Paclitaxel and lapatinib compound nanocrystal and preparation method thereof

A paclitaxel lapatinib and nanocrystal technology, which can be applied in pharmaceutical formulations, medical preparations without active ingredients, and medical preparations containing active ingredients, etc. problem, to achieve the effect of good water dispersibility, improved stability, and easy targeted modification

Inactive Publication Date: 2020-10-09
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have shown that the low water solubility of paclitaxel and lapatinib has created a major problem in formulation; the solubility of paclitaxel in water is only 0.5 μg / mL, and the cosolvent contained in its injection can induce allergic reactions, Large doses of antiallergic drugs must be given in advance for prevention; and the water solubility of lapatinib is also very poor, with a solubility of 0.007mg / mL in water, which leads to difficulties in preparing injection forms. Therefore, the current clinical application has to use oral tablets form with less than 20% oral bioavailability
[0003] Therefore, the researchers intend to pack paclitaxel and lapatinib into the same nanocarrier system, which can not only solve the common problems of the two drugs in the construction of injection dosage forms, but also facilitate the synergy of the two drugs, killing two birds with one stone; however, according to Studies have shown that due to the inherent structural characteristics of micelles, the drug loading of paclitaxel and lapatinib are both lower than 10%, which obviously limits the full exertion of pharmacological effects;
[0004] At present, there are very few reports on paclitaxel / lapatinib co-loaded injection preparations, such as the brain-targeted modification of paclitaxel / lapatinib co-loaded with polyethylene glycol- Polylactic acid (PEG-PLA) micelles, which involve the limitations of the inherent structural characteristics of micelles, the drug loading of paclitaxel and lapatinib are both low, which limits the full play of pharmacological effects and other defects
[0005] In recent years, drug nanocrystals with high drug-loading characteristics have attracted great attention from researchers in the field of pharmaceutical preparations; if paclitaxel and lapatinib are respectively made into nanocrystals, there must be certain differences in the size and surface properties of the particles. Differences, the behavior in the circulation and the distribution to the tumor after injection will also be different, affecting the synergistic effect, so it is necessary to make the two into compound crystals; on the other hand, paclitaxel and lapatinib are both It tends to form needle-shaped crystals, but practice has proved that needle-shaped nano-crystals have poor stability, are difficult to functionalize, and are easy to block blood vessels in the blood circulation. They lack sufficient practicability for intravenous administration. form improvement

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  • Paclitaxel and lapatinib compound nanocrystal and preparation method thereof
  • Paclitaxel and lapatinib compound nanocrystal and preparation method thereof
  • Paclitaxel and lapatinib compound nanocrystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Preparation of paclitaxel / lapatinib compound nanocrystals

[0038] Dissolve 1mg of paclitaxel, 2mg of lapatinib, 3mg of vitamin E polyethylene glycol 1000 succinate and 6mg of citric acid in an appropriate amount of absolute ethanol, place in a pear-shaped bottle for rotary evaporation, evaporate the ethanol, and form a thin film at the bottom of the bottle , add 5mL of sodium bicarbonate solution (4mg / mL), shake gently at room temperature for hydration, centrifuge the resulting suspension at 8000rpm for 15 minutes, discard the supernatant, collect the precipitate, and disperse with pure water to obtain Paclitaxel / lapatinib compound nanocrystal dispersion with light blue opalescence;

[0039] Analyze its particle size distribution with the dynamic light scattering method, the average particle size is 92nm, and the polydispersity coefficient (PDI 0.076) (such as figure 1shown); the so-called "polydispersity coefficient" is the particle polydispersity parameter...

Embodiment 2

[0046] Example 2 Preparation of phospholipid-coated paclitaxel / lapatinib compound nanocrystals

[0047] Weigh lecithin (1.15mg), cholesterol (0.58mg), octadecylamine (0.36mg), vitamin E macrogol 1000 succinate (0.58mg), phospholipid-polyethylene glycol-methoxy (0.70 mg) was dissolved in an appropriate amount of chloroform, placed in a pear-shaped bottle for rotary evaporation, and the chloroform was waved off to form a thin film at the bottom of the bottle. Add the paclitaxel / lapatinib compound nanocrystals described in Example 1, and gently shake Hydration, the resulting suspension was centrifuged at 8000rpm for 10 minutes to remove unreacted phospholipids to obtain phospholipid-coated paclitaxel / lapatinib compound nanocrystals (transmission electron microscope photos as shown in figure 1 Shown in D), average particle size 102nm, PDI 0.153 ( figure 2 B), stored at 25°C for 6 months, the particle size is basically unchanged, and the stability is good (such as image 3 shown...

Embodiment 3

[0052] Example 3 Preparation of folic acid-modified phospholipid-coated paclitaxel / lapatinib compound nanocrystals

[0053] The steps are the same as in Example 2, the difference is that the phospholipid material consists of lecithin (1.15mg), cholesterol (0.58mg), octadecylamine (0.36mg), vitamin E polyethylene glycol 1000 succinate (0.58mg) , folic acid-modified phospholipid-polyethylene glycol (0.70mg);

[0054] Cytotoxicity tests carried out on breast cancer drug-resistant cell lines (MCF-7 / ADR) showed that folic acid-modified phospholipid-coated paclitaxel / lapatinib compound nanocrystals had better inhibitory effects on tumor cell growth than those described in Example 2 The median lethal concentrations of phospholipid-coated paclitaxel / lapatinib compound nanocrystals, phospholipid-coated paclitaxel / lapatinib compound nanocrystals (without folic acid modification) and folic acid-modified phospholipid-coated paclitaxel / lapatinib compound nanocrystals (IC 50 ) are 1.7×10 ...

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Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to a paclitaxel lapatinib compound nanocrystal and a preparation method thereof. The compound nanocrystal is uniform in particle size, is spherical or nearly spherical, and contains paclitaxel and lapatinib at the same time, the paclitaxel drug loading capacity is 20-40%, the lapatinib drug loading capacity is 10-20%, and the mass ratio of paclitaxel to lapatinib is 1: 1-4: 1. The compound nanocrystal provided by the invention can solve the common problem of the two medicines in construction of injections, and meanwhile, the two medicines can achieve a synergistic effect; the compound nanocrystal has good stability after being coated with the phospholipid surface, is suitable for intravenous administration, canfurther improve the capability of being taken by tumor cells through targeted functional modification, and is suitable for treating various tumors after intravenous administration.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and relates to a paclitaxel lapatinib compound nanocrystal and a preparation method thereof. Background technique [0002] The prior art discloses that paclitaxel (Paclitaxel, PTX) is a classic antitumor drug, which mainly causes mitotic arrest and cell apoptosis by stabilizing the microtubule structure in cells, and is widely used in the treatment of various types of entities. tumor. Studies in recent years have shown that when PTX is used in combination with molecularly targeted drugs (small molecule targeted drug lapatinib targeting epidermal growth factor receptor), they can use their different action principles to act on different cell cycle stages or metabolic pathways, and work together In tumor cells, to achieve the purpose of synergistic effect, it has significant advantages in the treatment of breast cancer and other malignant tumors (YardleyD.A.Phase II study evalu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K9/14A61K31/337A61K31/517A61K47/22A61K47/24A61P35/00A61K47/69
CPCA61K31/337A61K31/517A61K9/146A61K9/5146A61K9/5123A61P35/00A61K47/6925A61K2300/00
Inventor 刘瑜王俊陆伟跃
Owner FUDAN UNIV
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