JP2023024600A - Pregabalin-containing solid pharmaceutical composition and method for producing the same - Google Patents
Pregabalin-containing solid pharmaceutical composition and method for producing the same Download PDFInfo
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- JP2023024600A JP2023024600A JP2022203709A JP2022203709A JP2023024600A JP 2023024600 A JP2023024600 A JP 2023024600A JP 2022203709 A JP2022203709 A JP 2022203709A JP 2022203709 A JP2022203709 A JP 2022203709A JP 2023024600 A JP2023024600 A JP 2023024600A
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- Prior art keywords
- pregabalin
- pharmaceutical composition
- solid pharmaceutical
- glyceryl monostearate
- weight
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- Granted
Links
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- 229960001233 pregabalin Drugs 0.000 title claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
- 239000007787 solid Substances 0.000 title claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 11
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims abstract description 58
- 229940075507 glyceryl monostearate Drugs 0.000 claims abstract description 28
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims abstract description 28
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、高い安定性を示すプレガバリン含有固形医薬組成物及びその製造方法に関する。 TECHNICAL FIELD The present invention relates to a pregabalin-containing solid pharmaceutical composition exhibiting high stability and a method for producing the same.
プレガバリンは、電位依存性カルシウムチャンネルをブロックして神経伝達物質の放出を減らし、臨床的には主として末梢性神経障害性疼痛の治療および部分発作てんかんの補助的治療に用いられる新規のカルシウムチャンネル調節薬(非γ-ブタン酸(GABA)受容体アゴニストまたはアンタゴニスト)である。 Pregabalin is a novel calcium channel modulator that blocks voltage-gated calcium channels to reduce neurotransmitter release and is clinically used primarily for the treatment of peripheral neuropathic pain and adjunctive treatment of partial-onset seizures. (non-γ-butanoic acid (GABA) receptor agonists or antagonists).
特許文献1には、プレガバリンを含むGABA誘導体で、製剤化及び製剤保存時にプレガバリンの分解物であるラクタム体が生成することが記載されており、そのラクタム体の生成を抑えるために、イソマルトを使用することが記載されている。 Patent Document 1 describes that a GABA derivative containing pregabalin produces a lactam that is a degradation product of pregabalin during formulation and storage, and isomalt is used to suppress the production of the lactam. It is stated that
また、特許文献2には、保水剤としてエチレングルコール、プロピレングリコール、ブチレングリコール、トリアセチン、又はモノラウリン酸デカグリセリルを使用することによりラクタム体生成が抑制できることが記載されている。 Moreover, Patent Document 2 describes that lactam production can be suppressed by using ethylene glycol, propylene glycol, butylene glycol, triacetin, or decaglyceryl monolaurate as a water retention agent.
更に、特許文献3には、α-アミノ酸を用いることによりラクタム体生成が抑制できるが記載されている。 Furthermore, Patent Document 3 describes that lactam production can be suppressed by using an α-amino acid.
しかしながら、これらのいずれの特許文献にも、モノステアリン酸グリセリンがプレガバリンからのラクタム体生成を抑制することについては、記載も示唆もされていない。 However, none of these patent documents describes or suggests that glyceryl monostearate suppresses lactam body formation from pregabalin.
本発明は、プレガバリン含有固形医薬組成物のラクタム体生成を抑制する新たな手段を提供することを目的とする。 An object of the present invention is to provide a new means for suppressing the formation of lactam bodies in solid pharmaceutical compositions containing pregabalin.
本発明者らは、上記課題を解決するため鋭意検討したところ、驚くべきことに、モノステアリン酸グリセリンが、プレガバリン含有固形医薬組成物のラクタム体生成を著しく抑制することを見出し、本発明を完成した。 The inventors of the present invention conducted intensive studies to solve the above problems, and surprisingly found that glyceryl monostearate significantly inhibits the formation of lactam bodies in solid pharmaceutical compositions containing pregabalin, and completed the present invention. bottom.
すなわち、本発明はプレガバリン及びモノステアリン酸グリセリンを含有する固形医薬組成物を提供する。 Accordingly, the present invention provides a solid pharmaceutical composition containing pregabalin and glyceryl monostearate.
また、プレガバリンの含有量が1固形医薬組成物あたり10~60重量%であるプレガバリン及びモノステアリン酸グリセリンを含有する固形医薬組成物を提供する。 Also provided is a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, wherein the content of pregabalin is 10 to 60% by weight per solid pharmaceutical composition.
また、モノステアリン酸グリセリンの含有量が1固形医薬組成物あたり1~20重量%であるプレガバリン及びモノステアリン酸グリセリンを含有する固形医薬組成物を提供する。 Also provided is a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, wherein the content of glyceryl monostearate is 1 to 20% by weight per solid pharmaceutical composition.
また、モノステアリン酸グリセリン含有量がプレガバリン含有量に対し0.01~20重量%であるプレガバリン及びモノステアリン酸グリセリンを含有する固形医薬組成物を提供する。 Also provided is a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, wherein the content of glyceryl monostearate is 0.01 to 20% by weight relative to the content of pregabalin.
また、モノステアリン酸グリセリン以外の添加剤も含むプレガバリン及びモノステアリン酸グリセリンを含有する固形医薬組成物を提供する。 Also provided is a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, which also contains additives other than glyceryl monostearate.
また、クロスポピドン、プレガバリン及びモノステアリン酸グリセリンを含有する固形医薬組成物を提供する。 Also provided is a solid pharmaceutical composition comprising crospovidone, pregabalin and glyceryl monostearate.
また、クロスポピドンの含有量が1固形医薬組成物あたり1~20重量%であるクロスポピドン、プレガバリン及びモノステアリン酸グリセリンを含有する固形医薬組成物を提供する。 Also provided is a solid pharmaceutical composition containing crospovidone, pregabalin and glyceryl monostearate, wherein the content of crospovidone is 1 to 20% by weight per solid pharmaceutical composition.
また、プレガバリン及びモノステアリン酸グリセリンを含有する錠剤、カプセル剤、散剤、顆粒剤、細粒剤を提供する。 Also provided are tablets, capsules, powders, granules and fine granules containing pregabalin and glyceryl monostearate.
また、プレガバリン及びモノステアリン酸グリセリンを含有する口腔内崩壊錠を提供する。 Also provided is an orally disintegrating tablet containing pregabalin and glyceryl monostearate.
また、プレガバリンとモノステアリン酸グリセリンを溶融造粒する工程を含む固形医薬組成物の製造方法を提供する。 Also provided is a method for producing a solid pharmaceutical composition comprising the step of melt granulating pregabalin and glyceryl monostearate.
本発明のプレガバリン含有固形医薬組成物は、有効成分であるプレガバリンのラクタム体生成が抑制されているため、プレガバリンの安定性が良好な医薬品として有用である。 INDUSTRIAL APPLICABILITY The pregabalin-containing solid pharmaceutical composition of the present invention is useful as a medicament with good stability of pregabalin because the formation of the lactam form of pregabalin, which is an active ingredient, is suppressed.
本発明において、プレガバリン((3S)-3-(Aminomethyl)-5-methylhexanoic acid)は、以下の化学式により表される化合物である。プレガバリンは、例えば、特表平7-508288号公報に記載の方法によって製造されうる。プレガバリンの含有量は、1固形医薬組成物あたり10~60重量%が好ましく、20~50重量%がより好ましく、30~40重量%が特に好ましい。
本発明において、モノステアリン酸グリセリンとは、当技術分野で用いられているものであれば何でもよい。モノステアリン酸グリセリンの含有量は、1固形医薬組成物あたり1~20重量%が好ましく、2~10重量%がより好ましい。
また、モノステアリン酸グリセリン含有量がプレガバリン含有量に対し0.01~20重量%であることが好ましく、0.1~10重量%がより好ましい。
In the present invention, glyceryl monostearate may be any one used in the technical field. The content of glyceryl monostearate is preferably 1 to 20% by weight, more preferably 2 to 10% by weight, per solid pharmaceutical composition.
Also, the glyceryl monostearate content is preferably 0.01 to 20% by weight, more preferably 0.1 to 10% by weight, based on the pregabalin content.
本発明において、添加剤とは、賦形剤、結合剤、崩壊剤、滑択剤を言うが、特にこれらに制限されない。当該添加剤以外に、当技術分野で用いられる着色剤、抗酸化剤、増粘剤、緩衝化剤、甘味付与剤、フレーバー付与剤、又はパフューム剤などを本発明の錠剤に配合してもよい。甘味付与剤としては、アスパルテーム、アセスルファムカリウム、スクラロース、ステビア、マルチトール、グリセリン、ラクチトール、ガラクチトールなどが挙げられる。着色剤としては、例えば二酸化チタン、酸化第二鉄などが挙げられる。 In the present invention, additives refer to excipients, binders, disintegrants and lubricants, but are not particularly limited to these. In addition to the additives, colorants, antioxidants, thickeners, buffering agents, sweetening agents, flavoring agents, perfume agents, and the like used in the art may be incorporated into the tablet of the present invention. . Sweetening agents include aspartame, acesulfame potassium, sucralose, stevia, maltitol, glycerin, lactitol, galactitol and the like. Examples of coloring agents include titanium dioxide and ferric oxide.
本発明において、賦形剤として、例えばD-マンニトール、乳糖(乳糖水和物、噴霧乾燥乳糖、流動層造粒乳糖、異性化乳糖、還元乳糖等)、ショ糖、エリトリトール、ソルビトール、キシリトールなどが挙げられる。本発明においては、ラクタム体生成抑制の観点からD-マンニトールが好ましい。 In the present invention, examples of excipients include D-mannitol, lactose (lactose hydrate, spray-dried lactose, fluid bed granulated lactose, isomerized lactose, reduced lactose, etc.), sucrose, erythritol, sorbitol, xylitol, and the like. mentioned. In the present invention, D-mannitol is preferred from the viewpoint of suppression of lactam production.
本発明において、結合剤として、例えばヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポビドン、ポリビニルピロリドン、メチルセルロース、ポリビニルアルコール、カルボキシメチルセルロース等が挙げられ、これらの1種あるいは2種以上適宜配合して用いてもよい。 In the present invention, binders include, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, polyvinylpyrrolidone, methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose and the like, and one or more of these may be appropriately blended and used. .
本発明において、崩壊剤として、例えばクロスポビドン、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、カルボキシプロピルスターチナトリウム、部分アルファ化デンプン、トウモロコシデンプンなどが挙げられる。本発明においては、ラクトン体等の不純物生成抑制の観点からクロスポビドン、低置換度ヒドロキシプロピルセルロース、トウモロコシデンプン、部分α化デンプンが好ましい。また、崩壊剤の含有量は、1固形医薬組成物あたり1~20重量%が好ましく、5~10重量%がより好ましい。 In the present invention, disintegrants include, for example, crospovidone, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, carboxypropyl starch sodium, partially pregelatinized starch, corn starch and the like. In the present invention, crospovidone, low-substituted hydroxypropyl cellulose, corn starch, and partially pregelatinized starch are preferred from the viewpoint of suppressing the formation of impurities such as lactone bodies. The content of the disintegrant is preferably 1-20% by weight, more preferably 5-10% by weight, per solid pharmaceutical composition.
本発明において、滑択剤として、例えばステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、タルクなどが挙げられる。 Examples of lubricants used in the present invention include magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, and talc.
本発明において、錠剤は、フィルムコーティングを施してもよく、例えば口腔内崩壊錠にフィルムコーティングを施してもよい。 In the present invention, the tablet may be film-coated, for example, an orally disintegrating tablet may be film-coated.
本発明の錠剤は、通常の錠剤製造方法により製造することが可能であるが、ラクトン体等の不純物生成抑制の観点から、溶融造粒法によって得られたプレガバリン顆粒に、添加剤を加え、混合後、打錠することにより製剤することが好ましい。
より具体的には、本発明のプレガバリン含有錠剤は、例えば、プレガバリンと、モノステアリン酸グリセリン等の低融点物質を混合後、通常、40~80℃程度に加温して、モノステアリン酸グリセリン等の低融点物質を融解させて、場合によっては、付着防止剤を加え、混合・造粒後、冷却、整粒して、溶融造粒物を調製し、次いで滑沢剤、崩壊剤、賦形剤等と混合後、打錠することによって、錠剤を製造できる。これらの操作の内、溶融造粒操作は、例えば、流動層造粒機、転動流動層造粒機、高速撹拌造粒機、押出造粒機等の装置を使用して行えばよい。また、打錠は、市販の打錠機を使用して行うことができる。
The tablet of the present invention can be produced by a conventional tablet production method, but from the viewpoint of suppressing the formation of impurities such as lactone bodies, pregabalin granules obtained by melt granulation are added with additives and mixed. After that, it is preferable to prepare a formulation by tableting.
More specifically, the pregabalin-containing tablet of the present invention can be produced, for example, by mixing pregabalin with a low-melting-point substance such as glyceryl monostearate and then heating to about 40 to 80° C. to give glyceryl monostearate and the like. In some cases, an anti-adhesion agent is added, mixed and granulated, cooled and granulated to prepare a molten granule, then a lubricant, disintegrant, excipient Tablets can be produced by tableting after mixing with agents and the like. Among these operations, the melt granulation operation may be performed using a fluidized bed granulator, a tumbling fluidized bed granulator, a high-speed stirring granulator, an extrusion granulator, or the like. Moreover, tableting can be performed using a commercially available tableting machine.
次いで、コーティングをする場合には、水性フィルムコーティング調製物を用いた噴霧被覆により施してもよい。また水性フィルムコーティング調製物は、例えばポリビニルアルコール、ヒドロキシプロピルメチルセルロース、ポリビニルポリエチレングリコールグラフトコポリマー、マクロゴール、二酸化チタン、酸化第二鉄を含んでもよい。コーティングの含量は、例えば錠剤組成物の0.5~10重量%が好ましく、1~6重量%がより好ましく、2~3重量%が特に好ましい。 Coating may then be applied by spray coating with an aqueous film coating preparation. Aqueous film coating formulations may also include, for example, polyvinyl alcohol, hydroxypropyl methylcellulose, polyvinyl polyethylene glycol graft copolymers, macrogol, titanium dioxide, ferric oxide. The coating content is, for example, preferably 0.5 to 10% by weight, more preferably 1 to 6% by weight, particularly preferably 2 to 3% by weight of the tablet composition.
以下に、実施例等により本発明をさらに具体的に説明するが、本発明は下記の実施例等
に何ら限定されるものではない。
EXAMPLES The present invention will be described in more detail with reference to Examples and the like below, but the present invention is not limited to the following Examples and the like.
流動層造粒乾燥機(パウレック社製;FD-MP-01)に、プレガバリン(住友化学社製)300g、モノステアリン酸グリセリン(理研ビタミン製;リケマールP-100)24g及びタルク(松村産業製;クラウンタルク)6gを投入し、給気温度100℃設定にて流動させながら加熱しモノステアリン酸グリセリンを70~80℃で溶融させ、モノステアリン酸グリセリンの融点以上に達してから約5分間流動させ造粒する。その後、モノステアリン酸グリセリンの融点以下まで冷却して造粒物を得る。得られた造粒物を流動層造粒乾燥機(パウレック社製;FD-MP-01)に投入し、D-マンニトール(三菱商事フードテック製;マンニットP)15.96g及びマルチトール(三菱商事フードテック製、アマルティー)8.04gを精製水216gに溶解した溶液を噴霧し、乾燥後、プレガバリン顆粒を得た。
得られたプレガバリン顆粒を500μmの篩で整粒した後、D-マンニトール(フロイント産業製、グラニュトールS)550.8g、クロスポビドン(BASF製;コリドンCF-L)48g及びステアリン酸マグネシウム(太平化学産業製;植物性)7.2gと混合して打錠用末とした後、ロータリー式打錠機を用いて打錠し、質量80mg、φ6mmの錠剤を得た。
300 g of pregabalin (manufactured by Sumitomo Chemical Co., Ltd.), 24 g of glycerin monostearate (manufactured by Riken Vitamin; Rikemal P-100) and talc (manufactured by Matsumura Sangyo; 6 g of crown talc) was added, heated while flowing at an air supply temperature of 100°C to melt glyceryl monostearate at 70 to 80°C, and flowed for about 5 minutes after reaching the melting point of glyceryl monostearate. Granulate. Thereafter, the mixture is cooled to below the melting point of glyceryl monostearate to obtain granules. The resulting granules were put into a fluid bed granulator dryer (manufactured by Powrex; FD-MP-01), and 15.96 g of D-mannitol (manufactured by Mitsubishi Shoji Foodtech; Mannitol P) and maltitol (Mitsubishi A solution of 8.04 g of Amalty, manufactured by Shoji Foodtech Co., Ltd. dissolved in 216 g of purified water was sprayed and dried to obtain pregabalin granules.
After sieving the obtained pregabalin granules with a 500 μm sieve, 550.8 g of D-mannitol (manufactured by Freund Corporation, Granutol S), 48 g of crospovidone (manufactured by BASF; Kollidon CF-L) and magnesium stearate (Taihei Kagaku Industrial product; vegetable) (7.2 g) to prepare a powder for tableting, which was then tableted using a rotary tableting machine to obtain tablets with a mass of 80 mg and a diameter of 6 mm.
また、比較例として、市販されているリリカOD錠25mg(プレガバリン含有口腔内崩壊錠、ファイザー株式会社、以下「比較例1」という)についても50℃7日間、14日間密栓状態で苛酷試験を実施した後類縁物質の割合を測定した。比較例1の組成は表1の通り。 As a comparative example, 25 mg of commercially available Lyrica OD tablets (pregabalin-containing orally disintegrating tablet, Pfizer Japan Inc., hereinafter referred to as "Comparative Example 1") were subjected to severe tests in a sealed state at 50°C for 7 days and 14 days. After that, the ratio of related substances was measured. The composition of Comparative Example 1 is shown in Table 1.
(試験例1)
実施例1及び比較例1の錠剤を50℃7日、14日間密栓状態で苛酷試験を実施し、苛酷試験後の錠剤中のラクタム体量を高速液体クロマトグラフィー(HPLC)にて測定した。
<純度試験方法>
純度の測定として、HPLCを用いて、下記測定条件でプレガバリンのピーク面積を測定し、プレガバリンのピーク面積に対するラクタム体のピーク面積比(%)を測定した。
プレガバリン100mgに対応する量を取り、水10mLを加えて、時々振り混ぜながら超音波処理する。この液を必要に応じて遠心分離し、上済液を孔径1.0μm以下のフィルターでろ過し試料溶液とする。
HPLC測定条件
検出器:紫外吸光光度計(210nm)
カラム:液体クロマトグラフィー用オクタデシルシリル化シリカゲル充填カラム
カラム温度:35℃付近
移動相A:リン酸水素二アンモニウム5.28gを水1000mLに溶かし、リン酸を加えてpH6.5に調整する。この液800mLにメタノール200mLを加える。
移動相B:アセトニトリル/メタノール混合液(9:1)
移動相の送液:移動相A及び移動相Bの混合比を次のように変えて濃度勾配制御する。
注入量:20μmL
(Test example 1)
The tablets of Example 1 and Comparative Example 1 were subjected to a severe test in a sealed state at 50°C for 7 days and 14 days, and the amount of lactam in the tablets after the severe test was measured by high performance liquid chromatography (HPLC).
<Purity test method>
As a measurement of purity, the peak area of pregabalin was measured using HPLC under the following measurement conditions, and the peak area ratio (%) of the lactam form to the peak area of pregabalin was measured.
Take an amount corresponding to 100 mg of pregabalin, add 10 mL of water, and sonicate with occasional shaking. This liquid is centrifuged if necessary, and the supernatant liquid is filtered through a filter having a pore size of 1.0 μm or less to obtain a sample solution.
HPLC measurement conditions Detector: UV absorption photometer (210 nm)
Column: octadecylsilylated silica gel packed column for liquid chromatography Column temperature: around 35° C. Mobile phase A: 5.28 g of diammonium hydrogen phosphate is dissolved in 1000 mL of water, and phosphoric acid is added to adjust the pH to 6.5. 200 mL of methanol is added to 800 mL of this liquid.
Mobile phase B: acetonitrile/methanol mixture (9:1)
Transfer of mobile phase: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.
Injection volume: 20 μmL
その結果、表3に示す通り、比較例1においては50℃7日間、14日間において開始時からラクタム体の著しい増加が認められたが、実施例1においてはラクタム体の生成が抑制された。 As a result, as shown in Table 3, in Comparative Example 1, a significant increase in the lactam form was observed from the start of the period of 7 days and 14 days at 50°C, but in Example 1, the production of the lactam form was suppressed.
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