CN105476952A - 一种白蛋白结合型紫杉醇缓释制剂及其制备方法 - Google Patents

一种白蛋白结合型紫杉醇缓释制剂及其制备方法 Download PDF

Info

Publication number
CN105476952A
CN105476952A CN201510860360.3A CN201510860360A CN105476952A CN 105476952 A CN105476952 A CN 105476952A CN 201510860360 A CN201510860360 A CN 201510860360A CN 105476952 A CN105476952 A CN 105476952A
Authority
CN
China
Prior art keywords
preparation
albumin
paclitaxel
slow release
bound type
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201510860360.3A
Other languages
English (en)
Inventor
王俊贤
张法
王建昌
阎隽
阎家麒
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Grand Biological Medicine Science And Technology Ltd Co Is Trained In Chengdu
Original Assignee
Grand Biological Medicine Science And Technology Ltd Co Is Trained In Chengdu
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Grand Biological Medicine Science And Technology Ltd Co Is Trained In Chengdu filed Critical Grand Biological Medicine Science And Technology Ltd Co Is Trained In Chengdu
Priority to CN201510860360.3A priority Critical patent/CN105476952A/zh
Publication of CN105476952A publication Critical patent/CN105476952A/zh
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/13—Coniferophyta (gymnosperms)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Inorganic Chemistry (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biotechnology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种白蛋白结合型紫杉醇缓释制剂及其制备方法。该制剂组分包含：无菌紫杉醇、人血清白蛋白、药用级壳聚糖。本发明提供的一种白蛋白结合型紫杉醇缓释制剂，可提高紫杉醇释放的稳定性和安全性，延长药效，提高靶向能力，减少药物副反应。选择壳聚糖凝胶类为载体和合适的配比能够保护药物免受环境影响，隔离活性成分，降低挥发性和毒性，可获得适宜的释药速度，起到作用和缓而持久、不良反应较少的效果，并且可以提高药物有效率。

Description

一种白蛋白结合型紫杉醇缓释制剂及其制备方法
技术领域
本发明涉及医药领域，具体涉及一种白蛋白结合型紫杉醇缓释制剂及其制备方法。
背景技术
紫杉醇是从红豆杉属植物中分离纯化得到的天然抗肿瘤药物。是新型抗微管药物，通过促进微管蛋白聚合，抑制解聚，保持微管蛋白稳定，抑制细胞有丝分裂。体外实验证明紫杉醇具有显著的放射增敏作用，可能是使细胞中止于对放疗敏感的G2和M期。药理和临床研究发现，紫杉醇具有广谱的抗癌活性，对卵巢癌和乳腺癌有独特的疗效，是继顺铂和阿霉素后最有希望的化疗药物，被国内外专家誉为90年代抗肿瘤药最重大成就之一。紫杉醇注射液是治疗卵巢癌、乳腺癌、肺癌、鼻咽癌等实体肿瘤的一线用药。对于头颈癌、食管癌，精原细胞瘤，复发非何金氏淋巴瘤等有一定疗效。是治疗难治性卵巢癌的最有效药物之一，在治疗乳腺癌疾病中占有重要地位；是高效、低毒和广谱的抗癌药，也是目前市场需求量最大和市场销售额增长最快的抗癌药，约占化疗药的30％以上。
白蛋白结合型紫杉醇(Abraxane)是美国FDA批准用于转移性乳腺癌治疗的注射用紫杉醇，是全球首个获批的无溶剂型紫杉类化疗药物，通过利用肿瘤摄取营养的生物机制和纳米微粒白蛋白结合技术平台，使药物高浓度地聚集在肿瘤组织内并发挥高效抗肿瘤作用。该剂型的药物有效率有所提高，但是由于白蛋白在药物传输过程中降解速率较大，对到达病灶的有效药物量有一定影响。
发明内容
本发明提供了一种白蛋白结合型紫杉醇缓释制剂及其制备方法。主要利用壳聚糖的成膜性能及其良好的生理活性，在白蛋白结合型紫杉醇外部包裹壳聚糖膜，既不会引起生物学反应，还可以提高紫杉醇的稳定性和安全性，提高药物利用率，延长药效，提高靶向能力，起列作用和缓而持久、不良反应较少的治疗效果。
具体实施方式
下面结合具体实施例对本发明作进一步说明，以助于理解本发明的内容。
实施例1
将纳米级无菌紫杉醇1g加入20ml温度为20℃的无水乙醇中溶解，加入橄榄油10g，搅拌均匀，加入大豆磷脂1g，注射用生理盐水40ml搅拌均匀，加入人血清白蛋白10g搅拌均匀，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，即得一种白蛋白结合型紫杉醇冻干制剂；
无菌壳聚糖20g加入温度为20℃的注射用水中50ml，保温搅拌过夜得透明液体，加入白蛋白结合型紫杉醇冻干制剂，高速搅拌形成包裹均匀的乳液，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，并加入注射用水150ml溶解得到缓释型制剂。
实施例2
将纳米级无菌紫杉醇0.5g加入20ml温度为30℃的无水乙醇中溶解，加入橄榄油7g，搅拌均匀，加入大豆磷脂2g，注射用生理盐水30ml搅拌均匀，加入人血清白蛋白10g搅拌均匀，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，即得一种白蛋白结合型紫杉醇冻干制剂；
无菌壳聚糖15g加入温度为35℃的注射用水中40ml，保温搅拌过夜得透明液体，加入白蛋白结合型紫杉醇冻干制剂，高速搅拌形成包裹均匀的乳液，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，并加入注射用水100ml溶解得到缓释型制剂。
实施例3
将纳米级无菌紫杉醇0.5g加入15ml温度为35℃的无水乙醇中溶解，加入橄榄油6g，搅拌均匀，加入大豆磷脂1g，注射用生理盐水40ml搅拌均匀，加入人血清白蛋白8g搅拌均匀，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，即得一种白蛋白结合型紫杉醇冻干制剂；
无菌壳聚糖10g加入温度为35℃的注射用水中40ml，保温搅拌过夜得透明液体，加入白蛋白结合型紫杉醇冻干制剂，高速搅拌形成包裹均匀的乳液，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，并加入注射用水100ml溶解得到缓释型制剂。
实施例4：
将纳米级无菌紫杉醇2g加入30ml温度为20℃的无水乙醇中溶解，加入橄榄油10g，搅拌均匀，加入大豆磷脂2g，注射用生理盐水200ml搅拌均匀，加入人血清白蛋白60g搅拌均匀，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，即得一种白蛋白结合型紫杉醇冻干制剂；
无菌壳聚糖10g加入温度为35℃的注射用水中40ml，保温搅拌过夜得透明液体，加入白蛋白结合型紫杉醇冻干制剂，高速搅拌形成包裹均匀的乳液，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，并加入注射用水250ml溶解得到缓释型制剂。
实施例5：
将纳米级无菌紫杉醇1g加入20ml温度为38℃的无水乙醇中溶解，加入橄榄油20g，搅拌均匀，加入大豆磷脂5g，注射用生理盐水200ml搅拌均匀，加入人血清白蛋白20g搅拌均匀，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，即得一种白蛋白结合型紫杉醇冻干制剂；
无菌壳聚糖50g加入温度为40℃的注射用水中200ml，保温搅拌过夜得透明液体，加入白蛋白结合型紫杉醇冻干制剂，高速搅拌形成包裹均匀的乳液，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，并加入注射用水400ml溶解得到缓释型制剂。

Claims (7)

1.一种白蛋白结合型紫杉醇缓释制剂，包括无菌紫杉醇(纳米级)、人血清白蛋白(纳米级)、表面活性剂、油相等，其特征在于制剂中加入无菌壳聚糖。
2.根据权利要求1所述白蛋白结合型紫杉醇缓释制剂，其含量比例为无菌紫杉醇用量1份、人血清白蛋白用量5-30份、无菌壳聚糖用量5-50份、油相10-20份、表面活性剂1-5份。
3.根据权利要求1所述白蛋白结合型紫杉醇缓释制剂，壳聚糖脱乙酰度为40-60％，相对分子质量低于1×104。
4.根据权利要求1所述白蛋白结合型紫杉醇缓释制剂，所述表面活性剂为磷脂、壳聚糖聚乙二醇等，其中磷脂为大豆磷脂、蛋黄磷脂或合成磷脂，所述磷脂纯度为90％以上。
5.根据权利要求1所述白蛋白结合型紫杉醇缓释制剂，油相选自橄榄油、薏苡仁油、三丁酸甘油酯、三辛酸甘油酯的一种或几种。
6.一种白蛋白结合型紫杉醇缓释制剂的制备方法，包括如下步骤：
(1)一定温度下将纳米级无菌紫杉醇加入无水乙醇中溶解，加入油相，搅拌均匀，陆续加入表面活性剂和注射用生理盐水搅拌均匀，加入人血清白蛋白搅拌均匀，用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，即得一种白蛋白结合型紫杉醇冻干制剂；
(2)一定温度下无菌壳聚糖加入加入注射用水中，搅拌过夜得透明液体，加入白蛋白结合型紫杉醇冻干制剂，高速搅拌形成包裹均匀的乳液。用0.22μm微孔滤膜过滤，得到微乳溶液；将所得微乳溶液冷冻干燥，并加入注射用水溶解得到缓释型制剂。
7.根据权利要求6所述一种白蛋白结合型紫杉醇缓释制剂的制备方法，制剂的制备温度为20-40℃。
CN201510860360.3A 2015-12-02 2015-12-02 一种白蛋白结合型紫杉醇缓释制剂及其制备方法 Pending CN105476952A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510860360.3A CN105476952A (zh) 2015-12-02 2015-12-02 一种白蛋白结合型紫杉醇缓释制剂及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510860360.3A CN105476952A (zh) 2015-12-02 2015-12-02 一种白蛋白结合型紫杉醇缓释制剂及其制备方法

Publications (1)

Publication Number Publication Date
CN105476952A true CN105476952A (zh) 2016-04-13

Family

ID=55664471

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510860360.3A Pending CN105476952A (zh) 2015-12-02 2015-12-02 一种白蛋白结合型紫杉醇缓释制剂及其制备方法

Country Status (1)

Country Link
CN (1) CN105476952A (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114681408A (zh) * 2020-12-26 2022-07-01 四川汇宇制药股份有限公司 白蛋白结合型紫杉醇纳米粒的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101161236A (zh) * 2007-11-23 2008-04-16 南京师范大学 在微乳中复凝聚工艺的载药纳米粒制备方法
CN101167706A (zh) * 2007-10-26 2008-04-30 东南大学 壳聚糖纳米微胶囊的合成方法
CN102908321A (zh) * 2012-11-07 2013-02-06 海南中化联合制药工业股份有限公司 一种白蛋白结合型紫杉醇纳米粒冻干制剂及其制备方法
CN103127002A (zh) * 2013-03-11 2013-06-05 南京中医药大学 一种注射用载纳米粒的微球系统及其制备方法
CN103655459A (zh) * 2013-12-19 2014-03-26 中国药科大学 一种多功能微乳凝胶制剂及其制备工艺
CN104288095A (zh) * 2014-01-15 2015-01-21 南京大学 一种用于膀胱内递送药理活性物质的漂浮凝胶及其药物制剂

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101167706A (zh) * 2007-10-26 2008-04-30 东南大学 壳聚糖纳米微胶囊的合成方法
CN101161236A (zh) * 2007-11-23 2008-04-16 南京师范大学 在微乳中复凝聚工艺的载药纳米粒制备方法
CN102908321A (zh) * 2012-11-07 2013-02-06 海南中化联合制药工业股份有限公司 一种白蛋白结合型紫杉醇纳米粒冻干制剂及其制备方法
CN103127002A (zh) * 2013-03-11 2013-06-05 南京中医药大学 一种注射用载纳米粒的微球系统及其制备方法
CN103655459A (zh) * 2013-12-19 2014-03-26 中国药科大学 一种多功能微乳凝胶制剂及其制备工艺
CN104288095A (zh) * 2014-01-15 2015-01-21 南京大学 一种用于膀胱内递送药理活性物质的漂浮凝胶及其药物制剂

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114681408A (zh) * 2020-12-26 2022-07-01 四川汇宇制药股份有限公司 白蛋白结合型紫杉醇纳米粒的制备方法
CN114681408B (zh) * 2020-12-26 2023-06-23 四川汇宇制药股份有限公司 白蛋白结合型紫杉醇纳米粒的制备方法

Similar Documents

Publication Publication Date Title
Qu et al. Docetaxel-loaded human serum albumin (HSA) nanoparticles: synthesis, characterization, and evaluation
Hussein et al. Novel drug delivery systems based on silver nanoparticles, hyaluronic acid, lipid nanoparticles and liposomes for cancer treatment
Cao et al. Paclitaxel-loaded macrophage membrane camouflaged albumin nanoparticles for targeted cancer therapy
Wang et al. Roles of ligand and TPGS of micelles in regulating internalization, penetration and accumulation against sensitive or resistant tumor and therapy for multidrug resistant tumors
Zhang et al. Ferroptosis-induced anticancer effect of resveratrol with a biomimetic nano-delivery system in colorectal cancer treatment
Li et al. Combination lung cancer chemotherapy: design of a pH-sensitive transferrin-PEG-Hz-lipid conjugate for the co-delivery of docetaxel and baicalin
Yang et al. Hyaluronic acid-coated nanostructured lipid carriers for targeting paclitaxel to cancer
Liu et al. Curcumin loaded polymeric micelles inhibit breast tumor growth and spontaneous pulmonary metastasis
Yang et al. Dual-targeting hybrid nanoparticles for the delivery of SN38 to Her2 and CD44 overexpressed human gastric cancer
Song et al. Combining disulfiram and poly (l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance
Giri et al. Nano-encapsulation of capsaicin on lipid vesicle and evaluation of their hepatocellular protective effect
CN103804472B (zh) 一种紫杉烷类药物前体
CN102908321A (zh) 一种白蛋白结合型紫杉醇纳米粒冻干制剂及其制备方法
Ungaro et al. Core-shell biodegradable nanoassemblies for the passive targeting of docetaxel: features, antiproliferative activity and in vivo toxicity
CN106083769A (zh) 一种还原响应的紫杉醇前药及制备纳米胶束载体方法
Fan et al. Self‐assembled bifunctional peptide as effective drug delivery vector with powerful antitumor activity
Chu et al. PEG-derivatized octacosanol as micellar carrier for paclitaxel delivery
Li et al. Targeted delivery of quercetin by biotinylated mixed micelles for non-small cell lung cancer treatment
US20190015335A1 (en) Hepatoprotective particles and systems and methods of use thereof
Li et al. Advanced nanovehicles-enabled delivery systems of epigallocatechin gallate for cancer therapy
Zha et al. In vitro/in vivo evaluation of pH-sensitive Gambogenic acid loaded Zein nanoparticles with polydopamine coating
Li et al. Targeting the Rac1 pathway for improved prostate cancer therapy using polymeric nanoparticles to deliver of NSC23766
Li et al. Self-assembled dual-targeted epirubicin-hybrid polydopamine nanoparticles for combined chemo-photothermal therapy of triple-negative breast cancer
Gao et al. Behavior and anti-glioma effect of lapatinib-incorporated lipoprotein-like nanoparticles
Hu et al. Enhanced antitumor efficacy of folate targeted nanoparticles co-loaded with docetaxel and curcumin

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20160413