CN105919955A - 一种鲁索利替尼制剂及其应用 - Google Patents
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Abstract
本发明公开了一种鲁索利替尼制剂及其应用,它是由鲁索利替尼、乳糖、微晶纤维素以及药学上可以接受的载体制备而成。可以获得流动性、稳定性、溶出度较好的鲁索利替尼制剂，从而适合工业化大生产。本发明的治疗中间或高危骨髓纤维化,包括原发性骨髓纤维化，真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化患者的药物组合，配比合理，可以快速释放药物，对所述病症能产生很好的疗效。
Description
技术领域
本发明涉及鲁索利替尼用于制备药物的用途，尤其是用于制备适于口服的片剂和胶囊剂。
鲁索利替尼（Ruxolitinib），分子式: C17H18N6，分子量: 3.6.37，是用于治疗中间或高危骨髓纤维化, 包括原发性骨髓纤维化，真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化患者的三类新药，目前正在进行临床前研究。
背景技术
Ruxolitinib （芦可替尼，又称鲁索利替尼）是一种激酶抑制剂，用于治疗中间或高危骨髓纤维化, 包括原发性骨髓纤维化，真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化患者。芦可替尼（ruxolitinib ，Jakavi）是一种口服JAK1和JAK2酪氨酸激酶抑制剂，于2012年8月获欧盟批准，用于治疗中级或高危骨髓纤维化，包括原发性骨髓纤维化，真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化。目前，鲁索利替尼Jakavi已获全球50多个国家批准，包括欧盟、加拿大和一些亚洲、拉丁美洲和南美洲国家。诺华从Incyte公司授权获得鲁索利替尼Ruxolitinib在美国以外的开发和商业化权利。欧盟委员会和FDA均已授予鲁索利替尼Ruxolitinib治疗骨髓纤维化的孤儿药地位。目前，Incyte已经在美国以商品名Jakafi销售，用于中级或高危骨髓纤维化的治疗。真性红细胞增多症（polycythemia vera，PV）是一种慢性、无法治愈的血液癌症，该病与血细胞生产过剩相关，导致血液增稠，血液凝块风险增加。这些血凝块可导致严重心血管并发症，如中风和心脏病发作，从而增加病发率和死亡率。红细胞增多症患者，常有脾脏肿大及额外衰弱的症状。许多患者经常规治疗后会变得不耐受或抵抗，这与病情恶化的风险升高有关。
发明内容
本发明涉及含有鲁索利替尼的药物组合物及这类组合物用于安全有效治疗中间或高危骨髓纤维化, 包括原发性骨髓纤维化，真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化患者的应用。
本发明还涉及含有鲁索利替尼与其他药物活性物质的口服给药的药物组合物。该组合物是通过使药物活性物质的颗粒粘着在载体基质的表面获得的。使药物活性物质沉着在载体基质上的方法是为了使活性物质/载体基质颗粒的聚集降低到最少。
本发明涉及含有约0.5mg--1000 mg鲁索利替尼的药物组合物，该组合物每日给药三次用于治疗中间或高危骨髓纤维化, 包括原发性骨髓纤维化，真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化患者。优选的药物组合物含有约3mg--100 mg的鲁索利替尼，最优选的药物组合物含有约5mg--50 mg的鲁索利替尼。并且，这类优选的和最优选的药物组合物每日给药2次用于治疗中间或高危骨髓纤维化, 包括原发性骨髓纤维化，真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化患者。
用于每日给药的上述鲁索利替尼药物组合物还可不太经常性的对某些患者给药。例如，对通过每日服用鲁索利替尼药物组合物进行治疗而使他们的中间或高危骨髓纤维化, 包括原发性骨髓纤维化，真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化患者得到控制的患者可施行维持治疗方案以使其免受进一步的感染。这种维持治疗方案包括每日不足一次的服用鲁索利替尼药物组合物。例如，每三或四天给药一次就足矣。
本发明的鲁索利替尼药物组合物可配制成经任何适当途径给药的形式，例如优选的口服给药组合可以是片剂、胶囊、颗粒或粉末形式。按照本领域熟知的方法，鲁索利替尼药物组合物还可以配制成非胃肠、直肠或经鼻腔给药的形式。这类制剂可包括可药用赋形剂，所述赋形剂包括这类组合物中常用的填充剂、助流剂、润滑剂、崩解剂、粘合剂等。本发明还包括缓释制剂。
含有约5mg—50mg鲁索利替尼的片剂和胶囊制剂可按照下述方法进行制备，以确保产品的高效力和良好的均匀性。首先将鲁索利替尼沉着到载体基质的表面上来制备组合物。该步骤通过下列操作完成：形成鲁索利替尼和粘合性物质的溶液，然后在载体基质颗粒保持运动的同时以喷雾的方式应用该溶液。控制条件以使颗粒的聚集降到最低。
干燥后将颗粒与组合物中包含的任何其他成分，例如崩解剂/助流剂/润滑剂混合。然后将得到的粉末压成片或填充到胶囊。
上述方法中的优选溶剂是水或不同浓度的乙醇。
粘合性物质优选是具有高稠度的聚合物。适合的物质包括聚维酮、甲基纤维素、羟甲基纤维素、羟丙甲基纤维素、羟丙基纤维素、羟乙基纤维素，聚维酮、羟甲基纤维素是优选的。终组合物中粘合性物质的含量优选为组合物总重的约1%--约10%（重量）。
终组合物中包括的崩解剂含量优选为组合物总重的约1%--7%。适合的崩解剂包括交联聚维酮、交联羧甲基纤维素、低取代羟丙甲纤维素、淀粉乙醇酸钠、预胶化淀粉和玉米淀粉，交联聚维酮是优选的。
终组合物中包括的润滑剂含量优选为组合物总重的约1%--5%。适合的润滑剂包括微粉硅胶、硬脂酸镁、硬脂酸、硬脂基富马酸钠和月桂基硫酸钠，微粉硅胶、硬脂酸镁是优选的。
具体实施方式
下列实施例说明本发明的鲁索利替尼组合物
实施例1
采用上述方法制备25毫克鲁索利替尼片
| 成分 | 量%（重量/重量） | 量/粒 |
| 鲁索利替尼 | 5 | 10mg |
| 微晶纤维素 | 47.00 | 94 mg |
| 乳糖 | 30.00 | 60 mg |
| 聚维酮 | 5.00 | 10 mg |
| 低取代羟丙甲纤维素 | 10.00 | 20.0mg |
| 硬脂酸镁 | 0.90 | 1.8mg |
| 二氧化硅 | 2.1 | 4.0 mg |
| 纯化水 | 适量 | 适量 |
| 总计 | 100.00 | 200 mg |
实施例2
采用上述方法制备20毫克鲁索利替尼片
| 成分 | 量%（重量/重量） | 量/粒 |
| 鲁索利替尼 | 10.00 | 20 mg |
| 微晶纤维素 | 25.00 | 50 mg |
| 乳糖 | 35.00 | 70 mg |
| 聚维酮 | 14.00 | 28mg |
| 交联聚维酮 | 15.00 | 30.0mg |
| 二氧化硅 | 0.01 | 2.00mg |
| 纯化水 | 适量 | 适量 |
| 总计 | 100.00 | 200 mg |
实施例3
采用上述方法制备15毫克鲁索利替尼片
| 成分 | 量%（重量/重量） | 量/枚 |
| 鲁索利替尼 | 7.50 | 15 mg |
| 微晶纤维素 | 22.50 | 45 mg |
| 乳糖 | 50.00 | 100 mg |
| 聚维酮 | 5.00 | 10 mg |
| 交联聚维酮 | 9.00 | 18 mg |
| 低取代羟丙甲纤维素 | 5.00 | 10 mg |
| 硬脂酸镁 | 1.00 | 2 mg |
| 纯化水 | 适量 | 适量 |
| 总计 | 100.00 | 200 mg |
实施例4
采用上述方法制备10毫克鲁索利替尼片
| 成分 | 量%（重量/重量） | 量/枚 |
| 鲁索利替尼 | 5.00 | 10 mg |
| 微晶纤维素 | 25.00 | 50 mg |
| 乳糖 | 50.00 | 100 mg |
| 聚维酮 | 6.50 | 13 mg |
| 低取代羟丙甲纤维素 | 11.00 | 22 mg |
| 硬脂酸镁 | 1.50 | 3 mg |
| 二氧化硅 | 1.00 | 2 mg |
| 纯化水 | 适量 | 适量 |
| 总计 | 100.00 | 200 mg |
实施例5
采用上述方法制备5毫克鲁索利替尼片
| 成分 | 量%（重量/重量） | 量/枚 |
| 鲁索利替尼 | 2.50 | 5 mg |
| 微晶纤维素 | 40.00 | 80 mg |
| 乳糖 | 52.50 | 105 mg |
| 聚维酮 | 3.00 | 6mg |
| 低取代羟丙甲纤维素 | 1.50 | 3 mg |
| 硬脂酸镁 | 0.5 | 1 mg |
| 二氧化硅 | 0.5 | 1 mg |
| 纯化水 | 适量 | 适量 |
| 总计 | 100.00 | 200.00 mg |
Claims (10)
1.鲁索利替尼用于制备口服给药每日2次用于治疗中间或高危骨髓纤维化, 包括原发性骨髓纤维化，真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化患者；
以片剂或胶囊形式的药物组合物的用途，其中所述药物组合物含有0.5mg—1000mg的鲁索利替尼。
2.权利要求1的用途，其中所述鲁索利替尼的含量为3mg—150mg。
3.权利要求1的用途，其中所述鲁索利替尼的含量为3mg—100mg。
4.权利要求3的用途，其中所述鲁索利替尼的含量为5mg。
5.权利要求3的用途，其中所述鲁索利替尼的含量为10mg。
6.权利要求3的用途，其中所述鲁索利替尼的含量为15mg。
7.权利要求3的用途，其中所述鲁索利替尼的含量为20mg。
8.权利要求3的用途，其中所述鲁索利替尼的含量为25mg。
9.权利要求1的用途，其中的所述组合物含有一种或多种其他药物活性物质。
10.权利要求书1的用途，其中所述的填充剂选自乳糖、木糖醇、微晶纤维素、糊精、甘露醇、山梨醇、蔗糖、淀粉、预胶化淀粉、葡萄糖、磷酸钙、磷酸氢钙、碳酸钙，及其混合物，并且所述鲁索利替尼是通过具有足够黏性的聚合黏性物质黏着在所述填充剂上的。
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019200254A1 (en) * | 2018-04-13 | 2019-10-17 | Tolero Pharmaceuticals, Inc. | Pim kinase inhibitors for treatment of myeloproliferative neoplasms and fibrosis associated with cancer |
| US10562925B2 (en) | 2015-05-18 | 2020-02-18 | Tolero Pharmaceuticals, Inc. | Alvocidib prodrugs having increased bioavailability |
| US10568887B2 (en) | 2015-08-03 | 2020-02-25 | Tolero Pharmaceuticals, Inc. | Combination therapies for treatment of cancer |
| US10624880B2 (en) | 2015-04-20 | 2020-04-21 | Tolero Pharmaceuticals, Inc. | Predicting response to alvocidib by mitochondrial profiling |
| US10875864B2 (en) | 2011-07-21 | 2020-12-29 | Sumitomo Dainippon Pharma Oncology, Inc. | Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitors |
| US11279694B2 (en) | 2016-11-18 | 2022-03-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
| US11471456B2 (en) | 2019-02-12 | 2022-10-18 | Sumitomo Pharma Oncology, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
| CN117298055A (zh) * | 2023-09-18 | 2023-12-29 | 正大制药（青岛）有限公司 | 一种磷酸芦可替尼片及其制备方法 |
| WO2024187415A1 (en) * | 2023-03-15 | 2024-09-19 | Zhejiang Qizheng Pharmaceutical Co., Ltd. | Pharmaceutical composition comprising ruxolitinib |
| WO2024187416A1 (en) * | 2023-03-15 | 2024-09-19 | Zhejiang Qizheng Pharmaceutical Co., Ltd. | Pharmaceutical composition comprising ruxolitinib |
| EP4491175A1 (en) * | 2023-07-10 | 2025-01-15 | Genepharm S.A. | A solid oral composition of ruxolitinib |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103282036A (zh) * | 2010-11-07 | 2013-09-04 | 塔格根公司 | 用于治疗骨髓纤维化的组合物和方法 |
| WO2014016396A1 (en) * | 2012-07-27 | 2014-01-30 | Ratiopharm Gmbh | Oral dosage forms for modified release comprising ruxolitinib |
| CN105007901A (zh) * | 2012-11-15 | 2015-10-28 | 因赛特公司 | 鲁索利替尼的缓释剂型 |
-
2016
- 2016-06-13 CN CN201610409408.3A patent/CN105919955A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103282036A (zh) * | 2010-11-07 | 2013-09-04 | 塔格根公司 | 用于治疗骨髓纤维化的组合物和方法 |
| WO2014016396A1 (en) * | 2012-07-27 | 2014-01-30 | Ratiopharm Gmbh | Oral dosage forms for modified release comprising ruxolitinib |
| CN105007901A (zh) * | 2012-11-15 | 2015-10-28 | 因赛特公司 | 鲁索利替尼的缓释剂型 |
Non-Patent Citations (1)
| Title |
|---|
| SRDAN VERSTOVSEK,ET AL: "A Double-Blind,Placebo-Cotrolled Trial of Ruxolitinib for Myelofibrosis", 《THE NEW ENGLAND JOURNAL OF MEDICINE》 * |
Cited By (14)
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|---|---|---|---|---|
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| US10835537B2 (en) | 2015-08-03 | 2020-11-17 | Sumitomo Dainippon Pharma Oncology, Inc. | Combination therapies for treatment of cancer |
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| WO2019200254A1 (en) * | 2018-04-13 | 2019-10-17 | Tolero Pharmaceuticals, Inc. | Pim kinase inhibitors for treatment of myeloproliferative neoplasms and fibrosis associated with cancer |
| CN112236139A (zh) * | 2018-04-13 | 2021-01-15 | 大日本住友制药肿瘤公司 | 用于治疗骨髓增殖性肿瘤和与癌症相关的纤维化的pim激酶抑制剂 |
| US11471456B2 (en) | 2019-02-12 | 2022-10-18 | Sumitomo Pharma Oncology, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
| WO2024187415A1 (en) * | 2023-03-15 | 2024-09-19 | Zhejiang Qizheng Pharmaceutical Co., Ltd. | Pharmaceutical composition comprising ruxolitinib |
| WO2024187416A1 (en) * | 2023-03-15 | 2024-09-19 | Zhejiang Qizheng Pharmaceutical Co., Ltd. | Pharmaceutical composition comprising ruxolitinib |
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