JP2021517115A - ポルマコキシブ及びプレガバリンを含む疼痛治療用薬剤学的組成物 - Google Patents
ポルマコキシブ及びプレガバリンを含む疼痛治療用薬剤学的組成物 Download PDFInfo
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- JP2021517115A JP2021517115A JP2020545470A JP2020545470A JP2021517115A JP 2021517115 A JP2021517115 A JP 2021517115A JP 2020545470 A JP2020545470 A JP 2020545470A JP 2020545470 A JP2020545470 A JP 2020545470A JP 2021517115 A JP2021517115 A JP 2021517115A
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- pregabalin
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- pain
- polmacoxib
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Abstract
Description
安定性が不足であるという特性を有するプレガバリン主成分と配合適合性試験を通じて薬物−賦形剤間の相互作用のない賦形剤を選別し、その種類を最小化した。ポルマコキシブとプレガバリンとを主成分として表1のような賦形剤を用いて湿式顆粒形態で連合、乾燥、定立及び混合し、カプセル充填した。メッシュ網は、30メッシュ(mesh)として使用した。
大韓民国薬典溶出試験法の第2法(パドル法、装置2)の規格によって、実施例1の製剤に対する生体外(in vitro)比較溶出試験を進行した。対照薬としては、現在市販中であるものを使用し、具体的に、ポルマコキシブに対して、現在アサ製品であるアクセレックスカプセルを対照薬として比較溶出試験を進行し、プレガバリンに対して、リリカカプセル製品を対照薬として比較溶出試験を進行した。
溶出率は、平均で示し、単位は、%である。
表4のように、崩壊剤を調節して、実施例1と同じ方法でカプセル充填した。
実施例2の製剤に対して、実験例1と同じ方法で比較溶出試験を進行した。
表7の組成で16または20メッシュのメッシュ網で処理したことを除き、実施例1と同じ方法でカプセル充填した。
製造工程のうち、メッシュの変化と崩壊剤の有無による溶出変化とを確認するために、実施例3のポルマコキシブに対して、実験例1と同じ方法で比較溶出試験を進行した。溶出液としては、pH1.2を使用し、対照薬としては、アクセレックスカプセルを使用し、その結果は、表8及び図5に示した。
表9の組成によって錠剤形態で製造したことを除き、実施例3と同じ方法で製造した。錠剤製造時に、プレガバリンの不安定性を考慮して、最適の打錠圧を選定して進行した。
実施例4の製剤を硬度別に錠剤で製造して、ポルマコキシブ成分に対して、実験例1と同じ方法で比較溶出試験を進行した。
実施例4の組成によって硬度別に錠剤を製造した後、プレガバリン成分に対して、pH1.2の大韓民国薬典第11改正崩壊試験法の第1液、pH4.0の日本薬典第17改正0.05mol/L酢酸・酢酸ナトリウム緩衝液、pH4.0、pH6.8の大韓民国薬典第11改正崩壊試験法の第2液または水で実験例1と同じ方法で比較溶出試験を進行した。対照薬としては、リリカカプセルを使用した。結果は、表11、表12、図7及び図8に示した。
実施例4による製剤の製造単位増加時に、生産施設で錠剤の打錠性を向上させるために、表13の組成にしたことを除き、実施例4と同じ方法で錠剤を製造した。結晶型のプレガバリン含有組成物打錠時に、キャッピング(capping)現象が発生する恐れがあるので、それを改善するために、微粉の粒子度を有する微結晶セルロースを添加し、賦形剤の量を増加させ、後混合に添加されたクロスカルメロースナトリウムを顆粒に添加した。
実施例5の製剤から打錠性をさらに改善させるために、表14の組成にしたことを除き、実施例4と同じ方法で錠剤を製造した。具体的に、賦形剤の含量を増加させ、二酸化ケイ素を添加した。
実施例6の製剤に対して、実験例1と同じ方法で比較溶出試験を進行した。溶出試験液としてpH1.2または水を使用し、ポルマコキシブに対する対照薬としては、アクセレックス錠剤を、プレガバリンに対する対照薬としては、リリカカプセルを使用した。
ポルマコキシブ成分に対する比較溶出試験結果は、表15及び図9に示し、プレガバリン成分に対する比較溶出試験結果は、表16及び図10に示した。
表17によって徐放出性を示すプレガバリン層と速放出を示すプレガバリン、ポルマコキシブ層を含有する二重層複合錠剤を製造した。上層である速放層には、主成分ポルマコキシブとプレガバリン半分に該当する量を添加して、速放出性薬物放出を示すように組成物を製造し、下層である徐放層には、プレガバリンの残りの半分に該当する量を徐放出性基材を添加して、二重層複合剤を製造した。徐放出性基材としては、ヒドロキシプロピルメチルセルロース、カルボマー及びPEOを使用した。
表18の組成によることを除き、実施例7と同じ方法で複合錠剤を製造した。徐放出性基材としては、ヒドロキシプロピルメチルセルロース、アルギン酸ナトリウム及びカルボキシメチルセルロースナトリウムを使用した。
実験例1と同じ方法で実施例7及び実施例8の錠剤溶出試験を進行し、その結果は、表19及び図11に示した。
実験例1と同じ方法で実施例7及び実施例8の溶出試験を進行し、胃腸管運動抵抗性の測定のために、溶出パドルrpmを50rpmから100rpmに増加させて、溶出試験進行した。
実施例7及び実施例8の組成のうち、徐放層部分の組成のみで錠剤を製造して、実験例1と同じ方法で溶出試験を進行した。二重層錠剤の全体的なプレガバリン溶出結果が、徐放出(sustain−release、SR)形態ではない遅効性(Controlled−release、CR)の放出形態を示して、下層部分である徐放層部分の溶出態様を確認するために、溶出試験を進行した。結果は、表21及び図13に示した。
二重層複合剤組成物のうち、プレガバリンを上、下層の速放層、徐放層に区分して分けず、徐放層部分に添加して、表22のような組成で錠剤を製造した。徐放性基材であるアルギン酸ナトリウムは、安定性試験進行時に、吸湿によって組成物の性状の変化に影響を及ぼすことがあるので、徐放基剤としてヒドロキシプロピルメチルセルロース、カルボマー及びPEOを使用した。
実施例9及び実施例10による錠剤に対して、実験例1と同じ方法で溶出試験を進行した。結果は、表23及び図14に示した。
実験例10の結果を基にして最適の組成物を選定した。溶出率に影響を与えず、錠剤のサイズを減らすための組成物の製造のために、表24の組成によって錠剤を製造した。表の組成のように、速放層の量を減少させると共に、徐放層に含有された賦形剤の量を減少させることにより、最終的な錠剤の重量を減少させた。また、プレガバリン主成分が有する打錠圧による不安定性を改善するために、錠剤の硬度別に製剤を製造した。具体的に、それぞれ5kp及び9kp硬度の錠剤を製造した。
プレガバリン主成分は、打錠圧による不安定性を有するので、実施例11の製剤を硬度別にして錠剤を製造して、溶出試験を進行した。結果は、表25及び図15に示した。
製造スケールを高めて、生産施設で錠剤製造時に、ポルマコキシブが含有された上層組成物の含量が低くて、製造後に錠剤の質量偏差及び含量が均一ではない問題点を改善するために、上層の質量を適量増加させて、表26のような組成で錠剤を製造した。
実施例11及び実施例12の錠剤に対して、実験例1と同じ方法で溶出試験を進行した。プレガバリン成分に対する比較溶出試験結果は、表27及び図16に示し、ポルマコキシブ成分に対する比較溶出試験結果は、表28及び図17に示した。
Claims (16)
- ポルマコキシブ及びプレガバリンを含む疼痛治療用薬剤学的組成物。
- 前記組成物が、炎症性または神経病症性で誘発された急性または慢性疼痛治療用である、請求項1に記載の薬剤学的組成物。
- 前記組成物が、糖尿病性神経障害を含む神経因性疼痛、全般性不安障害による疼痛、線維筋痛症、痛覚過敏症、異質痛、癌疼痛、骨関節炎、リウマチ性関節炎、脊椎炎、五十肩、腰痛または坐骨神経痛を適応症とする、請求項1に記載の薬剤学的組成物。
- ポルマコキシブ対プレガバリンの比率が、1〜300:1〜600重量比である、請求項1に記載の薬剤学的組成物。
- ポルマコキシブ対プレガバリンの比率が、1:1〜1:300重量比である、請求項1に記載の薬剤学的組成物。
- ポルマコキシブ対プレガバリンの比率が、2:1〜2:300重量比である、請求項1に記載の薬剤学的組成物。
- 組成物総重量に対して、ポルマコキシブ0.1〜10重量%及びプレガバリン10〜50重量%含む、請求項1に記載の薬剤学的組成物。
- 薬剤学的に許容される賦形剤をさらに含む、請求項1に記載の薬剤学的組成物。
- 前記賦形剤が、エチルセルロース、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、カルボキシメチルセルロースナトリウム、ポリエチレンオキシド、カルボマー、アルギン酸ナトリウム、マンニトール、クロスカルメロースナトリウム、炭酸水素ナトリウム、及びステアリン酸マグネシウムからなる群から選択される1つ以上を含む、請求項8に記載の薬剤学的組成物。
- 錠剤、カプセル剤または懸濁剤の形態である、請求項1に記載の薬剤学的組成物。
- ポルマコキシブ及びプレガバリンが混合された錠剤、カプセルまたは懸濁剤の形態であり、
前記錠剤は、二重錠、多層錠または単一錠の形態を含む、請求項10に記載の薬剤学的組成物。 - ポルマコキシブ、プレガバリンまたはこれらの混合物が、それぞれ他の層に区分された状態である二重層構造の二重錠または多層構造の多層錠で形成された、請求項1に記載の薬剤学的組成物。
- 徐放層及び速放層に区分されている二重層で形成された、請求項1に記載の薬剤学的組成物。
- 前記徐放層がプレガバリンを含み、前記速放層がポルマコキシブを含む、請求項13に記載の薬剤学的組成物。
- 薬剤学的に許容されるコーティング基剤をさらに含む、請求項1に記載の薬剤学的組成物。
- 薬剤学的に許容される担体をさらに含む、請求項1に記載の薬剤学的組成物。
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KR1020180037054A KR102631399B1 (ko) | 2018-03-30 | 2018-03-30 | 폴마콕시브 및 프레가발린을 포함하는 통증 치료용 약제학적 조성물 |
PCT/KR2019/003225 WO2019190118A1 (ko) | 2018-03-30 | 2019-03-20 | 폴마콕시브 및 프레가발린을 포함하는 통증 치료용 약제학적 조성물 |
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EP (1) | EP3777849A4 (ja) |
JP (1) | JP2021517115A (ja) |
KR (1) | KR102631399B1 (ja) |
CN (1) | CN111867578A (ja) |
BR (1) | BR112020017773A2 (ja) |
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WO2022097764A1 (ko) * | 2020-11-04 | 2022-05-12 | 전남대학교병원 | 프레가발린 및 티아넵틴을 포함하는 신경병성 통증 치료용 약학적 조성물 |
WO2024068242A1 (en) * | 2022-09-29 | 2024-04-04 | Triviumvet Designated Activity Company | Veterinary compositions for use in the treatment of neuropathic pain |
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KR102631399B1 (ko) | 2024-02-01 |
KR20190114403A (ko) | 2019-10-10 |
CN111867578A (zh) | 2020-10-30 |
CA3093899A1 (en) | 2019-10-03 |
US11602517B2 (en) | 2023-03-14 |
BR112020017773A2 (pt) | 2020-12-22 |
WO2019190118A1 (ko) | 2019-10-03 |
EP3777849A1 (en) | 2021-02-17 |
US20210113515A1 (en) | 2021-04-22 |
EP3777849A4 (en) | 2022-02-23 |
US20230293476A1 (en) | 2023-09-21 |
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