WO2016008289A1 - Préparation de faisceau nanolipidique de chlorhydrate d'irinotécan et son procédé de préparation - Google Patents

Préparation de faisceau nanolipidique de chlorhydrate d'irinotécan et son procédé de préparation Download PDF

Info

Publication number
WO2016008289A1
WO2016008289A1 PCT/CN2015/071048 CN2015071048W WO2016008289A1 WO 2016008289 A1 WO2016008289 A1 WO 2016008289A1 CN 2015071048 W CN2015071048 W CN 2015071048W WO 2016008289 A1 WO2016008289 A1 WO 2016008289A1
Authority
WO
WIPO (PCT)
Prior art keywords
irinotecan hydrochloride
preparation
nanolipid
peg
injection
Prior art date
Application number
PCT/CN2015/071048
Other languages
English (en)
Chinese (zh)
Inventor
梁兴杰
李婵
张春秋
王浩
吴雁
杨蓉
Original Assignee
国家纳米科学中心
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 国家纳米科学中心 filed Critical 国家纳米科学中心
Publication of WO2016008289A1 publication Critical patent/WO2016008289A1/fr

Links

Images

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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines

Definitions

  • the invention belongs to the technical field of medicine, relates to a nano-fat bundle preparation and a preparation method thereof, in particular to a irinotecan hydrochloride nano-lipid preparation and a preparation method thereof.
  • Irinotecan hydrochloride is a derivative of camptothecin.
  • Camptothecin is a five-membered alkaloid extracted from the Chinese native plant camptotheca acuminata in 1966, USA. Camptothecin has strong anticancer activity and a broad antitumor spectrum. Camptothecin can specifically bind to type I topoisomerase and inhibit DNA replication repair, gene recombination and transcription associated with it by inhibiting topoisomerase.
  • camptothecin has certain problems in its use as a drug. Its toxic side effects such as myelosuppression and hemorrhagic cystitis, as well as its poor water solubility, have largely limited its clinical application. Therefore, researchers have developed camptothecin derivatives with higher anticancer activity and lower toxicity, such as 10-hydroxycamptothecin, 7-ethyl-10-hydroxycamptothecin (SN-38). Among them, the hydrochloride salt of CPT-11 (ie irinotecan hydrochloride) not only has higher anticancer activity and low toxicity, but also has certain water solubility, which greatly improves its convenience in clinical application. Irinotecan hydrochloride was used as a prodrug and was metabolized to the active SN-38 after administration, showing its antitumor activity.
  • CPT-11 ie irinotecan hydrochloride
  • irinotecan hydrochloride Since the administration of irinotecan hydrochloride produces side effects such as bone marrow function inhibition and gastrointestinal disorders, its use is strictly limited. In addition, the ⁇ -hydroxylactone ring having anticancer activity is easily hydrolyzed, resulting in a decrease in its anticancer activity.
  • a cell cycle-specific metabolic antagonistic substance a camptothecin analog
  • the half-life is short, only a few hours; therefore, in order to prolong the circulation time of the drug in the body, it is conceivable to carry the carrier by using a carrier having a closed vesicle form.
  • camptothecin liposome formulation schemes have been proposed, for example, by including camptothecin in a liposome membrane, Thereby inhibiting the hydrolysis of the ⁇ -hydroxylactone ring; in addition, a method of including the irinotecan hydrochloride active SN-38 itself in the liposome membrane is disclosed, but since SN-38 is difficult to stabilize in the liposome membrane It disappears rapidly in the blood, so it is difficult to maintain the concentration of SN-38 in plasma for a long time; it is also disclosed that the water-soluble derivative irinotecan hydrochloride is encapsulated in the liposome by passive embedding method, and the electrostatic fixation is performed.
  • Passive loading method An example of preparation by a conventional method in which a lipid bilayer membrane is stabilized (Passive loading method).
  • Liticon which is present in the blood for a long time in the state of inhibiting the hydrolysis of the ⁇ -hydroxylactone ring, can maintain the concentration of the active metabolite SN-38 in plasma for a long time, and ensures that the production process is simple and easy to repeat, and is easy to industrialize.
  • tumor tissue has permeability enhancement and retention effect, which can achieve the enrichment of nanoparticles at the tumor site, and the nanoparticle with particle size ⁇ 50 nm is particularly effective for passive targeting of tumor sites. Therefore, it is desirable in the art to prepare nanoparticles of small particle size and make full use of their passive targeting of tumor tissues to achieve enrichment of drugs at tumor sites.
  • Patent CN201410016965 discloses a hydroxycamptothecin nano-lipid preparation and a preparation method thereof
  • the patent CN201410014128 discloses an irinotecan nano-lipid preparation and a preparation method thereof.
  • the nanolipid preparation has the effects of reducing drug toxicity, enhancing tumor targeted enrichment, and improving patient compliance.
  • the composition of the lipid bundle preparation of the above patent is complicated, it is difficult to grasp the ratio, and it is difficult to prepare and has poor practicability; in the above patent, the particle size of the lipid bundle preparation is about 100 nm, and it is reported in the literature that the nanoparticle of ⁇ 50 nm is obvious.
  • irinotecan hydrochloride nanolipid preparation having a simple preparation method, a small particle size and a high encapsulation efficiency, which is easy to obtain, has a good targeting effect, and can achieve sufficient clinical effects.
  • the amount of drug entrapment, and the concentration of irinotecan hydrochloride active metabolite SN-38 in plasma was maintained for a long time.
  • One of the objects of the present invention is to provide a irinotecan hydrochloride nanolipid preparation having a simple preparation method, a small particle size and a high encapsulation efficiency.
  • the present invention employs the following technical solutions:
  • the irinotecan hydrochloride nanolipid preparation comprises an encapsulating material, irinotecan hydrochloride and an aqueous solution for injection, the encapsulating material being selected from the group consisting of PLGA-PEG, PGA-PEG, PCL-PEG, PEG-NH 2 , PEG. a mixture of one or at least two of -COOH, DSPE-PEG, Solutol HS15 and phospholipids.
  • the encapsulating material used is PLGA-PEG.
  • the irinotecan hydrochloride nanolipid preparation comprises at least one of alpha-lactose, sucrose, glucose, and mannitol.
  • the aqueous solvent for injection is selected from the group consisting of deionized water, PBS buffer solution, physiological saline, glucose injection, amino acid injection, or a mixture of at least two.
  • the aqueous solvent for injection used is deionized water.
  • the formulation comprises 10 to 60 parts by weight of the encapsulating material and 10 to 30 parts by weight of irinotecan hydrochloride.
  • the mass of the aqueous solvent for injection is 5 to 100 times, preferably 10 to 30 times the total mass of the carrier material and irinotecan hydrochloride.
  • the irinotecan hydrochloride nanolipid preparation of the invention has simple composition and does not contain complicated components in any existing similar preparations such as dodecahydroxystearate, phospholipid, ethanol, glycerin, etc., thereby having a simple preparation scheme. Reproducible and easy to scale up production.
  • Another object of the present invention is to provide a process for preparing the irinotecan hydrochloride nanolipid preparation of the present invention, the two preferred methods of which are as follows:
  • the first method comprises: dissolving the encapsulating material in the aqueous solution for injection to form a clarification system, adding irinotecan hydrochloride, stirring under a water bath until a clarification system is formed, that is,
  • the nanolipid preparation has a water bath temperature of 30-55 °C.
  • a second method comprising: dissolving the inclusion material together with irinotecan hydrochloride in an organic solvent, removing the organic solvent, and then adding the aqueous solution of the injection solution to hydrate, thereby obtaining the nano-lipid preparation .
  • the organic solvent is one of chloroform, dichloromethane, acetone, ethanol, methanol or a mixture of at least two;
  • the method for removing the organic solvent includes a solvent evaporation method, a spin coating method, a dialysis method, and lyophilization. One of the methods or a combination of at least two of them.
  • the irinotecan hydrochloride nanolipid preparation prepared by the above method is a pale yellow liquid with good stability. As shown in Fig. 1 and Fig. 2, the particle size distribution of the irinotecan hydrochloride nanolipid preparation showed that the particle size distribution of the irinotecan hydrochloride nanolipid preparation conformed to the normal distribution. It indicates that the irinotecan hydrochloride nanolipid preparation has a uniform particle size and exhibits an average particle diameter of about 10 nm.
  • a further object of the present invention is to provide a irinotecan hydrochloride nano preparation which is diluted 5-100 times with water for injection by using the irinotecan hydrochloride nanolipid preparation according to any one of claims 1 to 5, for example, 20 Prepared by times, 30 times, 40 times, 50 times or 60 times, preferably 20 times.
  • the irinotecan hydrochloride nano preparation of the invention is a nano particle system, and the particle size detection result after dilution is as shown in FIG. 3, the average particle diameter is still 5-20 nm, and the irinotecan hydrochloride nanolipid preparation can still be maintained.
  • the size of the nanoparticles can be directly used for intravenous injection and can prolong the in vivo circulation time of irinotecan hydrochloride and achieve the purpose of tumor targeting.
  • the irinotecan hydrochloride nanolipid preparation provided by the present invention can also be prepared into a powder preparation by freeze-drying.
  • Another object of the present invention is to provide a irinotecan hydrochloride nanolipid powder preparation prepared by bottling, freeze-drying and nitrogen-sealed storage of the irinotecan hydrochloride nanolipid preparation of the present invention.
  • the powdered preparation can be hydrated to form a nano-lipid for intravenous injection, which can reduce the toxicity of irinotecan hydrochloride and prolong the circulation in the body. Time, increase the drug concentration of the tumor targeting site, and reduce side effects.
  • lipid preparation is equivalent to a micelle preparation in the general sense.
  • the provided irinotecan hydrochloride nanolipid preparation has a specific and simple inclusion material, which greatly improves the solubility of irinotecan hydrochloride and the compliance of the preparation, and realizes the drug encapsulation with sufficient clinical effect.
  • the amount of irinotecan hydrochloride is encapsulated in the closed vesicle with a high loading of at least 1.0 (drug (mol) / total lipid bundle (mol)), and the encapsulation efficiency of irinotecan hydrochloride can be as high as 85%.
  • the carrier tape of irinotecan hydrochloride is achieved at a lower amount of excipients;
  • the irinotecan hydrochloride nanolipid preparation and the irinotecan hydrochloride nano preparation have a particle size of about 10 nm, and can utilize the penetration enhancement and retention effect (EPR effect) of the tumor tissue to realize the passive target of the nano preparation to the tumor.
  • EPR effect penetration enhancement and retention effect
  • the irinotecan hydrochloride nanolipid powder preparation of the present invention improves the safety and compliance of the irinotecan hydrochloride preparation.
  • the powdered preparation can be hydrated to form a nanolipid bundle for intravenous injection, which can reduce the toxicity of irinotecan hydrochloride, prolong the circulation time in the body, increase the drug concentration of the tumor targeting site, and reduce side effects.
  • the irinotecan hydrochloride nanolipid preparation of the present invention can achieve an IC 50 of 19.2 ⁇ g/ml, which is far lower than similar preparations in the field; and in the tumor suppression experiment, it has been obtained within 24 days.
  • the commercial irinotecan hydrochloride drug has a stronger tumor suppressing ability.
  • the preparation process of the invention is simple and easy, and has good repeatability, and is suitable for industrial production.
  • Fig. 1 is a particle size detection result of a irinotecan hydrochloride nanolipid preparation - a bar graph of a multi-peak distribution of light intensity.
  • Figure 2 is the particle size detection result of irinotecan hydrochloride nanolipid preparation - light intensity particle size normal distribution curve Figure.
  • Fig. 3 is a graph showing the particle size detection result of the nano-formulation obtained by diluting the irinotecan hydrochloride nanolipid preparation with a light-weight particle size normal distribution curve.
  • Figure 4 is a comparison of the ability of irinotecan hydrochloride nanolipid preparations in a tumor-bearing mouse to inhibit tumor growth by commercial irinotecan hydrochloride drug Campto.
  • step b) Add 1 g of irinotecan hydrochloride to the solution prepared in step a, dissolve at room temperature, and stir well to obtain a clear solution, and then filter to obtain a irinotecan hydrochloride nanolipid preparation, which is protected by nitrogen and sealed.
  • the irinotecan hydrochloride nanolipid preparation prepared in the step 1 was diluted with 20 volumes of glucose solution to obtain a irinotecan hydrochloride nano preparation.
  • step b) Add 1 g of irinotecan hydrochloride to the solution prepared in step a, dissolve in a water bath at 50 ° C, and stir well to obtain a clear solution, and then filter to obtain a irinotecan hydrochloride nanolipid preparation, which is protected by nitrogen and sealed.
  • the irinotecan hydrochloride nanolipid preparation prepared in the step 1 was diluted with 20 volumes of physiological saline to obtain a irinotecan hydrochloride nano preparation.
  • step b) Add 1 g of irinotecan hydrochloride to the solution prepared in step a, dissolve in a water bath at 50 ° C, and stir well to obtain a clear solution, and then filter to obtain a irinotecan hydrochloride nanolipid preparation, which is protected by nitrogen and sealed.
  • the irinotecan hydrochloride nanolipid preparation prepared in the step 1 was diluted with 30 volumes of glucose solution to obtain a irinotecan hydrochloride nano preparation.
  • step b) Add 1 g of irinotecan hydrochloride to the solution prepared in step a, dissolve in a 45 ° C water bath, stir well to obtain a clear solution, and then filter to obtain a irinotecan hydrochloride nanolipid preparation, which is sealed with nitrogen and sealed.
  • the irinotecan hydrochloride nanolipid preparation prepared in the step 1 was diluted with 30 volumes of physiological saline to obtain a irinotecan hydrochloride nano preparation.
  • the particle size of the irinotecan nanolipid preparation was measured using a ZS90 instrument from Malven Instruments, UK. The dynamic light scattering results are similar to those shown in Fig. 1 and Fig. 2.
  • the prepared irinotecan nanolipid preparation is a uniform particle size nanoparticle with a particle size of about 10 nm.
  • the particle size of irinotecan nano-preparation was measured by the ZS90 instrument of Malven Instruments, UK. The dynamic light scattering results are shown in Fig. 3.
  • the prepared irinotecan nano-preparation is a nanoparticle with uniform particle size and a particle size of about 10 nm.
  • cytotoxicity (IC 50 ) of irinotecan hydrochloride lipid bundle and irinotecan hydrochloride and commercial irinotecan hydrochloride drug captopril were compared among several different tumor cell lines. The results are shown in Table 1. In the three tumor cell lines, the irinotecan hydrochloride lipid bundle had a smaller IC 50 value than the irinotecan hydrochloride and captopril, indicating that irinotecan hydrochloride in the present invention.
  • the nanolipid preparation has higher tumor cytotoxicity than irinotecan hydrochloride and the commercial irinotecan hydrochloride drug captopril.
  • nude mice were subcutaneously implanted with colorectal cancer cell HCT-8, comparing irinotecan hydrochloride The inhibition effect of the bundle with commercial irinotecan hydrochloride drug captopril on tumors.
  • the tumor volume of the irinotecan hydrochloride liposome preparation group was 26% of the tumor volume of the control group (normal saline), and 68% of the tumor volume of the Cape Tuo group, and hydrochloric acid was observed.
  • the irinotecan lipid tract preparation has a more pronounced tumor suppressing effect than the captopril.
  • the irinotecan hydrochloride nanolipid preparation selects a specific and simple inclusion material, which greatly improves the solubility of irinotecan hydrochloride and the compliance of the preparation, and realizes the drug encapsulation with sufficient clinical effect.
  • the amount of irinotecan hydrochloride is encapsulated in the closed vesicle with a high loading of at least 1.0 (drug (mol) / total lipid bundle (mol)), and the encapsulation efficiency of irinotecan hydrochloride can be as high as 85%.
  • the carrier of irinotecan hydrochloride is achieved at a lower amount of excipient; the irinotecan hydrochloride nanolipid preparation and the irinotecan hydrochloride nano preparation have a particle size of about 10 nm, which can utilize the enhancement and retention of tumor tissue.
  • the effect realizes the passive targeting of the nano preparation to the tumor, promotes the selective distribution of the drug in the tumor tissue, can increase the drug effect and reduce the system toxic side effect; the irinotecan hydrochloride nanolipid powder preparation of the present invention, Improve the safety and compliance of irinotecan hydrochloride preparations.
  • the powdered preparation can be hydrated to form a nano-lipid for intravenous injection, which can reduce the toxicity of irinotecan hydrochloride, prolong the circulation time in the body, increase the drug concentration of the tumor targeting site, and reduce side effects in the cytotoxicity test.
  • the irinotecan hydrochloride nanolipid preparation can achieve an IC 50 of 19.2 ⁇ g/ml, which is far lower than similar preparations in the field; and in the tumor inhibition experiment, a commercialized hydrochloric acid is obtained within 24 days.
  • the irinotecan drug has a stronger tumor inhibiting ability; the preparation process of the invention is simple and easy, and has good repeatability and is suitable for industrial production.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une préparation d'un faisceau nanolipidique de chlorhydrate d'irinotécan et son procédé de préparation, qui comprend une substance d'encapsulation, du chlorhydrate d'irinotécan et un solvant aqueux injectable, ladite substance d'encapsulation étant choisie parmi le PLGA-PEG, le PGA-PEG, le PCL-PEG, le PEG-NH2, le PEG-COOH, le DSPE-PEG, le Solutol HS15 et un mélange d'un type ou d'au moins deux types de phospholipides. La nanopréparation de chlorhydrate d'irinotécan et la préparation de poudre de faisceau nanolipidique de chlorhydrate d'irinotécan sont préparées à partir de ladite préparation de faisceau nanolipidique de chlorhydrate d'irinotécan.
PCT/CN2015/071048 2014-07-18 2015-01-19 Préparation de faisceau nanolipidique de chlorhydrate d'irinotécan et son procédé de préparation WO2016008289A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410344489.4 2014-07-18
CN201410344489.4A CN104083325B (zh) 2014-07-18 2014-07-18 一种盐酸伊立替康纳米脂束制剂及其制备方法

Publications (1)

Publication Number Publication Date
WO2016008289A1 true WO2016008289A1 (fr) 2016-01-21

Family

ID=51631161

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/071048 WO2016008289A1 (fr) 2014-07-18 2015-01-19 Préparation de faisceau nanolipidique de chlorhydrate d'irinotécan et son procédé de préparation

Country Status (2)

Country Link
CN (1) CN104083325B (fr)
WO (1) WO2016008289A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230078391A1 (en) * 2019-05-16 2023-03-16 Megapro Biomedical Co., Ltd. Pharmaceutical compositions containing mixed polymeric micelles

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106074376A (zh) * 2016-06-27 2016-11-09 江苏师范大学 一种胰高血糖素样肽‑1缓释纳米制剂、制备方法及应用
CN109771371B (zh) * 2019-03-19 2020-03-20 安徽联谊药业股份有限公司 一种克林霉素磷酸酯注射液及其制备方法
CN111450080A (zh) * 2020-03-31 2020-07-28 天津大学 一种IgA肾病治疗纳米制剂的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102961332A (zh) * 2012-12-05 2013-03-13 复旦大学 提高喜树碱类衍生物活性闭环率的液体胶束制剂及其制备方法和应用
CN103735504A (zh) * 2013-12-10 2014-04-23 国家纳米科学中心 一种伊立替康纳米脂束制剂及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102475891A (zh) * 2010-11-23 2012-05-30 中国科学院化学研究所 具有pH响应性的聚乙二醇-抗癌药键合物及其合成方法和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102961332A (zh) * 2012-12-05 2013-03-13 复旦大学 提高喜树碱类衍生物活性闭环率的液体胶束制剂及其制备方法和应用
CN103735504A (zh) * 2013-12-10 2014-04-23 国家纳米科学中心 一种伊立替康纳米脂束制剂及其制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230078391A1 (en) * 2019-05-16 2023-03-16 Megapro Biomedical Co., Ltd. Pharmaceutical compositions containing mixed polymeric micelles
US11931456B2 (en) * 2019-05-16 2024-03-19 Megapro Biomedical Co. Ltd. Pharmaceutical compositions containing mixed polymeric micelles

Also Published As

Publication number Publication date
CN104083325A (zh) 2014-10-08
CN104083325B (zh) 2015-11-04

Similar Documents

Publication Publication Date Title
DK2508170T3 (en) LIPOSOM OF IRINOTECAN OR ITS HYDROCHLORIDE AND ITS PROCEDURE
Wang et al. Cancer nanomedicines stabilized by π-π stacking between heterodimeric prodrugs enable exceptionally high drug loading capacity and safer delivery of drug combinations
TWI355946B (en) Proliposomal and liposomal compositions of poorly
EP2480207B1 (fr) Encapsulation d'agents thérapeutiques dans des micelles
JP5923177B2 (ja) 新規な遺伝子伝達用組成物
KR101578273B1 (ko) 화학요법적 항종양 약물을 함유하는 나노입자
TWI549679B (zh) 疏水性喜樹鹼衍生物之醫藥組合物
TWI732773B (zh) 用於奈米顆粒冷凍乾燥形式的組成物及方法
CN109771663B (zh) 一种酸响应性抗癌纳米药物的制备及应用
TW450811B (en) Lyophilizate of lipid complex of water insoluble camptothecins
WO2016008289A1 (fr) Préparation de faisceau nanolipidique de chlorhydrate d'irinotécan et son procédé de préparation
WO2014155146A1 (fr) Nanocomposition stable comprenant du paclitaxel, procédé pour sa préparation, son utilisation et compositions pharmaceutiques la contenant
CN110665003A (zh) 一种双载药无载体纳米粒及其制备方法
WO2017120586A1 (fr) Formulations pour le traitement du cancer de la vessie
US20140296173A1 (en) Stable nanocomposition comprising epirubicin, process for the preparation thereof, its use and pharmaceutical compositions containing it
JP2018536679A (ja) リポソームの製造方法
EP2153821A1 (fr) Formules orales de dérivés de camptothécine
CN106913882B (zh) 一种聚乙二醇-藤黄酸脂质体和制备方法及其在治疗恶性肿瘤中的应用
Zhu et al. Intranasal administration of pullulan-based nanoparticles for enhanced delivery of adriamycin into the brain: in vitro and in vivo evaluation
CN102188379A (zh) 载药脂质体的制备方法
US20150147385A1 (en) Intravenous synthetic curcumin (s-curcumin) for the treatment of proliferative disorders
ES2759621T3 (es) Formulación farmacéutica que contiene curcumina
US20150057305A1 (en) Pharmaceutical composition
CN103638027B (zh) 利用双亲性药物包载疏水性抗肿瘤药物的方法及制剂
Granada et al. O emprego de sistemas de liberação como estratégia para melhorar as propriedades terapêuticas de fármacos de origem natural: o exemplo da camptotecina e seus derivados

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15822374

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15822374

Country of ref document: EP

Kind code of ref document: A1