JP7450013B2 - 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
- Publication number
- JP7450013B2 JP7450013B2 JP2022203709A JP2022203709A JP7450013B2 JP 7450013 B2 JP7450013 B2 JP 7450013B2 JP 2022203709 A JP2022203709 A JP 2022203709A JP 2022203709 A JP2022203709 A JP 2022203709A JP 7450013 B2 JP7450013 B2 JP 7450013B2
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- JP
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- Prior art keywords
- pregabalin
- pharmaceutical composition
- glyceryl monostearate
- solid pharmaceutical
- present
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims description 49
- 229960001233 pregabalin Drugs 0.000 title claims description 48
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 23
- 239000007787 solid Substances 0.000 title claims description 23
- 238000004519 manufacturing process Methods 0.000 title claims description 13
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 60
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 29
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 29
- 239000003826 tablet Substances 0.000 claims description 18
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 12
- 150000003951 lactams Chemical group 0.000 claims description 12
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 229960000913 crospovidone Drugs 0.000 claims description 7
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 7
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 7
- 229920002261 Corn starch Polymers 0.000 claims description 5
- 239000008120 corn starch Substances 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 239000004376 Sucralose Substances 0.000 claims description 2
- 229940099112 cornstarch Drugs 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims 3
- 239000002253 acid Substances 0.000 claims 2
- 238000005303 weighing Methods 0.000 claims 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229940057948 magnesium stearate Drugs 0.000 claims 1
- 230000000087 stabilizing effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 9
- 239000008187 granular material Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
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- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- -1 lactam compound Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
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- 235000003599 food sweetener Nutrition 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000010449 maltitol Nutrition 0.000 description 2
- 239000000845 maltitol Substances 0.000 description 2
- 229940035436 maltitol Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000007909 melt granulation Methods 0.000 description 2
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- ZJMWDULLCAJDLQ-VGMFFHCQSA-N (3s)-3-(aminomethyl)-5-methylhexanoic acid Chemical compound CC(C)C[C@H](CN)CC(O)=O.CC(C)C[C@H](CN)CC(O)=O ZJMWDULLCAJDLQ-VGMFFHCQSA-N 0.000 description 1
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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。 The present invention relates to a solid pharmaceutical composition containing pregabalin that exhibits 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 and reduces neurotransmitter release and is clinically used primarily for the treatment of peripheral neuropathic pain and adjunctive treatment of partial-onset epilepsy. (non-γ-butanoic acid (GABA) receptor agonist or antagonist).
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 in GABA derivatives containing pregabalin, a lactam compound, which is a decomposition product of pregabalin, is produced during formulation and storage, and isomalt is used to suppress the production of the lactam compound. 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。 Further, Patent Document 2 describes that lactam formation 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。 Further, Patent Document 3 describes that lactam formation can be suppressed by using α-amino acids.
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 inhibits the production of lactams 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 lactam formation in a solid pharmaceutical composition 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 present inventors conducted intensive studies to solve the above problems and surprisingly discovered that glyceryl monostearate significantly suppresses the formation of lactams in solid pharmaceutical compositions containing pregabalin, and completed the present invention. did.
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。 That is, 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。 The present invention also provides a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, in which 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。 The present invention also provides a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, in which 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。 The present invention also provides a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, in which the glyceryl monostearate content is 0.01 to 20% by weight based on the pregabalin content.
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 that 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 containing 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。 The present invention also provides a solid pharmaceutical composition containing crospovidone, pregabalin, and glyceryl monostearate, in which 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。 The present invention also provides 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。 The present invention also provides a method for producing a solid pharmaceutical composition, which includes a 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。 The pregabalin-containing solid pharmaceutical composition of the present invention suppresses the production of lactam of pregabalin, which is an active ingredient, and is therefore useful as a pharmaceutical with good pregabalin stability.
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 glyceryl monostearate as long as it is used in the art. The content of glyceryl monostearate is preferably 1 to 20% by weight, more preferably 2 to 10% by weight per solid pharmaceutical composition.
Further, the content of glyceryl monostearate is preferably 0.01 to 20% by weight, more preferably 0.1 to 10% by weight, based on the content of pregabalin.
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 include excipients, binders, disintegrants, and lubricants, but are not particularly limited thereto. In addition to the additives, colorants, antioxidants, thickeners, buffering agents, sweeteners, flavoring agents, perfumes, etc. used in the technical field may be incorporated into the tablets of the present invention. . Examples of sweeteners include aspartame, acesulfame potassium, sucralose, stevia, maltitol, glycerin, lactitol, galactitol, and the like. Examples of the coloring agent 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, excipients include, for example, D-mannitol, lactose (lactose hydrate, spray-dried lactose, fluidized bed granulated lactose, isomerized lactose, reduced lactose, etc.), sucrose, erythritol, sorbitol, xylitol, etc. Can be mentioned. In the present invention, D-mannitol is preferred from the viewpoint of inhibiting 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, examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, etc., and one or more of these may be used in combination as appropriate. .
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, examples of the disintegrant include crospovidone, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, sodium carboxypropyl starch, 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 production of impurities such as lactone bodies. Further, the content of the disintegrant is preferably 1 to 20% by weight, more preferably 5 to 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。 In the present invention, examples of the lubricant 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 coated with a film, for example, an orally disintegrating tablet may be coated with a film.
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 tablets of the present invention can be manufactured by a normal tablet manufacturing method, but from the viewpoint of suppressing the production of impurities such as lactone bodies, additives can be added to pregabalin granules obtained by melt granulation and mixed. After that, it is preferable to formulate the product by compressing it into tablets.
More specifically, the pregabalin-containing tablet of the present invention can be prepared by, for example, mixing pregabalin and a low melting point substance such as glyceryl monostearate, and then heating the mixture to about 40 to 80° C. A low melting point substance is melted, an anti-adhesion agent is added in some cases, and after mixing and granulation, cooling and sizing are performed to prepare a molten granulated product. Tablets can be manufactured by mixing with a drug and the like and then compressing the mixture. Among these operations, the melt granulation operation may be performed using a device such as a fluidized bed granulator, a tumbling fluidized bed granulator, a high-speed stirring granulator, or an extrusion granulator. Moreover, tabletting 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, if any, may then be applied by spray coating using an aqueous film coating formulation. Aqueous film coating formulations may also include, for example, polyvinyl alcohol, hydroxypropyl methyl cellulose, polyvinyl polyethylene glycol graft copolymers, macrogol, titanium dioxide, ferric oxide. The content of the coating is, for example, preferably 0.5 to 10% by weight, more preferably 1 to 6%, 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 explained in more detail below with reference to examples, but the present invention is not limited to the following examples.
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。
In a fluidized bed granulation dryer (manufactured by Powrex; FD-MP-01), 300 g of pregabalin (manufactured by Sumitomo Chemical), 24 g of glycerin monostearate (manufactured by Riken Vitamin; Rikemar P-100), and talc (manufactured by Matsumura Sangyo; 6g of crown talc) was added and heated while flowing with the supply air temperature set at 100℃ to melt the glyceryl monostearate at 70 to 80℃, and after reaching the melting point of glyceryl monostearate or higher, the mixture was allowed to flow for about 5 minutes. Granulate. Thereafter, the mixture is cooled to below the melting point of glyceryl monostearate to obtain granules. The obtained granules were put into a fluidized bed granulation dryer (manufactured by Powrex; FD-MP-01), and 15.96 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Corporation Food Tech) and maltitol (Mitsubishi A solution prepared by dissolving 8.04 g of Amalty (manufactured by Shoji Foodtech) in 216 g of purified water was sprayed, and after drying, pregabalin granules were obtained.
After sifting the obtained pregabalin granules with a 500 μm sieve, 550.8 g of D-mannitol (Granutol S, manufactured by Freund Sangyo), 48 g of crospovidone (manufactured by BASF; Kollidon CF-L) and magnesium stearate (manufactured by Taihei Chemical Co., Ltd.) were added. After mixing with 7.2 g of industrially produced (vegetable) powder to make a powder for tabletting, it was compressed using a rotary tabletting 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。 In addition, as a comparative example, a stress test was conducted on commercially available Lyrica OD tablets 25 mg (orally disintegrating tablets containing pregabalin, Pfizer Inc., hereinafter referred to as "Comparative Example 1") at 50°C for 7 days and 14 days in a sealed state. After that, the proportion 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)
A stress test was conducted on the tablets of Example 1 and Comparative Example 1 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>
To measure the purity, the peak area of pregabalin was measured using HPLC under the following measurement conditions, and the ratio (%) of the peak area of the lactam compound to the peak area of pregabalin was measured.
Take an amount corresponding to 100 mg of pregabalin, add 10 mL of water, and perform ultrasonic treatment while shaking occasionally. This liquid is centrifuged if necessary, and the supernatant liquid is filtered through a filter with a pore size of 1.0 μm or less to obtain a sample solution.
HPLC measurement conditions Detector: Ultraviolet absorption photometer (210 nm)
Column: Octadecyl silylated silica gel packed column for liquid chromatography Column temperature: Around 35°C Mobile phase A: Dissolve 5.28 g of diammonium hydrogen phosphate in 1000 mL of water, and adjust the pH to 6.5 by adding phosphoric acid. Add 200 mL of methanol 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: 20μmL
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 lactam was observed from the beginning at 50°C for 7 days and 14 days, but in Example 1, the production of lactam was suppressed.
Claims (2)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2022203709A JP7450013B2 (en) | 2018-02-27 | 2022-12-20 | Pregabalin-containing solid pharmaceutical composition and method for producing the same |
| JP2024032166A JP2024051175A (en) | 2018-02-27 | 2024-03-04 | Pregabalin-containing solid pharmaceutical composition and method for producing same |
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| CN110742868A (en) * | 2019-11-20 | 2020-02-04 | 合肥拓锐生物科技有限公司 | Mirogabalin Besilate orally disintegrating tablet |
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| WO2019124358A1 (en) | 2017-12-19 | 2019-06-27 | 大原薬品工業株式会社 | Method for improving chemical stability of pregabalin by particle size control |
| WO2019146642A1 (en) | 2018-01-24 | 2019-08-01 | 大原薬品工業株式会社 | METHOD FOR IMPROVING CHEMICAL STABILITY OF γ-AMINOBUTYRIC ACID DERIVATIVE- CONTAINING TABLET |
| JP2019142834A (en) | 2017-07-31 | 2019-08-29 | 大原薬品工業株式会社 | Solid formulations containing pregabalin and suitable excipients |
| JP7200408B2 (en) | 2018-02-27 | 2023-01-06 | 日本ジェネリック株式会社 | Solid pharmaceutical composition containing pregabalin and method for producing the same |
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| WO2009066325A1 (en) * | 2007-11-23 | 2009-05-28 | Lupin Limited | Controlled release pharmaceutical compositions of pregabalin |
| JP2019073478A (en) * | 2017-10-17 | 2019-05-16 | 日本ケミファ株式会社 | Solid preparation containing 4-aminobutanoic acid analog and production method thereof |
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| JP2019142834A (en) | 2017-07-31 | 2019-08-29 | 大原薬品工業株式会社 | Solid formulations containing pregabalin and suitable excipients |
| WO2019124358A1 (en) | 2017-12-19 | 2019-06-27 | 大原薬品工業株式会社 | Method for improving chemical stability of pregabalin by particle size control |
| WO2019146642A1 (en) | 2018-01-24 | 2019-08-01 | 大原薬品工業株式会社 | METHOD FOR IMPROVING CHEMICAL STABILITY OF γ-AMINOBUTYRIC ACID DERIVATIVE- CONTAINING TABLET |
| JP7200408B2 (en) | 2018-02-27 | 2023-01-06 | 日本ジェネリック株式会社 | Solid pharmaceutical composition containing pregabalin and method for producing the same |
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| JP2023024600A (en) | 2023-02-16 |
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