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Novel taxol lipid microsphere injection and preparation method thereof

A technology of lipid microspheres and paclitaxel, applied in the field of medicine, can solve problems such as difficult to withstand autoclave sterilization, limited solubility, thermodynamic instability, etc., to improve physical and chemical stability, not easy to precipitate and oxidize, and chemically stable sex good effect

Inactive Publication Date: 2012-01-04
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The phase III clinical trial results of this preparation that ended in the second half of 2007 did not meet expectations
But, there are some defects in using this method to prepare paclitaxel submicroemulsion injection: 1. need to use acetone, tetrahydrofuran and other toxic organic reagents such as acetone in the complex process of paclitaxel lipid complex, therefore, trace organic solvent residue will give Health poses a huge hidden danger
2. Lipid complexes are easily lost during the transfer process after removing the organic solvent, making drug quantification inaccurate
3. The paclitaxel submicroemulsion injection prepared by this method cannot withstand autoclaving, and has to be made into a freeze-dried preparation by freeze-drying
Although refrigerated storage inhibited the growth of paclitaxel-related substances to a certain extent, the growth rate of related substances was still very large (0.9-1.9%) during 6 months of refrigerated storage
[0010] Therefore, the prior art cannot well solve many problems such as limited drug loading of paclitaxel lipid microsphere preparations, poor stability, and difficult to withstand autoclave sterilization.
On the one hand, this is due to the limited solubility of paclitaxel itself in the oil-water two-phase, resulting in poor stability of the preparation; Unstable system, prone to demulsification, aggregation, coalescence and deposition during sterilization and storage, eventually leading to oil-water layering or drug sedimentation

Method used

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  • Novel taxol lipid microsphere injection and preparation method thereof
  • Novel taxol lipid microsphere injection and preparation method thereof
  • Novel taxol lipid microsphere injection and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1 Preparation of Paclitaxel Lipid Microsphere Injection Containing Amphiphilic Polyamino Acids

[0062] [Prescription 1] Specification: 30mg / 50ml

[0063] Paclitaxel 0.06%

[0064] Medium Chain Triglycerides (MCT) 15%

[0065] PEG 5000 - Racemic polyleucine 3000 0.1%

[0066] Soy Lecithin 3%

[0067] Tween 80 0.1%

[0068] Poloxamer 188 0.3%

[0069] Glycerin 2.5%

[0070] Edetate Disodium 0.02%

[0071] Add water for injection to 100%

[0072] Preparation:

[0073] (1) Dissolve the prescribed amount of paclitaxel and soybean lecithin in absolute ethanol under heating and stirring at 75°C, and evaporate the absolute ethanol to dryness. Add the prescribed amount of medium-chain fatty acid triesters and oleic acid, heat and stir at 75°C, continue to evaporate ethanol under nitrogen flow, and obtain a clear medicated oil phase for future use.

[0074] (2) Change the prescription amount to PEG 5000 - Racemic polyleucine 3000 , polysorbate-...

Embodiment 2

[0207] Prescription of paclitaxel lipid microsphere injection containing amphiphilic polyamino acid (prescription 4)

[0208] 6-month acceleration and long-term stability investigation

[0209] Since this product is a thermodynamically unstable system, it is a heat-sensitive dosage form. According to the instructions of the Chinese Pharmacopoeia 2005 edition of the guidelines for the stability test of raw materials and pharmaceutical preparations: the accelerated test of heat-sensitive drugs should be placed at 25±2°C for 6 months; at 6±2°C for 12 months, the investigation Changes in physical and chemical stability, the experiment has been carried out for 6 months, and the results of the 6-month investigation are given.

[0210] Table 1 25±2℃ Accelerated 6-month test results

[0211]

[0212] Table 2 Result of long-term retention sample test at 6±2°C

[0213]

[0214] After 6 months of accelerated testing, all quality indicators are within the qualified range. Th...

Embodiment 3

[0216] Study on Plasma Pharmacokinetics of Paclitaxel Lipid Microsphere Injection of the Present Invention in Rats

[0217] Dosing regimen:

[0218] 36 rats were randomly divided into 6 groups, 6 rats in each group, fasted overnight before the experiment. The commercially available paclitaxel injection and the paclitaxel lipid microsphere injection containing amphiphilic polyamino acid of the present invention were injected into the right posterior femoral vein respectively, and the grouping and administration conditions are as follows:

[0219]

[0220] Before administration (0 o'clock), 0.3 mL of orbital blood was collected at 5 min, 15 min, 30 min, 60 min, 90 min, 2 h, 4 h, 6 h, 8 h, and 12 h, and placed in pre-heparinized 1.5 Centrifuge at 4000 rpm for 15 min in mL conical-bottomed centrifuge tubes, accurately draw 100 μL of the upper layer of plasma, put it in another clean conical-bottomed centrifuge tube, store in the refrigerator, add 25.4 μg·mL -1 20 μL of inte...

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Abstract

The invention discloses a novel taxol lipid microsphere injection containing amphiphilic polyamino acid and a preparation method thereof. The injection contains taxol, amphiphilic polyamino acid, oil for injection, an emulsifying agent, an auxiliary emulsifying agent, a potential regulator, an antioxidant, a metal chelating agent, an iso-osmotic adjusting agent and water for injection, wherein the amphiphilic polyamino acid is a segmented copolymer consisting of a hydrophilic chain segment and racemic hydrophobic polyamino acid. The novel taxol lipid microsphere injection represents a microscopic structure different from that of a traditional lipid microsphere preparation, therefore the injection has excellent stability superior to that of the traditional lipid microsphere preparation. Inthe preparation, polyoxyethylene castor oil is not contained, VE (vitamin E) is not used massively, and no organic solvent is introduced; in addition, the injection can tolerate thermal pressure sterilization, has the advantages of no irritation, low toxicity, good stability and low cost, and is suitable for industrial production in large scale.

Description

technical field [0001] The invention relates to a novel paclitaxel lipid microsphere injection and a preparation method thereof, more specifically to a paclitaxel lipid microsphere injection containing an amphiphilic polyamino acid as a stabilizer and a preparation method thereof, belonging to the pharmaceutical industry. technology field. Background technique [0002] Paclitaxel is an anticancer drug extracted from the bark of the yew (Taxus chinensis), which is effective for advanced ovarian cancer, breast cancer, lung cancer, head and neck cancer, esophageal cancer, germ cell tumors, endometrial cancer, lymphoma , bladder cancer have a certain effect. Combined with other commonly used anti-tumor drugs, the curative effect can be further improved. Because paclitaxel has a unique mechanism of action for stabilizing cell microtubules, and has good therapeutic effects, strong broad-spectrum, and small side effects, it is internationally recognized as the preferred anticance...

Claims

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Application Information

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IPC IPC(8): A61K9/10A61K31/337A61K47/34A61K47/44A61P35/00
Inventor 唐星何海冰王艳娇蔡翠芳
Owner SHENYANG PHARMA UNIVERSITY
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