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A kind of paclitaxel palmitate liposome and preparation method thereof

A technology of palmitate and liposomes, which is applied in the field of medicine, can solve the problems of liver and kidney function and reproductive function damage, poor compatibility of infusion equipment, frequent allergic reactions, etc., to overcome poor drugability, improve anti-tumor, The effect of high drug concentrations

Active Publication Date: 2019-03-29
SHANGHAI WEI ER BIOPHARM TECH CO LTD +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although "Taxol" has solved the problem that paclitaxel is insoluble in water and has shown good anti-tumor effect, but because of the addition of a large amount of solubilizer polyoxyethylene castor oil with toxic side effects in the prescription, resulting in The preparation has many defects: ①Frequent allergic reactions: Taxol instructions and literature (Gao Peng, Tu Jiasheng, Polyoxyethylene castor oil and its safety research progress. Pharmacy and Clinical Research, 2010,18(1):59-63. ) pointed out that polyoxyethylene castor oil is an active substance, which causes the body to release histamine with allergic effects, which leads to the occurrence of allergic reactions. Reaction is the biggest safety hazard of Taxol; ② Poor compatibility with infusion equipment: literature reports (Zhang Hong, Yang Fengmin, Wu Jing, et al. Paclitaxel injection has no effect on phthalic acid bis(2) in disposable precision infusion sets Dissolution of monoethyl)hexyl ester. China Medical Device Information, 2014,20(3):61-66; Zhang Enjuan, Chen Lin, Cao Jian. Dissolution of dioctyl phthalate in infusion set for paclitaxel injection Clinical investigation. Traditional Chinese Medicine, 2008.19 (2): 698-700), polyoxyethylene castor oil is a surfactant, which can dissolve the plasticizer (phthalic acid di(2) monoethyl)hexyl ester), which can cause damage to human liver, kidney and reproductive functions; ③ inconvenient medication: it is clear in the Taxol instructions that strict desensitization treatment and necessary protective measures are required before medication
[0016] At present, there is no safe, efficient and stable quality paclitaxel palmitate nano-preparation

Method used

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  • A kind of paclitaxel palmitate liposome and preparation method thereof
  • A kind of paclitaxel palmitate liposome and preparation method thereof
  • A kind of paclitaxel palmitate liposome and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Comparative evaluation of series of different paclitaxel fatty acid esters in vivo efficacy tests

[0064] Chinese patent CN1202166A and literature (Shaukat Ali, Imran Ahmad etc., Hydrolyzablehydrophobic taxesanes:synthesis and anti-cancer activities, Anti-Cancer Drugs, 2001,12:117-128; Walter R.Perkins, Imran Ahmad etc., Novel therapeutic nano-particles (lipocores): trapping poorly water soluble compounds, InternationalJournal of Pharmaceutics 2000, 200:27–39), which is an α-bromo-based fatty acid ester of paclitaxel, and the fatty acid carbon chain length covered is between C6-C16 Paclitaxel fatty acid ester prodrug; US patent (US 7,235,583B1) and international patent (WO 00 / 53231), have studied a kind of paclitaxel fatty acid ester and preparation thereof, and its fatty acid length is C8-C26. The above-mentioned patent documents have recorded paclitaxel fatty acid ester prodrugs with fatty acid carbon chain lengths between C6-C26, but no differential resea...

Embodiment 2

[0085] Example 2: Study on the druggability of paclitaxel palmitate in different formulations

[0086] The druggability and antitumor effect of liposomes, polymer micelles, fat emulsions, and nanoparticles were compared and studied respectively. For the sake of conservatism, the fixed drug loading was 3 mg / ml for parallel comparison. With reference to the current clinical dosage of paclitaxel ( The total dosage for adults is about 400mg each time), and the drug loading of 3mg / ml is only a lower requirement. On this basis, research on related preparations is carried out, and the main research programs and results are summarized as follows:

[0087] 1. Study on the druggability of preparations

[0088] 1.1 Liposome

[0089] Weigh 300mg of paclitaxel palmitate, 3.5g of high-purity egg yolk lecithin (EPCS), 0.3g of DSPE-PEG2000, add 3g of propylene glycol, heat and dissolve at 65°C to obtain an organic phase; weigh 85g of water for injection, heat to 65°C, Stir and dissolve to ...

Embodiment 3

[0113] Example 3: Importance of Propylene Glycol Infusion for Paclitaxel Palmitate Liposome Development

[0114] Commonly used liposome preparation methods include thin film evaporation, reverse evaporation, and ethanol injection. Among them, thin film evaporation has poor controllability and cumbersome steps in large-scale production. Therefore, we plan to use relatively simple reverse evaporation and ethanol injection. Injection method to prepare liposomes. But for paclitaxel palmitate, reverse evaporation method and ethanol injection method all can't realize the preparation of this liposome well, when selecting propylene glycol to inject, just received fundamental effect. In Example 2 above, good liposomes can be prepared by injecting a small amount of propylene glycol, so taking this as an example, the commonly used reverse evaporation method and ethanol injection method are respectively verified using the same prescription. The methods and results are as follows:

[011...

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Abstract

The invention belongs to the technical field of medicine, and specifically relates to a paclitaxel palmitate liposome and a preparation method thereof, wherein paclitaxel palmitate is obtained by esterifying palmitic acid and the 2' hydroxyl of paclitaxel, and belongs to the pro-paclitaxel liposome medicine. The prodrug fundamentally changes the problem of poor fat solubility of paclitaxel, and substantially solves the problem of poor druggability of paclitaxel nano-preparations. Aiming at the special physical and chemical properties of paclitaxel palmitate, the present invention has carried out matching research on the composition of the prescription and the preparation process, and developed a polyoxyethylene castor oil-free, safe, stable quality and simple preparation process in the true sense. Paclitaxel palmitate liposomes have laid a solid foundation for the further research and application of paclitaxel in the field of anti-tumor.

Description

Technical field: [0001] The invention relates to the technical field of medicine, in particular to a paclitaxel palmitate liposome and a preparation method thereof. Background technique: [0002] Paclitaxel (Paclitaxe1) is a diterpenoid compound extracted from Taxaceae plants. Hexahydroxytaxane-11-en-9-one-4,10-diacetate-2-benzoate-13[(2,R,3,S)-N-benzoyl-3- Phenylisoserine]. This product is a white crystalline powder, odorless, tasteless, insoluble in water, and poorly fat-soluble, almost not absorbed after oral administration. Due to its poor fat solubility and water solubility, it has brought difficulties to the development and application of clinical preparations. The related research began in the late 1950s and lasted for more than 30 years. Until December 1992, the FDA approved for the first time the paclitaxel injection of Bristol-Myers Squibb, which was named "Taxol", which was widely used in various malignant tumors such as ovarian cancer, cervical cancer, breast ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/337A61K9/127A61K47/24A61K47/10A61K9/19A61P35/00
CPCA61K9/127A61K9/19A61K31/337A61K47/10A61K47/24A61K9/0019A61K9/08A61K9/1277A61K47/02A61K47/26A61K47/28A61P35/00
Inventor 单彬周琴琴余侬
Owner SHANGHAI WEI ER BIOPHARM TECH CO LTD
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