステリドは、男性ホルモンであるテストステロンを男性型脱毛症と良性前立腺肥大症の原因物質であるジヒドロテストステロンに変換させる５α還元酵素の作用を阻害することにより、良性前立腺肥大症（ｂｅｎｉｇｎ ｐｒｏｓｔａｔｉｃ ｈｙｐｅｒｐｌａｓｉａ）及び男性型脱毛症（ａｎｄｒｏｇｅｎｅｔｉｃ ａｌｏｐｅｃｉａ）の治療に使用される。 Dutasteride inhibits the action of 5α reductase, which converts male hormone testosterone into dihydrotestosterone, the causative agent of androgenetic alopecia and benign prostatic hypertrophy, thereby causing benign prostatic hyperplasia and men Used in the treatment of androgenetic alopecia.
一般に、デュタステリドは、２４２〜２５０℃の融点を有する白色粉末の形態であり（特許文献１）、エタノールに４４ｍｇ／ｍＬ、メタノールに６４ｍｇ／ｍＬ、ポリエチレングリコール４００に３ｍｇ／ｍＬ、水には０．０３８ｎｇ／ｍＬの溶解度を示す難溶性薬物である（ＡＶＯＤＡＲＴ（登録商標）、ＦＤＡ ｃｌｉｎｉｃａｌ ｐｈａｒｍａｃｏｌｏｇｙ ｂｉｏｐｈａｒｍａｃｅｕｔｉｃｓ ｒｅｖｉｅｗ）。また、デュタステリドは、主に酸化と加水分解によって分解されることが知られている［非特許文献１］。 In general, dutasteride is in the form of a white powder having a melting point of 242-250 ° C. (Patent Document 1), 44 mg / mL for ethanol, 64 mg / mL for methanol, 3 mg / mL for polyethylene glycol 400, and 0. It is a poorly soluble drug that exhibits a solubility of 038 ng / mL (AVODART®, FDA clinical pharmacology biopharmaceuticals reviews). In addition, it is known that dutasteride is decomposed mainly by oxidation and hydrolysis [Non-Patent Document 1].
このような特性を持つデュタステリドは、アボダート（ＡＶＯＤＡＲＴ（登録商標）、Ｇｌａｘｏｓｍｉｔｈｋｌｉｎｅ）という商品名で市販されている。アボダートは、デュタステリドを安定化（ｓｔａｂｉｌｉｚａｔｉｏｎ）させるとともに、経口投与時に胃腸管内で吸収できるように可溶化（ｓｏｌｕｂｉｌｉｚａｔｉｏｎ）させた医薬品であって、０．５ｍｇのデュタステリドとブチル化ヒドロキシトルエン（酸化及び加水分解に対する安定化剤として）０．０３５ｍｇを、油相であるカプリン酸／カプリル酸のモノ・ジグリセリド３４９．５ｍｇに溶解した後、ゼラチンからなる軟質カプセル（ｓｏｆｔ ｇｅｌａｔｉｎ ｃａｐｓｕｌｅ）に充填して市販されている［ＡＶＯＤＡＲＴ（登録商標）、ＦＤＡ ｃｈｅｍｉｓｔｒｙ ｒｅｖｉｅｗ］。 Dutasteride having such characteristics is commercially available under the trade name Avodate (registered trademark), Glaxosmithline. Avodate is a pharmaceutical product that stabilizes dutasteride and is solubilized so that it can be absorbed in the gastrointestinal tract upon oral administration, and 0.5 mg of dutasteride and butylated hydroxytoluene (oxidized and hydrolyzed) 0.035 mg) (as a stabilizer against the above) is dissolved in 349.5 mg of caprylic acid / caprylic acid mono-diglyceride as an oil phase, and then filled in a soft capsule made of gelatin. [AVODART (registered trademark), FDA chemistry review].
しかし、アボダートは、軟質カプセルの主成分であるゼラチンの熱及び水分に対する感受性のため、保管中に１）カプセル皮膜の軟化及び硬化による性状変形、２）カプセル皮膜の粘着性増加によるカプセル間の付着、３）カプセル皮膜の破裂による内容液の流出、及び４）内容液と皮膜との反応によるゼラチン架橋化に起因する崩壊遅延などの現象が現れることにより、医薬品として必ず必要な保管中の安定性が低下する危険性が非常に高い。 However, Avodate is sensitive to heat and moisture of gelatin, which is the main component of soft capsules, so during storage 1) property deformation due to softening and hardening of the capsule film, and 2) adhesion between capsules due to increased adhesion of the capsule film. 3) Stability during storage that is always necessary for pharmaceutical products due to the appearance of phenomena such as the outflow of the content liquid due to the rupture of the capsule film, and 4) the delay of disintegration due to gelatin crosslinking due to the reaction between the content liquid and the film. The risk of lowering is very high.
また、デュタステリドの酸化に対する分解を防ぐために、安定化剤としてアボダートに添加されているブチル化ヒドロキシトルエン（Ｂｕｔｙｌａｔｅｄ ｈｙｄｒｏｘｙｌ ｔｏｌｕｅｎｅ）は、フェノール誘導体の一種であって、発癌性、喘息及び乳幼児の行動障害を引き起こす可能性について議論が絶えず［非特許文献２］、医薬品においてもその使用量が制限されている物質である。 In addition, butylated hydroxytoluene added to Avodate as a stabilizer to prevent the degradation of dutasteride against oxidation is a kind of phenol derivative, which is carcinogenic, asthma and behavioral disorder of infants. There is a constant debate about the possibility of causing it [Non-Patent Document 2], and the amount of its use in pharmaceuticals is also restricted.
このため、軟質カプセル剤形であるアボダート（ＡＶＯＤＡＲＴ（登録商標））が持っている欠点を克服するためのデュタステリド含有固形製剤への剤形変更に関する研究が盛んに行われてきた。 For this reason, research on the dosage form change to a dutasteride-containing solid preparation for overcoming the drawbacks of Avodate (AVODART (registered trademark)), which is a soft capsule dosage form, has been actively conducted.
特許文献２には、デュタステリド、吸着剤、賦形剤、水溶性高分子及び水不溶性高分子の混合物を含む１次コーティング液、及び水不溶性高分子を含む２次コーティング液を含むデュタステリドの固形化製剤が開示されている。上記の技術は、デュタステリド、界面活性剤であるポロキサマー、及び油性の可溶化剤であるモノカプリル酸プロピレングリコールを全てエタノールに溶解した後、これをケイ化微結晶セルロースと二酸化ケイ素からなる吸着剤に吸着させることにより、錠剤を製造することを特徴とする。しかし、このようなエタノールの使用は、製造工程中にデュタステリドの結晶性を変化させる可能性があり、これにより製造工程及び保管中にデュタステリド類縁物質の発生が加速化されて安定性が不良になるおそれがあり、必ずブチル化ヒドロキシトルエンなどの安定化剤が一緒に使用されなければならないという欠点がある。 Patent Document 2 discloses dutasteride, adsorbent, excipient, primary coating solution containing a mixture of a water-soluble polymer and a water-insoluble polymer, and solidification of dutasteride containing a secondary coating solution containing a water-insoluble polymer. A formulation is disclosed. In the above technology, all of dutasteride, surfactant poloxamer, and oil-based solubilizer propylene glycol monocaprylate are dissolved in ethanol, and then converted into an adsorbent composed of silicified microcrystalline cellulose and silicon dioxide. It is characterized by manufacturing a tablet by making it adsorb | suck. However, the use of such ethanol may change the crystallinity of dutasteride during the manufacturing process, which accelerates the generation of dutasteride-related substances during the manufacturing process and storage, resulting in poor stability. There is a disadvantage that a stabilizer such as butylated hydroxytoluene must be used together.
特許文献３には、デュタステリドの可溶化のための自己乳化組成物とこれから製造された錠剤について開示されている。上記の特許では、デュタステリドを多量の界面活性剤と油性の可溶化剤に溶解させて自己乳化エマルジョン組成物を製造し、これをエタノールと混合して得られた混合溶液を希釈剤、崩壊剤などの吸着剤に加えてデュタステリドを固形化することをその製造方法とする。前記自己乳化エマルジョン組成物は、水との接触時に、デュタステリドを含有する油性の可溶化剤が１０００ｎｍ以下の小さな油滴として自発的に分散する乳剤を形成させるために、ポロキサマー、スクロースエステルなどの界面活性剤を多量含有しなければならないという欠点がある。しかし、界面活性剤は、粘膜に対する刺激性があり、人体への服用時に胃腸障害などが発生するおそれがあるので、毎日服用しなければならないデュタステリドなどの薬物を、多量の界面活性剤が含有された自己乳化エマルジョン組成物に製剤化することは不適切である。 Patent Document 3 discloses a self-emulsifying composition for solubilizing dutasteride and a tablet produced therefrom. In the above patent, a self-emulsifying emulsion composition is prepared by dissolving dutasteride in a large amount of a surfactant and an oil-based solubilizer, and this is mixed with ethanol to obtain a diluent, a disintegrant, and the like. In addition to the adsorbent, solidification of dutasteride is the production method. The self-emulsifying emulsion composition has an interface such as poloxamer, sucrose ester, etc. in order to form an emulsion in which an oil-based solubilizer containing dutasteride spontaneously disperses as small oil droplets of 1000 nm or less upon contact with water. There is a disadvantage that a large amount of active agent must be contained. However, since surfactants are irritating to mucous membranes and may cause gastrointestinal disorders when taken to the human body, they contain drugs such as dutasteride that must be taken daily and contain a large amount of surfactants. It is inappropriate to formulate a self-emulsifying emulsion composition.
特許文献４は、デュタステリドをオイル状の可溶化剤に溶解させた後、吸着剤に吸着させて製造された固形の吸着物製造方法を提案している。こうして得られた吸着物を賦形剤の混合物に配合した後、水または有機溶媒を用いて製造された結合液を用いて湿式顆粒法で錠剤を製造する。このような製造方法は、可溶化剤に溶解させたデュタステリドを吸着させる段階と、結合液を用いて湿式顆粒を製造する段階が区分されていることが、特許文献２及び３で提示した方法と相違する。しかし、一般に、デュタステリドの可溶化剤は、油性の液体なので、固形製剤の製造のためにはその使用量が出来る限り最小限に抑えられなければならない。したがって、デュタステリドを溶解させた少量の可溶化剤を直接吸着剤に吸着させて固形化する場合、吸着物内でデュタステリドの含量が均一に分布し難い。このため、特許文献２及び３では、デュタステリドを均質に含有する固形の吸着物を製造するために、油性の可溶化剤であるモノカプリル酸プロピレングリコールに対して５倍量以上のエタノールを希釈溶媒として用いて吸着剤に均質にデュタステリドを吸着させる。しかし、特許文献４のように、デュタステリドを油性の可溶化剤に溶解させた溶液のみではデュタステリドを均質に吸着させ難いので、市販製品であるアボダート（登録商標）レベルの含量均一性を確保することが難しい。 Patent Document 4 proposes a method for producing a solid adsorbate produced by dissolving dutasteride in an oil-like solubilizer and then adsorbing it on an adsorbent. After blending the adsorbate thus obtained in a mixture of excipients, tablets are produced by a wet granulation method using a binding solution produced using water or an organic solvent. In such a production method, it is described in Patent Documents 2 and 3 that the step of adsorbing dutasteride dissolved in a solubilizing agent and the step of producing wet granules using a binding solution are classified. Is different. However, in general, since the solubilizer of dutasteride is an oily liquid, the amount used must be minimized as much as possible for the production of solid preparations. Therefore, when a small amount of solubilizing agent in which dutasteride is dissolved is directly adsorbed on the adsorbent and solidified, it is difficult to uniformly distribute the content of dutasteride in the adsorbate. For this reason, in Patent Documents 2 and 3, in order to produce a solid adsorbate that contains dutasteride in a homogeneous manner, 5 times or more of ethanol is diluted with propylene glycol monocaprylate, which is an oil-based solubilizer, as a diluting solvent. Used to adsorb dutasteride homogeneously to the adsorbent. However, as in Patent Document 4, it is difficult to uniformly adsorb dutasteride only with a solution in which dutasteride is dissolved in an oil-based solubilizing agent, so that the content uniformity of Avodate (registered trademark) level, which is a commercial product, is ensured. Is difficult.
軟質カプセル剤形の欠点を補完するための別の試みである特許文献５では、前述した技術とは異なり、オイル状の可溶化剤の使用を排除し、乾式顆粒または湿式顆粒を適用して錠剤を製造する方法を具体的に記述している。油性の可溶化剤を使用しないことにより、上記の発明で提供する顆粒組成物は、デュタステリドを粉末状に含有し、このような方法で提供される組成物は、難溶性薬物であるデュタステリドの十分な生体利用率を得難いという欠点がある。これに加えて、実際に、特許文献５ではいずれの生体利用率評価結果も提示されていない。 In Patent Document 5, which is another attempt to compensate for the disadvantages of the soft capsule dosage form, unlike the technique described above, the use of oil-type solubilizer is eliminated, and dry granules or wet granules are applied to tablets. The method of manufacturing is specifically described. By not using an oil-based solubilizer, the granule composition provided in the above invention contains dutasteride in the form of a powder, and the composition provided by such a method is sufficient for dutasteride, which is a poorly soluble drug. Has a drawback that it is difficult to obtain a high bioavailability. In addition to this, in fact, Patent Document 5 does not present any biological utilization rate evaluation results.
そこで、本発明者らは、有機溶剤であるエタノール及びブチル化ヒドロキシトルエンなどの人体に有害な安定化剤を使用せず、軟質カプセルよりも優れた保管安定性を有するデュタステリド含有固形製剤の製造方法を確立した。本発明では、デュタステリドを含む油相及び／または別途の水相溶液に硬質無水ケイ酸を懸濁させ、これらの溶液を均質に乳化させて得られた乳化液（ｅｍｕｌｓｉｏｎ）を崩壊剤、希釈剤などの固形の賦形剤に加えて湿式顆粒法で顆粒を製造した後、圧縮成形して製造される錠剤形態が、市販製品であるアボダート（登録商標）軟質カプセルよりも優れた保管安定性を示し、類縁物質の発生を最小限に抑え、優れた含量均一性を有することを確認することにより、本発明を完成した。 Therefore, the present inventors do not use stabilizers harmful to the human body, such as ethanol and butylated hydroxytoluene, which are organic solvents, and a method for producing a dutasteride-containing solid preparation having better storage stability than soft capsules Established. In the present invention, an emulsion obtained by suspending hard anhydrous silicic acid in an oil phase and / or a separate aqueous phase solution containing dutasteride and uniformly emulsifying these solutions is used as a disintegrant or diluent. In addition to solid excipients such as tablets, tablets produced by wet granulation and then compression-molded have better storage stability than Avodate (registered trademark) soft capsules, which are commercially available products. The present invention was completed by showing and confirming that it has excellent content uniformity with minimal generation of related substances.
本発明は、難溶性薬物であるデュタステリドを含有する固形製剤であって、人体に有害であると知られているブチル化ヒドロキシトルエンを安定化剤として使用しなくても類縁物質の発生を最小限に抑えて優れた保管安定性を示し、含量均一性を示す固形製剤、及びその製造方法を提供することを目的とする。 The present invention is a solid preparation containing dutasteride, a poorly soluble drug, and minimizes the generation of related substances without using butylated hydroxytoluene, which is known to be harmful to the human body, as a stabilizer. An object of the present invention is to provide a solid preparation exhibiting excellent storage stability and content uniformity, and a method for producing the same.
上記目的を達成するために、本発明は、デュタステリド、可溶化剤、及び安定化剤としての硬質無水ケイ酸を含む固形の薬学的組成物を用いて、固形製剤、特に錠剤形態の固形製剤の製造方法を提供する。 In order to achieve the above object, the present invention uses a solid pharmaceutical composition comprising dutasteride, a solubilizer, and hard silicic acid as a stabilizer, to form a solid preparation, particularly a solid preparation in tablet form. A manufacturing method is provided.
これに加えて、本発明は、上記の製造方法により製造される薬学的組成物を用いたデュタステリドを含む固形製剤を提供する。 In addition, the present invention provides a solid preparation containing dutasteride using the pharmaceutical composition produced by the production method described above.
本発明によって提供されるデュタステリド含有固形製剤の製造方法は、
（１）デュタステリド１重量部を可溶化剤２０〜６０重量部に溶解させた溶液の製造段階と、
（２）前記（１）段階で製造された溶液に硬質無水ケイ酸０．３〜１重量部を攪拌して懸濁させた溶液の製造段階と、
（３）別途の精製水１００〜１０００重量部に硬質無水ケイ酸５〜３０重量部を攪拌して懸濁させた溶液の製造段階と、
（４）前記（２）で製造された溶液と（３）で製造された溶液とを混合して乳化させた乳化液の製造段階と、
（５）前記（４）で製造された乳化液を崩壊剤、吸着剤、希釈剤などの固形の賦形剤の混合粉末に結合液として加えて混合・乾燥させた顆粒の製造段階と、
（６）前記（５）で製造された顆粒から通常の製造方法で固形製剤を製造する段階とを含んでなる、デュタステリド含有固形製剤の製造方法である。
A method for producing a dutasteride-containing solid preparation provided by the present invention includes:
(1) A production stage of a solution in which 1 part by weight of dutasteride is dissolved in 20 to 60 parts by weight of a solubilizing agent;
(2) A step of producing a solution obtained by stirring and suspending 0.3 to 1 part by weight of hard silicic acid in the solution produced in the step (1),
(3) A step for producing a solution in which 5 to 30 parts by weight of hard silicic acid is stirred and suspended in 100 to 1000 parts by weight of separate purified water;
(4) A step of producing an emulsion obtained by mixing and emulsifying the solution produced in (2) and the solution produced in (3),
(5) A step of producing granules in which the emulsion prepared in (4) above is added as a binding liquid to a mixed powder of solid excipients such as a disintegrant, an adsorbent, and a diluent, and mixed and dried.
(6) A method for producing a dutasteride-containing solid preparation comprising the step of producing a solid preparation from the granules produced in (5) by a conventional production method.
本発明の製造方法において、（２）段階または（３）段階のうちいずれか一つの段階でのみ硬質無水ケイ酸を懸濁させた後、（４）段階で乳化させる製造方法も本発明に含まれる。 In the production method of the present invention, the present invention also includes a production method in which the hard silicic acid is suspended only in any one of the steps (2) and (3) and then emulsified in the step (4). It is.
本発明において、硬質無水ケイ酸は、製造工程中にデュタステリドの類縁物質の発生を抑制することにより安定化効果を得るために添加されるものであり、硬質無水ケイ酸を懸濁させる工程は、（２）段階及び／または（３）段階、すなわち、可溶化剤混合溶液及び／または精製水に硬質無水ケイ酸を懸濁させる段階の製造方法によってデュタステリドの類縁物質の発生を抑制することにより安定化効果を持つ。 In the present invention, hard silicic acid is added in order to obtain a stabilizing effect by suppressing the generation of dutasteride-related substances during the production process, and the step of suspending hard silicic acid, Stable by inhibiting the generation of dutasteride-related substances by the production method of step (2) and / or step (3), that is, a step of suspending hard silicic acid in a solubilizer mixed solution and / or purified water Has an effect.
但し、安定化剤である硬質無水ケイ酸が（２）段階及び（３）段階の両方ともで含まれないか、或いは硬質無水ケイ酸が粉末状に（５）段階で添加される場合には、製造工程中にデュタステリドの類縁物質が発生するので、十分な安定化効果を示さない。 However, if the hard silicic acid as a stabilizer is not included in both the (2) stage and the (3) stage, or if the hard silicic acid is added to the powder in the (5) stage, Since a related substance of dutasteride is generated during the manufacturing process, it does not show a sufficient stabilizing effect.
本発明の（１）段階は、デュタステリドを可溶化剤に溶解させて有相溶液を製造するものである。デュタステリドを溶解させる可溶化剤の溶解度を考慮して、デュタステリド１重量部を可溶化剤２０〜６０重量部に溶解させるのが良い。 In the step (1) of the present invention, dutasteride is dissolved in a solubilizer to produce a phased solution. Considering the solubility of the solubilizer that dissolves dutasteride, 1 part by weight of dutasteride is preferably dissolved in 20 to 60 parts by weight of the solubilizer.
本発明において、（２）段階及び／または（３）段階で、すなわち、可溶化剤混合溶液及び／または精製水に硬質無水ケイ酸を懸濁させるとき、（２）段階ではデュタステリド１重量部当たり硬質無水ケイ酸０．３〜１重量部、（３）段階では精製水１００〜１０００重量部に硬質無水ケイ酸５〜３０重量部を懸濁させるのが良い。（２）段階でデュタステリド１重量部を含む可溶化剤溶液に硬質無水ケイ酸１重量部よりも多くの量で懸濁させるか、或いは（３）段階で精製水に硬質無水ケイ酸３０重量部より多くの量で懸濁させる場合には、以降の乳化段階で乳化液の粘度があまりにも強くなって湿式顆粒法で顆粒を製造することが難しいおそれがある。 In the present invention, in the step (2) and / or (3), that is, when hard silicic acid is suspended in the solubilizer mixed solution and / or purified water, in step (2), per 1 part by weight of dutasteride. It is preferable to suspend 5 to 30 parts by weight of hard silicic acid in 100 to 1000 parts by weight of purified water in 0.3 to 1 part by weight of hard silicic acid and in step (3). Suspend in a solubilizer solution containing 1 part by weight of dutasteride in step (2) in an amount greater than 1 part by weight of hard silicic acid, or 30 parts by weight of hard silicic acid in purified water in step (3) In the case of suspending in a larger amount, the viscosity of the emulsion becomes too strong in the subsequent emulsification stage, and it may be difficult to produce granules by the wet granulation method.
また、（３）段階の水相を用いた乳化工程なしで、（２）段階でデュタステリドを溶解させた油相を直接（５）段階の崩壊剤、希釈剤などの固形の賦形剤に加えて顆粒を製造する場合、デュタステリドの吸着が均一に起こらないため、含量の不均一な顆粒が製造される可能性がある。 Also, without the emulsification step using the aqueous phase in step (3), the oil phase in which dutasteride is dissolved in step (2) is added directly to solid excipients such as a disintegrant and diluent in step (5). In the case of producing granules, since dutasteride is not uniformly adsorbed, granules having a non-uniform content may be produced.
本発明において、「可溶化剤」は、有機溶剤であって、室温でデュタステリドに対する溶解度が１０ｍｇ／ｇ以上であることが好ましい。デュタステリドに対する溶解度が低い可溶化剤を使用する場合には、十分な可溶化効果を示すための可溶化剤の使用量が多くなり、これにより錠剤の大きさが大きくなるので好ましくない。前記デュタステリドに対する溶解度が１０ｍｇ／ｇ以上である可溶化剤の例としては、モノカプリル酸プロピレングリコール、モノラウリン酸プロピレングリコール、ジエチレングリコールモノエチルエーテル、モノカプリル酸グリセリル、モノカプリン酸グリセリル及びこれらの混合物よりなる群から選択できるが、これに限定されない。 In the present invention, the “solubilizing agent” is an organic solvent, and preferably has a solubility in dutasteride of 10 mg / g or more at room temperature. When a solubilizing agent having low solubility in dutasteride is used, the amount of the solubilizing agent used to show a sufficient solubilizing effect is increased, which increases the size of the tablet, which is not preferable. Examples of solubilizers having a solubility in dutasteride of 10 mg / g or more include propylene glycol monocaprylate, propylene glycol monolaurate, diethylene glycol monoethyl ether, glyceryl monocaprylate, glyceryl monocaprate, and mixtures thereof. Although it can select from a group, it is not limited to this.
一般に、可溶化剤は油性の液体であるため、デュタステリドに対する溶解度が低い可溶化剤は、デュタステリドの十分な可溶化効果を得るために、相対的に多くの量が使用されなければならない。しかし、このような液相の可溶化剤の添加量が多くなるほど、固形化に必要な吸着剤の量が増加し、さらには、固形化された後でも、可溶化剤が吸着剤から分離される場合が発生することもある。したがって、デュタステリドに対する溶解性に優れる可溶化剤の選定が重要である。 In general, since solubilizers are oily liquids, solubilizers with low solubility in dutasteride must be used in relatively large amounts to obtain a sufficient solubilizing effect of dutasteride. However, as the amount of such a liquid phase solubilizing agent increases, the amount of adsorbent necessary for solidification increases, and further, the solubilizer is separated from the adsorbent even after solidification. May occur. Therefore, it is important to select a solubilizer that is excellent in solubility in dutasteride.
本発明によって提供される固形の薬学的組成物は、薬学的に許容される賦形剤、例えば、崩壊剤以外にも、希釈剤、結合剤、滑沢剤またはコーティング基剤などを含むことができる。 The solid pharmaceutical composition provided by the present invention may contain a diluent, a binder, a lubricant or a coating base in addition to a pharmaceutically acceptable excipient, for example, a disintegrant. it can.
本発明で使用できる崩壊剤は、クロスポビドン、デンプングリコール酸ナトリウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロースなど、一般に、錠剤、硬質カプセル剤などの固形の製剤が水との接触時に迅速に崩壊されるようにするための目的で使用される物質、及びその混合物よりなる群から選択できるが、これに限定されない。 Disintegrants that can be used in the present invention include crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropylcellulose, etc. Generally, solid preparations such as tablets and hard capsules can be rapidly brought into contact with water. Although it can select from the group which consists of the substance used for the purpose for making it disintegrate, and its mixture, it is not limited to this.
本発明で使用できる希釈剤は、微結晶セルロース、粉末セルロース、糊化デンプン、乳糖水和物、マンニトール、ソルビトール、ホルマリン−カゼイン、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ）、キチン、キトサン、重合された寒天アクリルアミド、キシラン（ｘｙｌａｎ）、スメクタ（ｓｍｅｃｔａ）、キー−ジョ−クレイ（ｋｅｙ−ｊｏ−ｃｌａｙ）、架橋カルボキシグアー及び変性タピオカ澱粉、アルギン酸またはアルギン酸塩、ヒドロキシプロピルセルロース及びその他のセルロース誘導体、ポラクリリンカリウム、クロスカルメロースナトリウム（Ａｃ−Ｄｉ−Ｓｏｌ、ＣＬＤ−２）、デンプン、カルボキシメチルデンプン、ジェランガムなどである。 Diluents that can be used in the present invention are microcrystalline cellulose, powdered cellulose, gelatinized starch, lactose hydrate, mannitol, sorbitol, formalin-casein, low-substituted hydroxypropylcellulose (L-HPC), chitin, chitosan, polymerization Agar acrylamide, xylan, smecta, key-jo-clay, cross-linked carboxyguar and modified tapioca starch, alginic acid or alginates, hydroxypropylcellulose and other cellulose derivatives, Polacrilin potassium, croscarmellose sodium (Ac-Di-Sol, CLD-2), starch, carboxymethyl starch, gellan gum and the like.
本発明において、乳化液の固形化をより容易にするために使用できる吸着剤としては、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウムなどがある。 In the present invention, examples of the adsorbent that can be used to make the emulsion easier to solidify include calcium silicate and magnesium aluminate metasilicate.
本発明で使用できる結合剤は、ポリビニルピロリドン（ポビドン）、ビニルピロリドン及びその他のビニル誘導体の共重合体（コポビドン）、微結晶セルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ヒドロキシプロピルセルロースなどである。 Binders that can be used in the present invention include polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone), microcrystalline cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and the like.
本発明で使用できる滑沢剤は、ステアリン酸カルシウム、ステアリン酸マグネシウム、ステアリン酸、水素化植物油、タルク、石松子、カオリン、ワセリン、ステアリン酸ナトリウム、カカオ脂、サリチル酸ナトリウム、サリチル酸マグネシウム、ポリエチレングリコール４０００、ポリエチレングリコール６０００、流動パラフィン、水素添加大豆油、ステアリン酸アルミニウム、ステアリン酸亜鉛、ラウリル硫酸ナトリウム、酸化マグネシウム、マクロゴール、合成ケイ酸アルミニウム、無水ケイ酸、高級脂肪酸、高級アルコール、シリコン油、パラフィン油、ポリエチレングリコール脂肪酸エーテル、デンプン、塩化ナトリウム、酢酸ナトリウム、オレイン酸ナトリウムなどである。 Lubricants that can be used in the present invention include calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, stone matsuko, kaolin, petrolatum, sodium stearate, cocoa butter, sodium salicylate, magnesium salicylate, polyethylene glycol 4000, Polyethylene glycol 6000, liquid paraffin, hydrogenated soybean oil, aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, anhydrous silicic acid, higher fatty acid, higher alcohol, silicone oil, paraffin oil Polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate and the like.
本発明の製造方法は、市販製品であるアボダート（登録商標）を始めとして、従来開示されたデュタステリド含有製剤において人体に有害であると知られているブチル化ヒドロキシトルエンなどのフェノール系酸化防止剤を含有しないため安全性に優れるデュタステリド含有固形製剤を製造することができるだけでなく、市販製品であるアボダート（登録商標）よりも類縁物質の発生量が少なくて保管安定性に優れるうえ、保管中に性状変化に対する危険性がないという利点を有する。 The production method of the present invention includes phenolic antioxidants such as butylated hydroxytoluene that are known to be harmful to the human body in the conventionally disclosed dutasteride-containing preparations including Avodate (registered trademark) which is a commercial product. In addition to producing a solid preparation containing dutasteride that is superior in safety because it does not contain it, it produces less related substances than Avodate (registered trademark), a commercial product, and has excellent storage stability and properties during storage. Has the advantage of no risk to change.
また、本発明によって製造されるデュタステリド含有固形製剤は、含量均一性を向上させることができるため、製剤の含量偏差を最小化することができる。 Moreover, since the dutasteride-containing solid preparation produced by the present invention can improve the content uniformity, the content deviation of the preparation can be minimized.
以下、実施例によって本発明をさらに詳細に説明する。これらの実施例は、本発明を具体的に説明するためのもので、本発明の範囲を制限するものではない。 Hereinafter, the present invention will be described in more detail with reference to examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
＜実施例１乃至５＞結合剤なしに乳化液を結合液とする本発明に係るデュタステリド錠剤の製造
下記の実施例は、結合剤の使用なしにも、本発明の固形剤製造方法が実現可能であることを示すためのもので、顆粒の製造時に別途の結合剤なしに乳化液のみを結合液として製造した。
<Examples 1 to 5> Production of dutasteride tablet according to the present invention using an emulsified liquid as a binder without a binder The following examples can realize the method for producing a solid preparation of the present invention without using a binder. In order to show this, only an emulsion was produced as a binder without using a separate binder when the granules were produced.
可溶化剤としてモノカプリル酸プロピレングリコール及びジエチレングリコールモノエチルエーテルを用いて、下記表１の組成で下記の方法によってデュタステリド錠剤を製造し、それぞれ実施例１〜５とした。下記表１は１錠当たりの含量を示すものである。 Dutasteride tablets were produced by the following method with the composition shown in Table 1 below using propylene glycol monocaprylate and diethylene glycol monoethyl ether as solubilizers, and were designated as Examples 1 to 5, respectively. Table 1 below shows the content per tablet.
１）デュタステリドを、可溶化剤であるモノカプリル酸プロピレングリコールとジエチレングリコールモノエチルエーテルとの混合溶液に加え、機械式攪拌機（大韓科学ＨＴ−１２０ＤＸ）を用いて３００〜５００ｒｐｍで３０分間攪拌して溶解させた。 1) Add dutasteride to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether, which are solubilizers, and dissolve by stirring for 30 minutes at 300 to 500 rpm using a mechanical stirrer (Korean Science HT-120DX). I let you.
２）１）の溶液に硬質無水ケイ酸を加え、機械式攪拌機を用いて８００〜１０００ｒｐｍで攪拌して均質に懸濁させた。 2) Hard anhydrous silicic acid was added to the solution of 1), and the suspension was homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.
３）別途の精製水に硬質無水ケイ酸を加え、機械式攪拌機を用いて８００〜１０００ｒｐｍで攪拌して均質に懸濁させた。 3) Hard anhydrous silicic acid was added to separate purified water, and the suspension was homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.
４）３）の懸濁液を８００〜１０００ｒｐｍで攪拌し、２）の懸濁液を加えて乳化させて均質な乳化液（ｅｍｕｌｓｉｏｎ）を製造した。 4) The suspension of 3) was stirred at 800 to 1000 rpm, and the suspension of 2) was added and emulsified to produce a homogeneous emulsion.
５）４）の乳化液を、希釈剤である微結晶セルロース及びマンニトールと崩壊剤である低置換度ヒドロキシプロピルセルロースとの粉末混合物に結合液として加え、練合機（Ｈｉｇｈ Ｓｈｅａｒ Ｍｉｘｅｒ、Ｄｉｏｓｎａ）を用いて練り合わせた後、箱型乾燥機を用いて６０℃で１２時間乾燥させて顆粒を製造した。 5) The emulsion of 4) is added as a binder to a powder mixture of microcrystalline cellulose and mannitol as a diluent and low-substituted hydroxypropyl cellulose as a disintegrant, and a kneader (High Shear Mixer, Diosna) is added. After kneading together, it was dried at 60 ° C. for 12 hours using a box dryer to produce granules.
６）５）の顆粒を１８号のふるいに通して整粒し、ステアリン酸マグネシウムを加えて滑沢した。 6) The granules of 5) were sized through a No. 18 sieve, and magnesium stearate was added and lubricated.
７）６）の最終混合物を圧縮成形して錠剤を製造した。 7) The final mixture of 6) was compression molded to produce tablets.
８）７）の錠剤をオパドライイエロー（０３Ｂ６２００１７）でコーティングしてフィルムコーティング錠を製造した。 8) The tablet of 7) was coated with Opadry Yellow (03B620017) to produce a film-coated tablet.
＜実施例６乃至７＞結合剤として粉末状のヒドロキシプロピルセルロースを用いた本発明に係るデュタステリド錠剤の製造
モノカプリル酸プロピレングリコール及びジエチレングリコールモノエチルエーテルを可溶化剤として用い、結合剤としてヒドロキシプロピルセルロースを一緒に用いて、下記表２の組成で下記の方法によってデュタステリド錠剤を製造した。下記表２は１錠当たりの含量を示すものである。
<Examples 6 to 7> Production of dutasteride tablets according to the present invention using powdered hydroxypropylcellulose as a binder Propylene glycol monocaprylate and diethylene glycol monoethyl ether as solubilizers and hydroxypropylcellulose as a binder Were used together to produce dutasteride tablets with the composition shown in Table 2 below. Table 2 below shows the content per tablet.
１）実施例１の１）乃至４）と同様の方法で乳化液（ｅｍｕｌｓｉｏｎ）を製造した。 1) An emulsion was prepared in the same manner as in 1) to 4) of Example 1.
２）前記製造された乳化液を、希釈剤であるマンニトール及び微結晶セルロース、崩壊剤である低置換度ヒドロキシプロピルセルロース、及び結合剤であるヒドロキシプロピルセルロースなどの混合物に加えて、練合機を用いて練り合わせた後、箱型乾燥機を用いて６０℃で１２時間乾燥させることにより、湿式顆粒法で顆粒を製造した。 2) Add the produced emulsion to a mixture of mannitol and microcrystalline cellulose as diluents, low-substituted hydroxypropyl cellulose as disintegrant, and hydroxypropyl cellulose as binder, and kneading machine After kneading together, the granules were produced by a wet granulation method by drying at 60 ° C. for 12 hours using a box-type dryer.
３）以下、実施例１の６）乃至８）と同様の方法で製造してそれぞれ実施例６及び７とした。 3) Hereinafter, it manufactured by the method similar to 6) thru | or 8) of Example 1, and was set as Example 6 and 7, respectively.
＜実施例８＞結合剤としてヒドロキシプロピルセルロースを乳化液の水相に溶解させて用いた本発明に係るデュタステリド錠剤の製造
可溶化剤としてモノカプリル酸プロピレングリコールを用い、結合剤であるヒドロキシプロピルセルロースを水相に溶解させて添加する方式で用いて、下記表３の組成で下記の方法によってデュタステリド錠剤を製造した。下記表３は１錠当たりの含量を示すものである。
<Example 8> Production of a dutasteride tablet according to the present invention using hydroxypropylcellulose dissolved in an aqueous phase of an emulsion as a binder, and using propylene glycol monocaprylate as a solubilizer, hydroxypropylcellulose as a binder Was dissolved in an aqueous phase and added, and dutasteride tablets were produced by the following method with the composition shown in Table 3 below. Table 3 below shows the content per tablet.
１）デュタステリドを可溶化剤であるモノカプリル酸プロピレングリコールに加え、機械式攪拌機を用いて３００〜５００ｒｐｍで３０分間攪拌して溶解させた。 1) Dutasteride was added to propylene glycol monocaprylate as a solubilizing agent, and dissolved by stirring for 30 minutes at 300 to 500 rpm using a mechanical stirrer.
２）１）の溶液に硬質無水ケイ酸を加え、機械式攪拌機を用いて８００〜１０００ｒｐｍで攪拌して均質に懸濁させた。 2) Hard anhydrous silicic acid was added to the solution of 1), and the suspension was homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.
３）別途の精製水に結合剤であるヒドロキシプロピルセルロースを溶解させた後、安定化剤である硬質無水ケイ酸を加え、機械式攪拌機を用いて８００〜１０００ｒｐｍで攪拌して均質に懸濁させた。 3) After dissolving hydroxypropylcellulose as a binder in separate purified water, add hard anhydrous silicic acid as a stabilizer, and stir at 800-1000 rpm using a mechanical stirrer to suspend homogeneously. It was.
４）３）の懸濁液を８００〜１０００ｒｐｍで攪拌し、２）の懸濁液を加えて乳化させて均質な乳化液（ｅｍｕｌｓｉｏｎ）を製造した。 4) The suspension of 3) was stirred at 800 to 1000 rpm, and the suspension of 2) was added and emulsified to produce a homogeneous emulsion.
５）４）の乳化液を、希釈剤である微結晶セルロース及びマンニトールと、崩壊剤である低置換度ヒドロキシプロピルセルロースとの粉末混合物に結合液として加え、練合機（Ｈｉｇｈ Ｓｈｅａｒ Ｍｉｘｅｒ、Ｄｉｏｓｎａ）を用いて練り合わせた後、箱型乾燥機を用いて６０℃で１２時間乾燥させることにより顆粒を製造した。 5) The emulsion of 4) is added as a binder to a powder mixture of microcrystalline cellulose and mannitol as diluents and low-substituted hydroxypropylcellulose as disintegrant, and a kneader (High Shear Mixer, Diosna). After kneading using, granules were produced by drying at 60 ° C. for 12 hours using a box dryer.
６）以下、実施例１の６）乃至８）と同様の方法で製造して実施例８とした。 6) Hereinafter, Example 8 was produced in the same manner as in 6) to 8) of Example 1.
＜実施例９＞吸着剤としてケイ酸カルシウムを追加した本発明に係るデュタステリド錠剤の製造
可溶化剤としてモノカプリル酸プロピレングリコール及びジエチレングリコールモノエチルエーテルを用い、吸着剤としてケイ酸カルシウムを追加した表４の組成を用いて、下記の方法でデュタステリド錠剤を製造した。下記表４は１錠当たりの含量を示すものである。
<Example 9> Production of a dutasteride tablet according to the present invention to which calcium silicate was added as an adsorbent. Propylene glycol monocaprylate and diethylene glycol monoethyl ether were used as solubilizers, and calcium silicate was added as an adsorbent. Using this composition, dutasteride tablets were produced by the following method. Table 4 below shows the content per tablet.
１）実施例１の１）乃至４）の順序による方法と同様の方法で乳化液（ｅｍｕｌｓｉｏｎ）を製造した。 1) An emulsion was prepared in the same manner as in the order of 1) to 4) of Example 1.
２）前記製造された乳化液を、吸着剤であるケイ酸カルシウム、希釈剤であるマンニトール及び微結晶セルロース、崩壊剤である低置換度ヒドロキシプロピルセルロース、及び結合剤であるヒドロキシプロピルセルロースなどの混合物に加えて、練合機を用いて練り合わせた後、箱型乾燥機を用いて６０℃で１２時間乾燥させることにより、湿式顆粒法で顆粒を製造した。 2) Mix the emulsified liquid prepared above with calcium silicate as an adsorbent, mannitol and microcrystalline cellulose as a diluent, low substituted hydroxypropyl cellulose as a disintegrant, and hydroxypropyl cellulose as a binder. In addition, after kneading using a kneader, it was dried at 60 ° C. for 12 hours using a box dryer to produce granules by a wet granulation method.
３）以下、実施例１の６）乃至８）と同様の方法で製造して実施例９とした。 3) Hereinafter, Example 9 was prepared in the same manner as in 6) to 8) of Example 1.
＜実施例１０＞油相にのみ硬質無水ケイ酸を含ませて製造される本発明に係るデュタステリド錠剤の製造
硬質無水ケイ酸の添加方式に従う安定化効果を比較評価するために、油相にのみ硬質無水ケイ酸を含ませ、水相には硬質無水ケイ酸を添加していない下記表５の組成で、デュタステリド錠製を製造した。
<Example 10> Manufacture of a dutasteride tablet according to the present invention, which is produced by containing hard silicic acid only in the oil phase In order to compare and evaluate the stabilizing effect according to the method of adding hard silicic acid, only in the oil phase Dutasteride tablets were produced with the composition shown in Table 5 below, which contained hard silicic acid and no hard silicic acid was added to the aqueous phase.
１）実施例１の１）及び２）と同様の方法でデュタステリドを懸濁させた油相溶液を製造した。 1) An oil phase solution in which dutasteride was suspended was produced in the same manner as in 1) and 2) of Example 1.
２）精製水に前記製造された懸濁液を加えて乳化させることにより均質な乳化液（ｅｍｕｌｓｉｏｎ）を製造した。 2) A homogenous emulsion was prepared by adding the emulsified suspension to purified water and emulsifying it.
３）前記製造された乳化液を、希釈剤であるマンニトール及び微結晶セルロース、崩壊剤である低置換度ヒドロキシプロピルセルロース、及び結合剤であるヒドロキシプロピルセルロースなどの混合物に加えて、練合機を用いて練り合わせた後、箱型乾燥機を用いて６０℃で１２時間乾燥させることにより、湿式顆粒法で顆粒を製造した。 3) Add the produced emulsion to a mixture of mannitol and microcrystalline cellulose as diluents, low-substituted hydroxypropyl cellulose as disintegrant, and hydroxypropyl cellulose as binder, and kneading machine After kneading together, the granules were produced by a wet granulation method by drying at 60 ° C. for 12 hours using a box-type dryer.
４）以下、実施例１の６）乃至８）と同様の方法で製造してそれぞれ実施例１０とした。 4) Hereinafter, it manufactured by the method similar to 6) thru | or 8) of Example 1, and was set as Example 10, respectively.
＜実施例１１＞水相にのみ硬質無水ケイ酸を含ませて製造される本発明に係るデュタステリド錠剤の製造
硬質無水ケイ酸の添加方式による安定化効果を比較評価するために、水相にのみ硬質無水ケイ酸を含ませ、油相には硬質無水ケイ酸を添加していない下記表６の組成で、デュタステリド錠剤を製造した。
<Example 11> Manufacture of a dutasteride tablet according to the present invention produced by containing hard anhydrous silica only in the aqueous phase In order to compare and evaluate the stabilization effect by the addition method of hard anhydrous silicic acid, only in the aqueous phase Dutasteride tablets were produced with the composition shown in Table 6 below, which contained hard silicic acid and no hard silicic acid was added to the oil phase.
１）デュタステリドを、可溶化剤であるモノカプリル酸プロピレングリコールとジエチレングリコールモノエチルエーテルとの混合溶液に加えて、機械式攪拌機を用いて３００〜５００ｒｐｍで３０分間攪拌して溶解させた。 1) Dutasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether, which are solubilizers, and dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer.
２）別途の精製水に硬質無水ケイ酸を加え、機械式攪拌機を用いて８００〜１０００ｒｐｍで攪拌して均質に懸濁させた。 2) Hard silicic acid was added to separate purified water, and the mixture was stirred uniformly at 800 to 1000 rpm using a mechanical stirrer and suspended uniformly.
３）２）の懸濁液を８００〜１０００ｒｐｍで攪拌し、２）の溶液を加えて乳化させて均質な乳化液（ｅｍｕｌｓｉｏｎ）を製造した。 3) The suspension of 2) was stirred at 800 to 1000 rpm, and the solution of 2) was added and emulsified to produce a homogeneous emulsion.
４）前記製造された乳化液を、希釈剤であるマンニトール及び微結晶セルロース、崩壊剤である低置換度ヒドロキシプロピルセルロース、及び結合剤であるヒドロキシプロピルセルロースなどの混合物に加えて、練合機を用いて練り合わせた後、箱型乾燥機を用いて６０℃で１２時間乾燥させることにより、湿式顆粒法で顆粒を製造した。 4) Add the produced emulsion to a mixture of mannitol and microcrystalline cellulose as diluents, low-substituted hydroxypropylcellulose as disintegrant, and hydroxypropylcellulose as binder, and kneading machine After kneading together, the granules were produced by a wet granulation method by drying at 60 ° C. for 12 hours using a box-type dryer.
５）以下、実施例１の６）乃至８）と同様の方法で製造してそれぞれ実施例１１とした。 5) Hereinafter, it manufactured by the method similar to 6) thru | or 8) of Example 1, and was set as Example 11, respectively.
＜実施例１２及び１３＞本発明を用いたその他の固形製剤への製造
下記表７の組成で、デュタステリドを含有する硬質カプセル剤と顆粒剤を製造した。
<Examples 12 and 13> Production to other solid preparations using the present invention Hard capsules and granules containing dutasteride were produced with the compositions shown in Table 7 below.
１）デュタステリドを、可溶化剤であるモノカプリル酸プロピレングリコール及びジエチレングリコールモノエチルエーテルに加え、機械式攪拌機を用いて３００〜５００ｒｐｍで３０分間攪拌して溶解させた。 1) Dutasteride was added to propylene glycol monocaprylate and diethylene glycol monoethyl ether, which are solubilizers, and dissolved by stirring at 300 to 500 rpm for 30 minutes using a mechanical stirrer.
２）１）の溶液に硬質無水ケイ酸を加え、機械式攪拌機を用いて８００〜１０００ｒｐｍで攪拌して均質に懸濁させた。 2) Hard anhydrous silicic acid was added to the solution of 1), and the suspension was homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.
３）別途の精製水に硬質無水ケイ酸を加え、機械式攪拌機を用いて８００〜１０００ｒｐｍで攪拌して均質に懸濁させた。 3) Hard anhydrous silicic acid was added to separate purified water, and the suspension was homogeneously suspended by stirring at 800 to 1000 rpm using a mechanical stirrer.
４）３）の懸濁液を８００〜１０００ｒｐｍで攪拌し、２）の懸濁液を加えて乳化させることにより、均質な乳化液（ｅｍｕｌｓｉｏｎ）を製造した。 4) The suspension of 3) was stirred at 800 to 1000 rpm, and the suspension of 2) was added and emulsified to produce a homogeneous emulsion.
５）希釈剤であるマンニトール及び微結晶セルロース、崩壊剤である低置換度ヒドロキシプロピルセルロース、及び結合剤であるヒドロキシプロピルセルロースで製造した粉末混合物に、４）で製造された乳化液を結合液として加えて練り合わせた後、箱型乾燥機を用いて６０℃で１２時間乾燥させた。 5) To the powder mixture produced with mannitol and microcrystalline cellulose as diluents, low-substituted hydroxypropylcellulose as disintegrant, and hydroxypropylcellulose as binder, the emulsion produced in 4) as a binder In addition, after kneading, it was dried at 60 ° C. for 12 hours using a box dryer.
６）５）の顆粒を１８号のふるいに通して整粒して顆粒剤を製造し、これを実施例１２とした。 6) The granules of 5) were passed through a No. 18 sieve to prepare granules, which were designated as Example 12.
７）６）の整粒された顆粒にステアリン酸マグネシウムを加えて滑沢した後、３号の硬質ゼラチンカプセルに充填して硬質カプセル剤を製造し、これを実施例１３とした。 7) Magnesium stearate was added to the sized granules of 6) and lubricated, and then filled into No. 3 hard gelatin capsules to produce hard capsules.
＜比較例１＞安定化剤である硬質無水ケイ酸を含有していないデュタステリド錠剤の製造
硬質無水ケイ酸の添加方式による安定化効果を比較評価するために、硬質無水ケイ酸を含んでいない下記表８の組成で、デュタステリド錠剤を製造した。
<Comparative example 1> Manufacture of a dutasteride tablet which does not contain hard silicic acid as a stabilizer In order to comparatively evaluate the stabilizing effect by the addition method of hard silicic acid, the following does not contain hard silicic acid Dutasteride tablets were prepared with the composition in Table 8.
１）デュタステリドを、可溶化剤であるモノカプリル酸プロピレングリコールとジエチレングリコールモノエチルエーテルとの混合溶液に加え、機械式攪拌機を用いて３００〜５００ｒｐｍで３０分間攪拌して溶解させた。 1) Dutasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether, which are solubilizers, and dissolved by stirring for 30 minutes at 300 to 500 rpm using a mechanical stirrer.
２）前記溶液を８００〜１０００ｒｐｍで攪拌し、精製水に加えて乳化させることにより均質な乳化液（ｅｍｕｌｓｉｏｎ）を製造した。 2) The said solution was stirred at 800-1000 rpm, and it added to the purified water and emulsified, and the homogeneous emulsion (emulsion) was manufactured.
３）前記製造された乳化液に、希釈剤であるマンニトール及び微結晶セルロース、崩壊剤である低置換度ヒドロキシプロピルセルロース、及び結合剤であるヒドロキシプロピルセルロースを加えて練り合わせた後、箱型乾燥機を用いて６０℃で１２時間乾燥させることにより、湿式顆粒法で顆粒を製造した。 3) After adding and kneading mannitol and microcrystalline cellulose as diluents, low-substituted hydroxypropylcellulose as disintegrant and hydroxypropylcellulose as binder to the produced emulsion, a box dryer Were dried at 60 ° C. for 12 hours to produce granules by a wet granulation method.
４）以下、実施例１の６）乃至８）と同様の方法で製造して比較例１とした。 4) Hereinafter, Comparative Example 1 was produced by the same method as 6) to 8) of Example 1.
＜比較例２＞可溶化剤溶液をエタノールに希釈して製造したデュタステリド錠剤の製造
可溶化剤としてモノカプリル酸プロピレングリコールを用いてデュタステリドを溶解させた後、これを水相に乳化させずに、有機溶媒を用いて希釈した懸濁液を用いて、崩壊剤、希釈剤などの固形の賦形剤に加えて比較例２の錠剤を製造した。比較例２の組成は下記表９のとおりである。
<Comparative Example 2> Production of a dutasteride tablet produced by diluting a solubilizer solution in ethanol After dissolving dutasteride using propylene glycol monocaprylate as a solubilizer, without emulsifying this in an aqueous phase, Using a suspension diluted with an organic solvent, tablets of Comparative Example 2 were produced in addition to solid excipients such as a disintegrant and a diluent. The composition of Comparative Example 2 is as shown in Table 9 below.
１）デュタステリドを、可溶化剤であるモノカプリル酸プロピレングリコールとジエチレングリコールモノエチルエーテルとの混合溶液に加え、機械式攪拌機を用いて３００〜５００ｒｐｍで３０分間攪拌して溶解させた。 1) Dutasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether, which are solubilizers, and dissolved by stirring for 30 minutes at 300 to 500 rpm using a mechanical stirrer.
２）１）の溶液を８００〜１０００ｒｐｍで攪拌し、硬質無水ケイ酸を加えて懸濁させた。 2) The solution of 1) was stirred at 800 to 1000 rpm, and hard silicic acid was added and suspended.
３）別途に精製水とエタノールとの混合溶液を８００〜１０００ｒｐｍで攪拌し、硬質無水ケイ酸を懸濁させた。 3) Separately, a mixed solution of purified water and ethanol was stirred at 800 to 1000 rpm to suspend hard silicic acid.
４）２）と３）を混合して硬質無水ケイ酸の懸濁された混合溶液を製造した。 4) 2) and 3) were mixed to produce a mixed solution in which hard silicic acid was suspended.
５）４）の段階で製造された懸濁液を結合液として、希釈剤であるマンニトール及び微結晶セルロース、崩壊剤である低置換度ヒドロキシプロピルセルロース及び結合剤であるヒドロキシプロピルセルロースの粉末混合物に加えて練り合わせ、これを箱型乾燥機を用いて６０℃で１２時間乾燥させることにより、湿式顆粒法で顆粒を製造した。 5) Using the suspension produced in step 4) as a binder solution, a powder mixture of mannitol and microcrystalline cellulose as diluents, low-substituted hydroxypropylcellulose as disintegrant and hydroxypropylcellulose as binder In addition, the mixture was kneaded and dried at 60 ° C. for 12 hours using a box dryer to produce granules by a wet granulation method.
６）以下、実施例１の６）乃至８）と同様の方法で製造して比較例２とした。 6) Hereinafter, Comparative Example 2 was produced by the same method as 6) to 8) of Example 1.
＜比較例３＞可溶化剤を直接固形の賦形剤に吸着させた錠剤の製造
水との混和性が不良な可溶化剤としてモノカプリル酸プロピレングリコールを用いてデュタステリドを溶解させた後、これを水相に乳化させるか或いは有機溶媒に希釈させず、直接崩壊剤、希釈剤などの固形の賦形剤に加えて比較例３の錠剤を製造した。比較例３の組成は下記表１０のとおりである。
<Comparative Example 3> Preparation of a tablet in which a solubilizer is directly adsorbed on a solid excipient After dissolving dutasteride using propylene glycol monocaprylate as a solubilizer having poor miscibility with water, this Was emulsified in an aqueous phase or not diluted in an organic solvent, and directly added to solid excipients such as a disintegrant and a diluent to produce a tablet of Comparative Example 3. The composition of Comparative Example 3 is as shown in Table 10 below.
１）デュタステリドを、可溶化剤であるモノカプリル酸プロピレングリコールとジエチレングリコールモノエチルエーテルとの混合溶液に加え、機械式攪拌機を用いて３００〜５００ｒｐｍで３０分間攪拌して溶解させた。 1) Dutasteride was added to a mixed solution of propylene glycol monocaprylate and diethylene glycol monoethyl ether, which are solubilizers, and dissolved by stirring for 30 minutes at 300 to 500 rpm using a mechanical stirrer.
２）１）の溶液を結合液として、希釈剤であるマンニトール及び微結晶セルロース、吸着剤であるケイ酸カルシウム、安定化剤である硬質無水ケイ酸、崩壊剤である低置換度ヒドロキシプロピルセルロース及び結合剤であるヒドロキシプロピルセルロースの粉末混合物に加えて混合した。 2) Using the solution of 1) as a binder, mannitol and microcrystalline cellulose as diluents, calcium silicate as adsorbent, hard anhydrous silicic acid as stabilizer, low-substituted hydroxypropylcellulose as disintegrant, and It was added to the powder mixture of hydroxypropyl cellulose as a binder and mixed.
３）２）の混合物に別途に精製水を加えて練り合わせ、これを箱型乾燥機を用いて６０℃で１２時間乾燥させることにより、湿式顆粒法で顆粒を製造した。 3) Separately, purified water was added to the mixture of 2) and kneaded, and this was dried at 60 ° C. for 12 hours using a box-type dryer, thereby producing granules by a wet granulation method.
４）以下、実施例１の６）乃至８）と同様の方法で製造して比較例３とした。 4) Hereinafter, Comparative Example 3 was produced by the same method as 6) to 8) of Example 1.
＜比較例４＞市販製品であるアボダート（登録商標）
本発明によって提供される錠剤形態のデュタステリド組成物との加速安定性を比較評価するために、市販製品であるアボダート（ＡＶＯＤＡＲＴ（登録商標）、ＧｌａｘｏＳｍｉｔｈＫｌｉｎｅ、Ｌｏｔ Ｎｏ．０６４４８１Ａ）を比較例４とした。
<Comparative Example 4> Avodate (registered trademark), which is a commercial product
In order to compare and evaluate the accelerated stability with the tablet-form dutasteride composition provided by the present invention, Avodate (AVODAR (registered trademark), GlaxoSmithKline, Lot No. 064481A), which is a commercial product, was used as Comparative Example 4.
＜実験例１＞デュタステリドの類縁物質の評価
硬質無水ケイ酸の安定化効果を調べるために、実施例１乃至５、実施例７、実施例１０、実施例１１及び比較例１乃至３を用いて、デュタステリドの類縁物質の含量を評価した。総類縁物質の含量は、すべてのピーク面積の合計のうち、デュタステリドの類縁物質のピーク面積の合計が占める百分率（％）で評価した。このとき、デュタステリド以外の賦形剤に由来するピークは排除した。ＨＰＬＣ分析法による結果は図１に示した。デュタステリドの類縁物質評価のための試験方法は下記ＨＰＬＣ条件を使用した。
<Experimental Example 1> Evaluation of Dutasteride Similar Substances In order to examine the stabilizing effect of hard silicic acid, Examples 1 to 5, Example 7, Example 10, Example 11 and Comparative Examples 1 to 3 were used. The content of dutasteride related substances was evaluated. The content of the total related substances was evaluated as a percentage (%) of the total peak area of dutasteride related substances out of the total of all peak areas. At this time, peaks derived from excipients other than dutasteride were excluded. The results obtained by HPLC analysis are shown in FIG. The following HPLC conditions were used as test methods for evaluating dutasteride analogues.
−ＨＰＬＣ分析条件−
カラム：Ｚｏｒｂａｘ ＳＢ Ｃ１８（２５０×４．６ｍｍ、５μｍ）
検出器：紫外部吸光光度計（測定波長２１０ｎｍ）
流速：１．０ｍＬ／ｍｉｎ
カラム温度：３０℃
注入量：１０μＬ
分析時間：６０分
移動相Ａ：リン酸二水素カリウム１．３６０９ｇを１０００ｍＬの超純水に溶解し、１０％リン酸溶液を用いてｐＨ３．０に合わせた後、脱気して使用
移動相Ｂ：アセトニトリルと水を９：１の比率で混合した後、脱気して使用
-HPLC analysis conditions-
Column: Zorbax SB C18 (250 × 4.6 mm, 5 μm)
Detector: UV spectrophotometer (measurement wavelength 210 nm)
Flow rate: 1.0 mL / min
Column temperature: 30 ° C
Injection volume: 10 μL
Analysis time: 60 minutes Mobile phase A: 1.3609 g of potassium dihydrogen phosphate dissolved in 1000 mL of ultrapure water, adjusted to pH 3.0 with 10% phosphoric acid solution, degassed and used Mobile phase B: Acetonitrile and water mixed at a ratio of 9: 1, then degassed and used
勾配溶離条件：
その結果、図１に示すように、油相と水相とを混合して乳化液（ｅｍｕｌｓｉｏｎ）を形成する段階を含み、安定化剤である硬質無水ケイ酸を乳化液の少なくとも一つの相に含む本発明に係る実施例１乃至５、実施例７、実施例１０及び実施例１１の場合は、製造工程中に発生するデュタステリド類縁物質の量が０．３１〜０．４４％と低かったが、比較例１（硬質無水ケイ酸を安定化剤として含まない錠剤）、比較例２（可溶化剤をエタノールで希釈して製造された錠剤）及び比較例３（安定化剤である硬質無水ケイ酸を粉末形態で用いて製造された錠剤）の場合は、０．８９％、０．７２％及び０．９７％と高い柔軟性物質の含量を示した。 As a result, as shown in FIG. 1, the method includes a step of mixing an oil phase and an aqueous phase to form an emulsion, and the hard silicic acid as a stabilizer is added to at least one phase of the emulsion. In the case of Examples 1 to 5, Example 7, Example 10 and Example 11 according to the present invention, the amount of dutasteride-related substances generated during the production process was as low as 0.31 to 0.44%. Comparative Example 1 (tablets not containing hard anhydrous silicic acid as a stabilizer), Comparative Example 2 (tablets prepared by diluting a solubilizer with ethanol) and Comparative Example 3 (hard anhydrous silicic acid as a stabilizer) In the case of tablets manufactured using acid in powder form, the content of flexible substances was as high as 0.89%, 0.72% and 0.97%.
したがって、本発明は、製造工程中に安定化剤として硬質無水ケイ酸を用いることにより、デュタステリドの類縁物質の発生を抑制することができることが分かる。つまり、市販製品であるアボダート（登録商標）の類縁物質の基準が類縁物質０．５％以下に管理されていることを参照すると、図１に示された結果は非常に優れた効果を示していることが分かる。これに加えて、デュタステリドを溶解させた可溶化剤溶液を水相に乳化させ、乳化液（ｅｍｕｌｓｉｏｎ）に安定化剤である硬質無水ケイ酸を懸濁して製造される結合液を用いて湿式顆粒を製造することが、製造工程中のデュタステリド類縁物質の発生抑制に優れた効果を示すことが分かる。 Therefore, it turns out that generation | occurrence | production of the related substance of a dutasteride can be suppressed by this invention by using a hard silicic acid anhydride as a stabilizer in a manufacturing process. In other words, referring to the fact that the standard of the related substance of Avodate (registered trademark), which is a commercial product, is controlled to 0.5% or less of the related substance, the result shown in FIG. 1 shows a very excellent effect. I understand that. In addition to this, wet granules using a binding solution prepared by emulsifying a solubilizer solution in which dutasteride is dissolved in an aqueous phase and suspending hard anhydrous silicic acid as a stabilizer in an emulsion (emulsion). It can be seen that the production of is effective in suppressing the generation of dutasteride-related substances during the production process.
＜実験例２＞製剤均一性の評価
市販製品であるアボダート（登録商標）は、デュタステリドを含有する軟質カプセル剤であって、デュタステリドと安定化剤であるブチル化ヒドロキシトルエンをカプリン酸／カプリル酸のモノ・ジグリセリドに溶解した後、軟質カプセルに充填することにより製造される。このような製法によって提供される製品の場合、個々のカプセル別含量の不均一現象が発生する可能性は非常に低い。
<Experimental Example 2> Evaluation of Formulation Uniformity Avodate (registered trademark), which is a commercial product, is a soft capsule containing dutasteride, and dutasteride and a butylated hydroxytoluene that is a stabilizer of capric acid / caprylic acid. It is manufactured by dissolving in mono-diglyceride and filling into soft capsules. In the case of a product provided by such a manufacturing method, it is very unlikely that a non-uniform phenomenon of individual capsule content will occur.
しかし、デュタステリドを含有する錠剤を製造するためには、少量の可溶化剤（油相）にデュタステリドを溶解させ、これを多量の粉末状の賦形剤もしくは吸着剤に均質に吸着させるための工程段階が必ず必要である。 However, in order to produce tablets containing dutasteride, a process for dissolving dutasteride in a small amount of a solubilizing agent (oil phase) and adsorbing it uniformly to a large amount of powdery excipient or adsorbent A stage is absolutely necessary.
このため、本発明で製造されたデュタステリド錠剤の含量均一性の程度を実験例１のＨＰＬＣ分析条件で評価した。本発明の実施例１乃至７と比較例１乃至３の含量均一性を評価した結果を下記表１１に示した。単位は％を示すものである。 Therefore, the degree of content uniformity of the dutasteride tablet produced in the present invention was evaluated under the HPLC analysis conditions of Experimental Example 1. The results of evaluating the content uniformity of Examples 1 to 7 and Comparative Examples 1 to 3 of the present invention are shown in Table 11 below. The unit is%.
実施例１乃至７及び比較例１は、デュタステリドを可溶化剤に溶解させた油相を水相に均一に分散させて得られた乳化液（ｅｍｕｌｓｉｏｎ）を固形の賦形剤に加えて製造された錠剤であり、比較例２は、乳化液（ｅｍｕｌｓｉｏｎ）を形成させずに、約５〜１０倍の５０％エタノールでデュタステリドを溶解させた油相を希釈し、これを固形の賦形剤に加えて製造された錠剤である。 Examples 1 to 7 and Comparative Example 1 are prepared by adding an emulsion obtained by uniformly dispersing an oil phase in which dutasteride is dissolved in a solubilizer to an aqueous phase to a solid excipient. In Comparative Example 2, the oil phase in which dutasteride was dissolved was diluted with about 5 to 10 times 50% ethanol without forming an emulsion, and this was used as a solid excipient. In addition, it is a manufactured tablet.
表１１に示すように、実施例１乃至７、比較例１及び比較例２は、含量均一性の判定値が５以内と非常に均一である錠剤が製造されたことが分かるが、比較例３のようにデュタステリドを可溶化剤に溶解させた油相をすぐ固形の賦形剤に吸着させて製造された錠剤の場合、デュタステリドを含有した油相が固形の賦形剤に均一に分散しないため、含量均一性の判定値が１５以上であって、個々の錠剤別デュタステリドの含量偏差が大きいことが分かる。 As shown in Table 11, in Examples 1 to 7, Comparative Example 1 and Comparative Example 2, it can be seen that tablets with a very uniform content uniformity judgment value of 5 or less were produced. Comparative Example 3 In the case of tablets manufactured by immediately adsorbing an oil phase in which dutasteride is dissolved in a solubilizing agent to a solid excipient, the oil phase containing dutasteride is not uniformly dispersed in the solid excipient. It can be seen that the content uniformity judgment value is 15 or more, and the content deviation of dutasteride for each tablet is large.
＜実験例３＞加速安定性の評価
本発明によって製造された実施例６と比較例４の市販品アボダート（登録商標）の安定性を比較評価した。実施例６は、一般な医薬品包装用ＨＤＰＥボトルに吸湿剤であるシリカゲルを入れて包装した。アボダート（登録商標）はＰＶＣ−アルミ箔ＰＴＰ包装された市販品をそのまま加速条件（４０℃７５％ＲＨ）で４ヶ月間保管し、デュタステリドの類縁物質の変化有無を評価して図２乃至４に示した。
<Experimental Example 3> Evaluation of Accelerated Stability Comparatively evaluated the stability of commercial product Avodate (registered trademark) of Example 6 and Comparative Example 4 produced according to the present invention. In Example 6, silica gel as a hygroscopic agent was placed in a general HDPE bottle for pharmaceutical packaging and packaged. Avodate (registered trademark) is a PVC-aluminum foil PTP packaged commercial product that is stored for 4 months under accelerated conditions (40 ° C. 75% RH), and the presence or absence of changes in the related substance of dutasteride is evaluated. Indicated.
市販製品であるアボダート（登録商標）は、安定化剤であって、１カプセル当たりブチル化ヒドロキシトルエン０．０３５ｍｇを含有しており、これに反し、本発明によって提供される実施例６は、いかなる抗酸化剤も含有していないものであるにも拘わらず、比較例４の市販品であるアボダート（登録商標）と同等の類縁物質安定性を示した。 The commercial product Avodate (R) is a stabilizer and contains 0.035 mg of butylated hydroxytoluene per capsule, whereas Example 6 provided by the present invention is Although it did not contain an antioxidant, it showed similar substance stability as Avodate (registered trademark), which is a commercial product of Comparative Example 4.
これに加えて、図４に示すように、比較例４は、軟質カプセルであって、加速安定性の評価条件で軟質皮膜の軟化及び変性が起こってカプセルが互いにくっ付いたり包装材にカプセルが付着したりする現象が現れた。これに対し、本発明に係る実施例６の場合は、いかなる性状変化も現れていないので、優れた安定性を示すことが分かる。 In addition to this, as shown in FIG. 4, the comparative example 4 is a soft capsule, and the soft film is softened and denatured under the accelerated stability evaluation condition, so that the capsule adheres to each other or the capsule is attached to the packaging material. The phenomenon of adhering appeared. On the other hand, in the case of Example 6 according to the present invention, since no property change appears, it can be seen that excellent stability is exhibited.
Claims (18)
（２）前記（１）段階で製造された溶液に硬質無水ケイ酸０．３〜１重量部を攪拌して懸濁させた溶液の製造段階と、
（３）別途の精製水１００〜１０００重量部に硬質無水ケイ酸５〜３０重量部を攪拌して懸濁させた溶液の製造段階と、
（４）前記（２）で製造された溶液と（３）で製造された溶液とを混合して乳化させた乳化液の製造段階と、
（５）前記（４）で製造された乳化液を崩壊剤及び希釈剤の混合粉末に結合液として加えて混合・乾燥させた顆粒の製造段階とを含んでなる、デュタステリド含有固形薬学的組成物の製造方法。 (1) A production stage of a solution in which 1 part by weight of dutasteride is dissolved in 20 to 60 parts by weight of a solubilizing agent;
(2) A step of producing a solution obtained by stirring and suspending 0.3 to 1 part by weight of hard silicic acid in the solution produced in the step (1),
(3) A step for producing a solution in which 5 to 30 parts by weight of hard silicic acid is stirred and suspended in 100 to 1000 parts by weight of separate purified water;
(4) A step of producing an emulsion obtained by mixing and emulsifying the solution produced in (2) and the solution produced in (3),
(5) A dutasteride-containing solid pharmaceutical composition comprising a granule production step comprising adding the emulsified liquid prepared in (4) above as a binder to a mixed powder of a disintegrant and a diluent and mixing and drying the mixture. Manufacturing method.
請求項１乃至５のいずれか一項に記載の製造方法によって製造された固形の薬学的組成物を含有することを特徴とする、固形製剤。 In a formulation for the treatment of benign prostatic hyperplasia and androgenetic alopecia,
A solid preparation comprising the solid pharmaceutical composition produced by the production method according to any one of claims 1 to 5.
（２）前記（１）段階で製造された溶液に硬質無水ケイ酸０．３〜１重量部を攪拌して懸濁させた溶液の製造段階と、
（３）前記（２）で製造された溶液と精製水とを混合して乳化させた乳化液の製造段階と、
（４）前記（３）で製造された乳化液を崩壊剤及び希釈剤の混合粉末に結合液として加えて混合・乾燥させた顆粒の製造段階とを含んでなる、デュタステリド含有固形薬学的組成物の製造方法。 (1) A production stage of a solution in which 1 part by weight of dutasteride is dissolved in 20 to 60 parts by weight of a solubilizing agent;
(2) A step of producing a solution obtained by stirring and suspending 0.3 to 1 part by weight of hard silicic acid in the solution produced in the step (1),
(3) A production stage of an emulsion obtained by mixing and emulsifying the solution produced in (2) and purified water;
(4) A dutasteride-containing solid pharmaceutical composition comprising a granule production step comprising adding the emulsified liquid prepared in (3) above as a binding liquid to a mixed powder of a disintegrant and a diluent, followed by mixing and drying. Manufacturing method.
請求項７乃至１１のいずれか一項に記載の製造方法によって製造された固形の薬学的組成物を含有することを特徴とする、固形製剤。 In a formulation for the treatment of benign prostatic hyperplasia and androgenetic alopecia,
A solid preparation comprising the solid pharmaceutical composition produced by the production method according to any one of claims 7 to 11.
（２）別途の精製水１００〜１０００重量部に硬質無水ケイ酸５〜３０重量部を攪拌して懸濁させた溶液の製造段階と、
（３）前記（１）段階で製造された溶液と（２）で製造された溶液とを混合して乳化させた乳化液の製造段階と、
（４）前記（３）で製造された乳化液を崩壊剤及び希釈剤の混合粉末に結合液として加えて混合・乾燥させた顆粒の製造段階とを含んでなる、デュタステリド含有固形薬学的組成物の製造方法。 (1) A production stage of a solution in which 1 part by weight of dutasteride is dissolved in 20 to 60 parts by weight of a solubilizing agent;
(2) A step of producing a solution in which 5 to 30 parts by weight of hard silicic acid is stirred and suspended in 100 to 1000 parts by weight of separate purified water;
(3) A step of producing an emulsion obtained by mixing and emulsifying the solution produced in step (1) and the solution produced in (2),
(4) A dutasteride-containing solid pharmaceutical composition comprising a granule production step comprising adding the emulsified liquid prepared in (3) above as a binding liquid to a mixed powder of a disintegrant and a diluent, followed by mixing and drying. Manufacturing method.
請求項１３乃至１７のいずれか一項に記載の製造方法によって製造された固形の薬学的組成物を含有することを特徴とする、固形製剤。 In a formulation for the treatment of benign prostatic hyperplasia and androgenetic alopecia,
A solid preparation comprising the solid pharmaceutical composition produced by the production method according to any one of claims 13 to 17.
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