CN1935121A - 改进的基于紫杉醇的抗肿瘤制剂 - Google Patents
改进的基于紫杉醇的抗肿瘤制剂 Download PDFInfo
- Publication number
- CN1935121A CN1935121A CNA2006100912563A CN200610091256A CN1935121A CN 1935121 A CN1935121 A CN 1935121A CN A2006100912563 A CNA2006100912563 A CN A2006100912563A CN 200610091256 A CN200610091256 A CN 200610091256A CN 1935121 A CN1935121 A CN 1935121A
- Authority
- CN
- China
- Prior art keywords
- paclitaxel
- preparation
- powder
- mixture
- injectable
- 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
Links
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 71
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 71
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title claims abstract description 70
- 239000000203 mixture Substances 0.000 title claims abstract description 35
- 238000009472 formulation Methods 0.000 title abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 3
- 102000008100 Human Serum Albumin Human genes 0.000 claims abstract description 25
- 108091006905 Human Serum Albumin Proteins 0.000 claims abstract description 25
- 239000002253 acid Substances 0.000 claims abstract description 12
- 239000002105 nanoparticle Substances 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims description 37
- 239000000843 powder Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 238000004108 freeze drying Methods 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 7
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000007853 buffer solution Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 claims 2
- 102000009027 Albumins Human genes 0.000 abstract description 16
- 108010088751 Albumins Proteins 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 239000007864 aqueous solution Substances 0.000 description 21
- 239000007908 nanoemulsion Substances 0.000 description 13
- 230000001954 sterilising effect Effects 0.000 description 11
- 238000004659 sterilization and disinfection Methods 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 230000008014 freezing Effects 0.000 description 10
- 238000007710 freezing Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 239000008174 sterile solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000008389 polyethoxylated castor oil Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000004531 microgranule Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- GBSSSZWYLFUJMB-NOSCCTPQSA-N paclitaxel chloroform Chemical compound ClC(Cl)Cl.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 GBSSSZWYLFUJMB-NOSCCTPQSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 125000002456 taxol group Chemical group 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
-
- 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
-
- 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
- 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
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
一种基于紫杉醇和人血清白蛋白的纳米颗粒的抗肿瘤制剂,它是在纳米颗粒制备过程中,将白蛋白水溶液与紫杉醇混合前,通过向白蛋白水溶液中加入生物相容性酸而得到的,此制剂的可注射的溶液具有在5.4-5.8之间的pH,并具有稳定性和不随时间改变性。
Description
本发明是2003年3月28日递交的申请号为03108362.5、发明名称为“改进的基于紫杉醇的抗肿瘤制剂”的中国专利申请的分案申请。
技术领域
本发明涉及基于紫杉醇和白蛋白纳米颗粒的抗肿瘤制剂,它能产生具有很高的不随时间改变性的可注射的重制水性混合物。
背景技术
紫杉醇是在文献中已知的天然物质,具有重要的抗肿瘤活性。其弱水溶性使其难于对人给药,由于此原因,已开发了多种能使其可注射的系统。
Bristol Myers Squibb(BMS)设计了一种组合物,并获得了专利,它的名称是TAXOL,在此组合物中,用克列莫佛(cremophor)使紫杉醇乳化,这样会使病人产生多种副作用(Lorenz等,药物作用(Agents Action)7,63-67(1987);Weiss等,J.Clin.Oncol.8,1263(1990))。由于活性成分的稀释,BMS制剂还涉及给药时间长的问题。
为了克服所述的缺点,BMS对有同样剂量的紫杉醇但使用其他能避免强过敏性反应的赋形剂的TAXOL制剂进行了专利保护(EP-A-0584001,EP-A-0783885,EP-A-0783886,US 5641803,US5670537)。然而,在所有情况下,必须非常缓慢地对病人给药,超过约3小时。
为防止TAXOL的副作用,鉴于人血清白蛋白(HSA)的生物相容性及其很强的与紫杉醇结合的能力,用它代替cremophor(Kumar等,Res.Comm.in Chem.Path.and Pharm.,80(3),337-343(1993);Paal等,Eur.J.Biochem.268,2187-2191(2001))。HSA形成含有溶解在水不溶性有机溶剂中的活性成分的微球的性质(Kramer等,J.Pharm.Sci.63,1646-1647(1974);Grinstaff和Suslick,J.Am.Chem.Soc.112,7807-7809(1990);Grinstaff和Suslick,Polym.Prepr.32,255-256(1991)),也使得开发以高于TAXOL的浓度给药紫杉醇的系统成为可能。
可以通过已知的超声波、高压匀化和微流化技术得到紫杉醇和HSA的可注射的纳米乳剂。
基于这些要素,并通过使用上述超声波、高压匀化技术,美国VivoRx药物公司已开发了含有紫杉醇和HSA的制剂CAPXOL(R)。
在US 5439686、US 5498421、US 5560933和相应的WO94/18954中,VivoRx要求保护用超声波技术制备的紫杉醇和HSA的微粒,得到平均粒径(MPS)<10微米的颗粒。在这些专利中记载的制备方法不能用于工业化规模,并且如此得到的微粒有太高的MPS,这使其不适于和不能用于对病人给药。
VivoRx很清楚这一点,因此它在US 5916596和US 6096331及WO98/14174和WO99/00113中记载并要求保护通过用无菌0.9%NaCl水溶液重制紫杉醇和HSA的冷冻干燥粉末而得到的无菌纳米乳剂,其MPS<0.2微米。如引证的专利所述的,这些用高压匀化方法得到的纳米乳剂据称有高的稳定性,此处术语“稳定性”的意义既表示MPS不随时间而改变,也表示不出现纳米颗粒沉淀(US6096331,实施例11)。
用最大的细心,本发明人已许多次重复了前述专利的实施例,特别是US 5916596的实施例1、5和6,不曾得到在此专利的实施例和权利要求书中说明的结果。本发明人制备了所记载的混合物,然后在US 5916596推荐的压力范围内用Avestin匀化器对其处理,得到pH=6.7的纳米乳剂,当如所述专利报道的,在旋转蒸发器中蒸发除溶剂时,总产生MPS约0.2微米(蒸发后MPS的增加>0.02微米)的纳米颗粒,它们在可注射的生理溶液中形成的制剂不稳定(MPS的增加约为0.05微米,在约12小时内倾向于沉积),并难于过滤通过0.22微米滤器进行灭菌,这与所述专利中声称的不同。
本申请人已付出最大耐心的努力以用US 5916596记载的膜进行过滤,但这些结果总是失败,造成滤器堵塞并且紫杉醇产率总是低于30%,与声称的70-100%不同。另外,用刚刚描述的方法制备,然后按US 5916596和US 6096331报道的方法冷冻干燥并重制的产品的稳定性(按US 6096331的实施例11的技术评价)从未达到24小时(因此大大少于在专利中所公开的72小时)。
发明内容
本发明的主要目的是提供一种由紫杉醇和人血清白蛋白的纳米颗粒构成的抗肿瘤制剂,它可以用生理溶液重组成可注射的混合物,所述颗粒在其中具有显著大于在现有技术中可能的稳定性,特别是超过24小时的稳定性。
通过由紫杉醇和人血清白蛋白的纳米颗粒的冷冻干燥粉末构成的制剂达到了这一目的和进一步的目的,在制剂中紫杉醇的量在1%-20%之间,白蛋白的量在60%-98%之间,百分数是按重量计,纳米颗粒的平均粒径小于0.2微米,其特征在于所述冷冻干燥的粉末含有1%-20%重量之间的生物相容性盐,此盐由至少一种生物相容性酸成盐或由于存在至少一种生物相容性酸性缓冲物质而得到的,酸或酸性缓冲物质的存在的量是使粉末重制形成的水性可注射混合物的pH在5.4和5.8之间。
盐的存在是由于酸及其盐形成了酸性缓冲物质(如化学家已知的),并且白蛋白中的一些碱性基团与酸成盐,因此得到了其pH低于白蛋白的典型pH(即根据墨克索引13版第1519页记载为6.79-6.89)的混合物。
实验已显示如果使用酸性缓冲物质(例如柠檬酸和柠檬酸钠的混合物),在关于上述稳定性方面,结果不如仅使用酸好(柠檬酸或其它生物相容性酸)。
显然,在加入水并与冷冻干燥粉末形成水性混合物后,可以容易地测定冷冻干燥粉末的pH。研究已显示,酸性纳米颗粒中也存在水:粉末中水的量至高为5%(W/W),通常约2%-4.5%(W/W)。因此,上述含有水的纳米颗粒也形成了本发明的一部分。
本发明还涉及此制剂的可注射的重组水性混合物,其中,紫杉醇的浓度在0.1-3mg/ml之间,优选0.5-2.5mg/ml。
也可以通过将人血清白蛋白(HSA)的无菌水溶液与紫杉醇的无菌溶液混合,并按前述Vivorx专利的教导处理此混合物,得到本发明的制剂,但与这些教导的不同之处在于,在与紫杉醇混合之前,向HSA的水溶液中加入至少一种生物相容性酸或酸性缓冲物质,其加入量足以将溶液的pH调节到5.4-5.8,优选5.5-5.7之间。
生物相容性酸可以选自盐酸、柠檬酸、磷酸、醋酸、生物相容性有机或无机酸。
也可以通过以下方法得到同样的制剂:将0℃-40℃的含有紫杉醇和白蛋白的水性混合物在9000-40000psi的高压下经过匀质化处理,得到纳米乳剂,将其在-20℃和-80℃之间冷冻,并最终在+20℃和+35℃之间的温度下加热冻干,在无菌条件下通过将白蛋白溶解在无菌水中达到2%-3%(W/V)的浓度,然后向此溶液中加入2%-4%(V/V)的氯仿,然后加入占溶液中白蛋白重量5.40%-15.0%,优选5.60%-13.7%的无菌粉末状的紫杉醇,在加入紫杉醇之前向所述白蛋白溶液中加入足够量的至少一种生物相容性酸或酸性缓冲物质以将混合物的pH调节到5.4-5.8,优选5.5-5.7之间,以得到所述的水性混合物。
可以注意到的是:在后一方法中使用无菌粉末状的紫杉醇不仅大大简化了流程本身,也使此方法能与现有技术相比,还使在匀化处理前完成各种组分的混合所需的时间大大缩短,而也能得到更好的最终产率,并简化了为得到所需的无菌冷冻干燥粉末所遵循的条件。
用根据本发明所述的制剂得到的结果是完全意外并令人惊奇的,因为它们与现有技术对于使用由于稀释符合FDA规范的白蛋白可注射溶液而产生的pH值在pH=6.9±0.5的HSA溶液提供的教导不同(见US 5916596的实施例1、5和6)。与现有技术的教导不同的是,已发现pH值在5.4和5.8之间时,对于重组的冷冻干燥产品,可以得到大于24小时的稳定性。
具体实施方式
为阐明对本发明特征的理解,现在描述其实施的一些非限定性的实施例。
实施例1
用HCl和溶解在氯仿中的紫杉醇制备制剂
以无菌软化水将符合FDA规范的可注射的25%(w/v)HSA水溶液(pH=6.9±0.5)稀释到3%(w/v),用1M HCl将其pH调节到5.6,HCl与白蛋白中的某些碱性基团成盐。将40ml预先灭菌的所述溶液与1.2ml紫杉醇的氯仿无菌溶液(59.0mg/ml)混合,然后将混合物在高压下(9000-40000psi)在匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS<0.2微米),将其在无菌条件下冷冻到-25℃,并冻干60小时,同时升温至+20℃。
将得到的含有4.25%(W/W)紫杉醇和3.6%(w/w)水的粉末,用0.9%NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.16微米的MPS,pH=5.6,稳定性>24小时。
用磷酸代替盐酸得到同样的结果。
实施例2
用柠檬酸和溶解在氯仿中的紫杉醇制备制剂
以无菌软化水将符合FDA规范的可注射的25%(w/v)HSA水溶液(pH=6.9±0.5)稀释到2.5%(w/v),用无菌柠檬酸将其pH调节到5.5,柠檬酸与白蛋白中的某些碱性基团成盐。将60ml所述溶液与1.7ml浓度为60.0mg/ml的紫杉醇的氯仿无菌溶液混合,然后将混合物在高压下(9000-40000psi)在匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS<0.2微米),将其在无菌条件下迅速冷冻到-40℃,并冻干55小时,同时升温至+35℃。
将得到的含有5.2%(W/W)紫杉醇和4.9%(w/w)水的粉末,用0.9%NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.17微米的MPS,pH=5.5,稳定性>24小时。
实施例3
用盐酸和溶解在氯仿中的紫杉醇制备制剂
以无菌软化水将符合FDA规范的可注射的25%(w/v)HSA水溶液稀释到3%(w/v),用1M HCl将其pH调节到5.6,盐酸与白蛋白中的某些碱性基团成盐。将60ml所述溶液与1.5ml浓度为75mg/ml的紫杉醇的氯仿无菌溶液混合,然后将混合物在高压下(9000-40000psi)在匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS<0.2微米),将其在无菌条件下迅速冷冻到-50℃,并冻干50小时,同时升温至+30℃。
将得到的含有4.41%(W/W)紫杉醇和3.8%水的粉末,用0.9%NaCl水溶液重制形成紫杉醇浓度为2.5mg/ml的溶液。得到的制剂具有0.175微米的MPS,pH=5.6,稳定性>24小时。
通过重复同样的过程但不加盐酸,因而在大约pH6.5进行,得到有0.24微米MPS且稳定性约10小时的制剂。
实施例4
用柠檬酸从紫杉醇溶液制备制剂
以无菌软化水将符合FDA规范的可注射的25%(w/v)HSA水溶液稀释到3%(w/v),用柠檬酸将其pH调节到5.4,柠檬酸与白蛋白中的某些碱性基团成盐。
在强力搅拌下,将50ml所述溶液与1.25ml紫杉醇的氯仿无菌溶液(75mg/ml)混合至少40分钟。。
将混合物在高压下(9000-40000psi)在匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS<0.2微米),将其在无菌条件下迅速冷冻到-30℃,并冻干57小时,同时升温至+35℃。
将得到的含有5.00%(W/W)紫杉醇和4.3%(w/w)水的粉末,用0.9%NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.19微米的MPS,pH=5.4,稳定性>24小时。
用醋酸代替柠檬酸得到同样的结果。
实施例5
用盐酸和粉末状的紫杉醇制备制剂
以无菌软化水将符合FDA规范的可注射的25%(w/v)HSA水溶液(pH=6.9±0.5)稀释到3%(w/v),用1M盐酸将其pH调节到5.6,盐酸与白蛋白中的某些碱性基团成盐。
将预先灭菌的57ml所述溶液,在强力搅拌下与1.40ml氯仿,并与108mg粉末状的无菌紫杉醇(效价>99%)混合至少30分钟。
将混合物在高压下(9000-40000psi)在匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS<0.2微米),将其在无菌条件下迅速冷冻到-80℃,并冻干55小时,同时升温至+30℃。
将得到的含有4.83%(W/W)紫杉醇和4%(w/w)水的粉末,用0.9%NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.175微米的MPS,pH=5.6,稳定性>24小时。
用磷酸代替盐酸得到同样的结果。
重要的是注意用粉末状的无菌紫杉醇能实现重要的优势:仅需要一种反应器形成含有HSA和紫杉醇的液体混合物,而降低完成此工艺必需的花费和时间。
实施例6
用柠檬酸和粉末状的紫杉醇制备制剂
以无菌软化水将符合FDA规范的可注射的25%(w/v)HSA水溶液稀释到3%(w/v),用柠檬酸将其pH调节到5.4,柠檬酸与白蛋白中的某些碱性基团成盐。
将预先灭菌的50ml所述溶液,在强力搅拌下与1.23ml无菌氯仿,并与98mg粉末状的无菌紫杉醇(效价>99%)混合至少40分钟。
将混合物在高压下(9000-40000psi)在匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS<0.2微米),将其在无菌条件下迅速冷冻到-30℃,并冻干57小时,同时升温至+35℃。
将得到的含有4.80%(W/W)紫杉醇和3.8%(w/w)水的粉末,用0.9%NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.19微米的MPS,pH=5.4,稳定性>24小时。
用醋酸代替柠檬酸得到同样的结果。
实施例7
用无菌柠檬酸和粉末状的紫杉醇制备制剂
以无菌软化水将符合FDA规范的可注射的25%(w/v)HSA水溶液稀释到3%(w/v),用柠檬酸将其pH调节到5.5,柠檬酸与白蛋白中的某些碱性基团成盐。
将37ml所述溶液,在强力搅拌下与0.91ml无菌氯仿和71mg粉末状的无菌紫杉醇(效价>99%)混合至少40分钟,然后将混合物冷却到5-8℃。
将混合物在高压下(9000-40000psi)在匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS<0.2微米),将其在无菌条件下迅速冷冻到-80℃,并冻干58小时,同时升温至+30℃。
将得到的含有4.70%(W/W)紫杉醇和4.5%(w/w)水的粉末,用0.9%NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.185微米的MPS,pH=5.5,稳定性>24小时。
实施例8
制备含有9.36%紫杉醇的制剂
以无菌软化水将符合FDA规范的可注射的25%(w/v)HSA水溶液稀释到3%(w/v),用1M盐酸将其pH调节到5.6,盐酸与白蛋白中的某些碱性基团成盐。60ml所述溶液适当灭菌,在强力搅拌下与2.15ml浓度为110mg/ml的紫杉醇氯仿无菌溶液混合,然后将混合物在高压下(9000-40000psi)在匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS<0.2微米),将其在无菌条件下迅速冷冻到-50℃,并冻干50小时,同时升温至+30℃。
将得到的含有9.36%紫杉醇和3.9%(W/W)水的粉末再与0.9%NaCl水溶液重制形成紫杉醇浓度为2.5mg/ml的溶液。得到的制剂具有0.175微米的MPS,pH=5.6,稳定性>24小时。
实施例9
制备pH 5.5的制剂
以无菌软化水将符合FDA规范的可注射的20%(w/v)HSA水溶液(pH=6.9±0.5)稀释到3%(w/v),用柠檬酸将其pH调节到5.5,柠檬酸与白蛋白中的某些碱性基团成盐。
将110ml所述溶液,在强力搅拌下与4.10ml无菌氯仿和639mg粉末状的无菌紫杉醇(效价>99%)混合,然后将混合物在高压匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS约0.2微米),真空蒸发除去溶剂,冷冻并冻干48小时。
将得到的含有10.8%(W/W)紫杉醇的粉末,用0.9%NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.15微米的MPS,稳定性>24小时。
Claims (7)
1.一种含有紫杉醇和人血清白蛋白的纳米颗粒的冷冻干燥粉末的抗肿瘤制剂,其中紫杉醇的量在1%-20%之间,白蛋白的量在60%-98%之间,百分数是按重量计,纳米颗粒的平均粒径小于0.2微米,其特征在于所述冷冻干燥的粉末含有1%-20%重量之间的的生物相容性盐,它是由至少一种生物相容性酸成盐或由于存在至少一种生物相容性酸缓冲物质而得到的,酸或酸性缓冲物质存在的量是使粉末重制形成的可注射水性混合物的pH在5.4和5.8之间。
2.权利要求1所述的制剂,其特征在于所述pH在5.5和5.7之间。
3.权利要求1和2所述的制剂,其特征在于所述冷冻干燥粉末含有至高为5%(W/W)的水。
4.权利要求1至3所述的制剂,其特征在于当重新形成生理学可注射的混合物时,其含有浓度为0.1-3mg/ml的紫杉醇。
5.根据权利要求1至4所述的制剂的可注射水性混合物,其特征在于其含有浓度为0.1-3mg/ml的紫杉醇。
6.根据权利要求5所述的可注射水性混合物,其特征在于其含有浓度为0.5-2.5mg/ml的紫杉醇。
7.能从根据前述任一权利要求所述的抗肿瘤制剂得到的生理学可注射的混合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2002A000680 | 2002-03-29 | ||
IT2002MI000680A ITMI20020680A1 (it) | 2002-03-29 | 2002-03-29 | Composizione antitumorale migliorata a base di paclitaxel e metodo per il suo ottenimento |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN03108362A Division CN1448132A (zh) | 2002-03-29 | 2003-03-28 | 改进的基于紫杉醇的抗肿瘤制剂 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1935121A true CN1935121A (zh) | 2007-03-28 |
Family
ID=11449618
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2006100912563A Pending CN1935121A (zh) | 2002-03-29 | 2003-03-28 | 改进的基于紫杉醇的抗肿瘤制剂 |
Country Status (15)
Country | Link |
---|---|
US (2) | US20030187062A1 (zh) |
EP (1) | EP1348430A1 (zh) |
JP (1) | JP2003300877A (zh) |
KR (1) | KR20030078740A (zh) |
CN (1) | CN1935121A (zh) |
AU (1) | AU2003200926A1 (zh) |
BR (1) | BR0300826A (zh) |
CA (1) | CA2423884A1 (zh) |
IL (1) | IL154761A0 (zh) |
IT (1) | ITMI20020680A1 (zh) |
MX (1) | MXPA03002544A (zh) |
NO (1) | NO340395B1 (zh) |
NZ (1) | NZ524604A (zh) |
RU (1) | RU2003108822A (zh) |
ZA (1) | ZA200302039B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101658516B (zh) * | 2008-08-26 | 2011-10-05 | 齐鲁制药有限公司 | 紫杉醇类药物组合物及其制备方法 |
CN115025053A (zh) * | 2021-03-05 | 2022-09-09 | 石药集团中奇制药技术(石家庄)有限公司 | 一种稳定的多西他赛白蛋白纳米粒组合物 |
Families Citing this family (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030133955A1 (en) * | 1993-02-22 | 2003-07-17 | American Bioscience, Inc. | Methods and compositions useful for administration of chemotherapeutic agents |
US20070116761A1 (en) * | 1993-02-22 | 2007-05-24 | Desai Neil P | Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
US8137684B2 (en) | 1996-10-01 | 2012-03-20 | Abraxis Bioscience, Llc | Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
US8853260B2 (en) * | 1997-06-27 | 2014-10-07 | Abraxis Bioscience, Llc | Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
US20030199425A1 (en) * | 1997-06-27 | 2003-10-23 | Desai Neil P. | Compositions and methods for treatment of hyperplasia |
NZ525580A (en) * | 1997-06-27 | 2004-08-27 | Vivorx Pharmaceuticals Inc | Vehicles for intravenous administration of paclitaxel having reduced toxicity |
JP2005515187A (ja) * | 2001-11-26 | 2005-05-26 | スーパージェン インコーポレイテッド | ポリオキシエチル化ひまし油を使用する医薬組成物の調製方法 |
JP4975964B2 (ja) | 2002-06-26 | 2012-07-11 | メディゲーネ アクチエンゲゼルシャフト | 脂肪親和性化合物から成る陽イオン性リポソームの製法 |
CN104587479A (zh) | 2002-12-09 | 2015-05-06 | 阿布拉西斯生物科学有限责任公司 | 组合物和传递药剂的方法 |
DK1694660T3 (da) | 2003-12-12 | 2009-08-10 | Biorganica Ltda | Fremgangsmåde til fremstilling af vandfri og hydrerede aktive farmaceutiske bestanddele (API's); stabile farmaceutiske sammensætninger fremstillet af disse og anvendelser af disse sammensætninger |
US8003122B2 (en) * | 2004-03-31 | 2011-08-23 | Cordis Corporation | Device for local and/or regional delivery employing liquid formulations of therapeutic agents |
US7989490B2 (en) | 2004-06-02 | 2011-08-02 | Cordis Corporation | Injectable formulations of taxanes for cad treatment |
US8735394B2 (en) * | 2005-02-18 | 2014-05-27 | Abraxis Bioscience, Llc | Combinations and modes of administration of therapeutic agents and combination therapy |
ATE531365T1 (de) | 2005-02-18 | 2011-11-15 | Abraxis Bioscience Llc | Kombinationen und modi zur verabreichung therapeutischer mittel und kombinationstherapie |
BRPI0615292A8 (pt) | 2005-08-31 | 2018-03-06 | Abraxis Bioscience Llc | composições e métodos para preparação de fármacos de má solubilidade em água com estabilidade aumentada |
DK3311805T3 (da) * | 2005-08-31 | 2020-04-14 | Abraxis Bioscience Llc | Sammensætninger, der omfatter svært vandopløselige farmaceutiske midler og antimikrobielle midler |
AR054215A1 (es) | 2006-01-20 | 2007-06-13 | Eriochem Sa | Una formulacion farmaceutica de un taxano, una composicion solida de un taxano liofilizado a partir de una solucion de acido acetico, un procedimiento para la preparacion de dicha composicion solida de un taxano, una composicion solubilizante de un taxano liofilizado, y un conjunto de elementos (kit |
US20080280987A1 (en) * | 2006-08-31 | 2008-11-13 | Desai Neil P | Methods of inhibiting angiogenesis and treating angiogenesis-associated diseases |
JP2008260705A (ja) * | 2007-04-11 | 2008-10-30 | Fujifilm Corp | 注射用組成物 |
AR063111A1 (es) | 2007-10-03 | 2008-12-30 | Eriochem Sa | Una formulacion farmaceutica de taxano |
EP2252266A1 (en) | 2008-02-11 | 2010-11-24 | Yissum Research Development Company of the Hebrew University of Jerusalem | Beta-casein assemblies for mucosal delivery of therapeutic bioactive agents |
US8871276B2 (en) | 2008-02-11 | 2014-10-28 | Technion Research And Development Foundation Ltd. | Beta-casein assemblies for mucosal delivery of therapeutic bioactive agents |
US8865222B2 (en) | 2008-02-11 | 2014-10-21 | Technion Research And Development Foundation Ltd. | Beta-casein assemblies for enrichment of food and beverages and methods of preparation thereof |
US8420110B2 (en) * | 2008-03-31 | 2013-04-16 | Cordis Corporation | Drug coated expandable devices |
US8409601B2 (en) * | 2008-03-31 | 2013-04-02 | Cordis Corporation | Rapamycin coated expandable devices |
AU2009234127B2 (en) * | 2008-04-10 | 2015-04-30 | Abraxis Bioscience, Llc | Compositions of hydrophobic taxane derivatives and uses thereof |
RU2559570C2 (ru) | 2009-04-15 | 2015-08-10 | АБРАКСИС БАЙОСАЙЕНС, ЭлЭлСи | Композиции без приона на основе наночастиц и способы их получения |
WO2011017835A1 (en) * | 2009-08-11 | 2011-02-17 | Nanjing University | Preparation method of protein or peptide nanoparticles for in vivo drug delivery by unfolding and refolding |
RU2561055C2 (ru) * | 2009-08-25 | 2015-08-20 | АБРАКСИС БАЙОСАЙЕНС, ЭлЭлСи | Комбинированная терапия композициями наночастиц таксана и ингибиторами хэджхог |
AU2011230512B2 (en) | 2010-03-26 | 2016-09-15 | Abraxis Bioscience, Llc | Methods of treatment of hepatocellular carcinoma |
PL2552415T3 (pl) | 2010-03-29 | 2017-03-31 | Abraxis Bioscience, Llc | Sposoby leczenia nowotworu |
CN105147613A (zh) | 2010-03-29 | 2015-12-16 | 阿布拉科斯生物科学有限公司 | 增强药物递送和治疗剂有效性的方法 |
MY162903A (en) | 2010-06-04 | 2017-07-31 | Abraxis Bioscience Llc | Methods of treatment of pancreatic cancer |
BR112014014323A2 (pt) | 2011-12-14 | 2017-06-13 | Abraxis Bioscience Llc | uso de excipientes poliméricos para liofilização ou congelamento de partículas |
US9149455B2 (en) | 2012-11-09 | 2015-10-06 | Abraxis Bioscience, Llc | Methods of treating melanoma |
NZ630392A (en) | 2013-03-12 | 2016-10-28 | Abraxis Bioscience Llc | Methods of treating lung cancer |
JP6309610B2 (ja) | 2013-03-14 | 2018-04-11 | アブラクシス バイオサイエンス, エルエルシー | 膀胱がんを処置する方法 |
WO2015134543A1 (en) * | 2014-03-05 | 2015-09-11 | Sorrento Therapeutics, Inc. | Pharmacokinetically equivalent nanoparticle compositions |
US10705070B1 (en) | 2015-03-05 | 2020-07-07 | Abraxis Bioscience, Llc | Methods of assessing suitability of use of pharmaceutical compositions of albumin and poorly water soluble drug |
US10527604B1 (en) | 2015-03-05 | 2020-01-07 | Abraxis Bioscience, Llc | Methods of assessing suitability of use of pharmaceutical compositions of albumin and paclitaxel |
DK3313401T3 (da) | 2015-06-29 | 2021-11-15 | Abraxis Bioscience Llc | Nanopartikler omfattende sirolimus og albumin til anvendelse i behandling af epithelioide celletumorer |
CN106420665B (zh) * | 2016-10-28 | 2019-04-16 | 浙江省林业科学研究院 | 一种包裹紫杉烷类药物的白蛋白纳米颗粒载体的制备方法 |
KR20200135410A (ko) | 2018-03-20 | 2020-12-02 | 아브락시스 바이오사이언스, 엘엘씨 | mTOR 억제제 및 알부민의 나노입자의 투여를 통한 중추 신경계 장애의 치료 방법 |
CA3112201A1 (en) * | 2018-10-16 | 2020-04-23 | US Nano Food & Drug INC | Intratumor injection formulation |
KR20220106758A (ko) | 2019-10-28 | 2022-07-29 | 아브락시스 바이오사이언스, 엘엘씨 | 알부민 및 라파마이신의 제약 조성물 |
IL297015A (en) | 2020-04-13 | 2022-12-01 | US Nano Food & Drug INC | Basic formulation of intratumoral chemotherapy injection |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6096331A (en) * | 1993-02-22 | 2000-08-01 | Vivorx Pharmaceuticals, Inc. | Methods and compositions useful for administration of chemotherapeutic agents |
US5439686A (en) * | 1993-02-22 | 1995-08-08 | Vivorx Pharmaceuticals, Inc. | Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor |
WO1994018954A1 (en) * | 1993-02-22 | 1994-09-01 | Vivorx Pharmaceuticals, Inc. | Methods for in vivo delivery of biologics and compositions useful therefor |
US5362478A (en) * | 1993-03-26 | 1994-11-08 | Vivorx Pharmaceuticals, Inc. | Magnetic resonance imaging with fluorocarbons encapsulated in a cross-linked polymeric shell |
US5916596A (en) * | 1993-02-22 | 1999-06-29 | Vivorx Pharmaceuticals, Inc. | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof |
US6441025B2 (en) * | 1996-03-12 | 2002-08-27 | Pg-Txl Company, L.P. | Water soluble paclitaxel derivatives |
NZ525580A (en) * | 1997-06-27 | 2004-08-27 | Vivorx Pharmaceuticals Inc | Vehicles for intravenous administration of paclitaxel having reduced toxicity |
EP1100494A1 (en) * | 1998-07-30 | 2001-05-23 | Novopharm Biotech, Inc. | Pharmaceutically composition comprising an aqueous solution of paclitaxel and albumin |
US6350464B1 (en) * | 1999-01-11 | 2002-02-26 | Guilford Pharmaceuticals, Inc. | Methods for treating ovarian cancer, poly (phosphoester) compositions, and biodegradable articles for same |
EP1178786A4 (en) * | 1999-05-21 | 2006-03-01 | American Bioscience Inc | PHARMACOLOGICALLY ACTIVE PROTEIN STABILIZING AGENTS; METHODS OF MANUFACTURE AND METHODS OF USE |
US6482439B2 (en) * | 1999-12-29 | 2002-11-19 | Nanodelivery, Inc. | Drug delivery system exhibiting permeability control |
JP2004507451A (ja) * | 2000-04-10 | 2004-03-11 | テバ ファーマシューティカル インダストリーズ リミティド | アポトーシス誘導性化学療法剤の投与による癌の治療のための方法及び組成物 |
ITMI20001107A1 (it) * | 2000-05-18 | 2001-11-18 | Acs Dobfar Spa | Metodo per il trattamento di tumori solici mediante microparticelle di albumina incorporanti paclitaxel |
-
2002
- 2002-03-29 IT IT2002MI000680A patent/ITMI20020680A1/it unknown
-
2003
- 2003-03-03 EP EP03004628A patent/EP1348430A1/en not_active Withdrawn
- 2003-03-05 AU AU2003200926A patent/AU2003200926A1/en not_active Abandoned
- 2003-03-05 IL IL15476103A patent/IL154761A0/xx unknown
- 2003-03-07 NZ NZ524604A patent/NZ524604A/en not_active IP Right Cessation
- 2003-03-10 US US10/383,616 patent/US20030187062A1/en not_active Abandoned
- 2003-03-13 ZA ZA200302039A patent/ZA200302039B/xx unknown
- 2003-03-14 JP JP2003069884A patent/JP2003300877A/ja active Pending
- 2003-03-24 MX MXPA03002544A patent/MXPA03002544A/es unknown
- 2003-03-26 BR BR0300826-6A patent/BR0300826A/pt not_active Application Discontinuation
- 2003-03-28 NO NO20031447A patent/NO340395B1/no not_active IP Right Cessation
- 2003-03-28 CA CA002423884A patent/CA2423884A1/en not_active Abandoned
- 2003-03-28 CN CNA2006100912563A patent/CN1935121A/zh active Pending
- 2003-03-28 KR KR10-2003-0019403A patent/KR20030078740A/ko not_active Application Discontinuation
- 2003-03-28 RU RU2003108822/15A patent/RU2003108822A/ru not_active Application Discontinuation
-
2006
- 2006-06-07 US US11/449,053 patent/US20070020337A1/en not_active Abandoned
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101658516B (zh) * | 2008-08-26 | 2011-10-05 | 齐鲁制药有限公司 | 紫杉醇类药物组合物及其制备方法 |
CN115025053A (zh) * | 2021-03-05 | 2022-09-09 | 石药集团中奇制药技术(石家庄)有限公司 | 一种稳定的多西他赛白蛋白纳米粒组合物 |
Also Published As
Publication number | Publication date |
---|---|
NO20031447D0 (no) | 2003-03-28 |
ITMI20020680A1 (it) | 2003-09-29 |
NZ524604A (en) | 2004-03-26 |
RU2003108822A (ru) | 2004-11-10 |
NO340395B1 (no) | 2017-04-10 |
AU2003200926A1 (en) | 2003-10-16 |
CA2423884A1 (en) | 2003-09-29 |
US20030187062A1 (en) | 2003-10-02 |
ZA200302039B (en) | 2004-03-10 |
EP1348430A1 (en) | 2003-10-01 |
IL154761A0 (en) | 2003-10-31 |
ITMI20020680A0 (it) | 2002-03-29 |
US20070020337A1 (en) | 2007-01-25 |
MXPA03002544A (es) | 2005-08-26 |
BR0300826A (pt) | 2004-08-17 |
NO20031447L (no) | 2003-09-30 |
JP2003300877A (ja) | 2003-10-21 |
KR20030078740A (ko) | 2003-10-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1935121A (zh) | 改进的基于紫杉醇的抗肿瘤制剂 | |
Jacob et al. | Emerging role of nanosuspensions in drug delivery systems | |
JP5539839B2 (ja) | 水不溶性物質のマイクロ粒子を製造するための組成物及び方法 | |
AU784416B2 (en) | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof | |
JP5405527B2 (ja) | 薬理薬物の新規製剤、その製造法及びその使用法 | |
US6337092B1 (en) | Composition and method of preparing microparticles of water-insoluble substances | |
KR101003204B1 (ko) | 약물 전달용 고형 지질 나노입자, 그 제조방법, 및 그나노입자를 포함하는 주사제 | |
JP2000501989A (ja) | 無菌条件下にろ過可能な安定化されたナノ粒子 | |
KR20180098702A (ko) | 약리학적 물질의 조성물 및 그 전달방법 | |
US20040058008A1 (en) | Microparticles having serum as a dispersing agent and process for their preparation and use | |
Agarwal et al. | Nanosuspension technology for poorly soluble drugs: recent researches, advances and patents | |
CN1448132A (zh) | 改进的基于紫杉醇的抗肿瘤制剂 | |
EP2272504A2 (en) | Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof | |
CN110075073B (zh) | 一种卡巴他赛蛋白纳米注射剂及其制备方法 | |
US11642420B2 (en) | Nanoparticle pharmaceutical delivery system | |
Elsebay et al. | Nanosuspension: A Formulation Technology for Tackling the Poor Aqueous Solubility and Bioavailability of Poorly Soluble Drugs | |
CN116710073A (zh) | 一种自缓释免疫佐剂混悬液及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |