Lipid microsphere injection containing sodium demethyl cantharidate-phosphatide complex and preparation method thereof

Abstract

The invention discloses a lipid microsphere injection containing sodium demethyl cantharidate-phosphatide complex and preparation method thereof. The injection comprises the sodium demethyl cantharidate-phosphatide complex, fat-soluble medium, surfactant and other ingredients. In the sodium demethyl cantharidate-phosphatide complex, the molar ratio of sodium demethyl cantharidate to phosphatide is 1-1:10. The prepared sodium demethyl cantharidate-phosphatide complex improves the distribution of sodium demethyl cantharidate in oil-water 2-phase interfacial film and oil phase greatly, increasesthe entrapment efficiency of the medicine in preparation, realizes the interfacial film loading medicine, reduces the toxicity, and can carry out targeting drug release in vivo. The prepared lipid microsphere injection reduces the vascular stimulation of sodium demethyl cantharidate, improves the curative effect, and reduces toxic and side effect.

Description

technical field

[0001] The invention relates to a lipid microsphere injection and a preparation method thereof, in particular to a lipid microsphere injection containing sodium demethylcantharidate phospholipid complex and a preparation method thereof, belonging to the technical field of medicine. Background technique

[0002] New anti-cancer drug demethylcantharidin (Norcantharidin, NCTD), obtained by removing 1 and 2 methyl groups from cantharidin. Sodium demethylcantharidinate is the sodium salt obtained by direct hydrolysis of norcantharidin. It is only soluble in a few organic solvents (such as acetone, ethyl acetate) and hot water, and its solubility in cold water and oil is very low. Compared with cantharidin, sodium demethylcantharidinate has greatly reduced the stimulating effect on the urinary system, and at the same time has a more significant effect on increasing white blood cells than cantharidin. Sodium demethylcantharidate is a cell cycle-specific drug that b...

Examples

Embodiment 1

[0064] Embodiment 1 The preparation of sodium demethylcantharidate raw material

[0065] Although sodium demethylcantharidinate has an injection, it is all obtained from the direct hydrolysis of norcantharidin to obtain a sodium saline solution. Its raw materials are not produced and sold. And preparing norcantharidin sodium from norcantharidin is the most basic organic reaction, therefore, we refer to bibliographical reports, take norcantharidin as raw material, through hydrolysis into salt, dehydration, washing, drying, make norcantharidin Sodium Cantharidinate. The reaction formula is as follows:

[0066]

[0067] The synthesis method is as follows:

[0068] Sodium hydroxide 10-30g, add water 100mL, let it cool after dissolving, add 10-30g of norcantharidin while stirring, after almost all dissolved, filter out a small amount of insoluble matter. Concentrate the solution under reduced pressure to nearly dryness to obtain a large amount of white powdery solid, add 5-5...

Embodiment 2

[0070] Example 2 Preparation of Phospholipid Complex

[0071] [Preparation 1] Sodium demethylcantharidinate-egg yolk lecithin complex

[0072] Take 4g of sodium demethylcantharidinate (calculated as demethylcantharidin), 6g of egg yolk lecithin, add 50ml of acetone, compound at 60°C for 1 hour, remove the acetone by rotary evaporation, and dry in vacuum for more than 12 hours (20-30°C) , the drug-loaded egg yolk lecithin complex is obtained, which is airtightly packaged and stored in a refrigerator.

[0073] [Preparation 2] Sodium demethylcantharidinate-soybean lecithin complex

[0074] Take 2g of sodium demethylcantharidinate (calculated as demethylcantharidin) and 6g of soybean lecithin, add 100ml of ethyl acetate, compound at 60°C for 1 hour, remove the ethyl acetate by rotary evaporation, and dry in vacuum for more than 12 hours (20- 30°C), the drug-loaded soybean phospholipid complex was obtained, sealed and stored in a refrigerator.

[0075] 【Preparation 3】 Sodium dem...

Embodiment 3

[0083] Example 3 Preparation of sodium demethylcantharidinate phospholipid complex lipid microsphere injection

[0084] [Prescription 1] Demethylcantharidinate sodium phospholipid complex lipid microsphere injection (specification: 0.5mg / ml)

[0085] Sodium demethylcantharidate complex (calculated as demethylcantharidin) 0.05 % Soybean oil 10% Lecithin 1.2% glycerin 2.5% sodium oleate 0.03% Poloxamer 188 0.2% Edetate Calcium Sodium 0.02% Water for Injection Add to 100%

[0086] Preparation:

[0087] (1) Disperse glycerin for injection, poloxamer 188, sodium oleate and calcium sodium edetate in an appropriate amount of water for injection, heat to 70°C in a magnetic stirrer and stir until completely dissolved as the water phase;

[0088] (2) Add the phospholipid complex and lecithin for injection in [Preparation 4] into soybean oil for injection, heat to 80°C and stir until completely dissolved as the oil phase;

[00...

technical field

[0001] The invention relates to a lipid microsphere injection and a preparation method thereof, in particular to a lipid microsphere injection containing sodium demethylcantharidate phospholipid complex and a preparation method thereof, belonging to the technical field of medicine. Background technique

[0002] New anti-cancer drug demethylcantharidin (Norcantharidin, NCTD), obtained by removing 1 and 2 methyl groups from cantharidin. Sodium demethylcantharidinate is the sodium salt obtained by direct hydrolysis of norcantharidin. It is only soluble in a few organic solvents (such as acetone, ethyl acetate) and hot water, and its solubility in cold water and oil is very low. Compared with cantharidin, sodium demethylcantharidinate has greatly reduced the stimulating effect on the urinary system, and at the same time has a more significant effect on increasing white blood cells than cantharidin. Sodium demethylcantharidate is a cell cycle-specific drug that b...

Examples

Embodiment 1

[0064] Embodiment 1 The preparation of sodium demethylcantharidate raw material

[0065] Although sodium demethylcantharidinate has an injection, it is all obtained from the direct hydrolysis of norcantharidin to obtain a sodium saline solution. Its raw materials are not produced and sold. And preparing norcantharidin sodium from norcantharidin is the most basic organic reaction, therefore, we refer to bibliographical reports, take norcantharidin as raw material, through hydrolysis into salt, dehydration, washing, drying, make norcantharidin Sodium Cantharidinate. The reaction formula is as follows:

[0066]

[0067] The synthesis method is as follows:

[0068] Sodium hydroxide 10-30g, add water 100mL, let it cool after dissolving, add 10-30g of norcantharidin while stirring, after almost all dissolved, filter out a small amount of insoluble matter. Concentrate the solution under reduced pressure to nearly dryness to obtain a large amount of white powdery solid, add 5-5...

Embodiment 2

[0070] Example 2 Preparation of Phospholipid Complex

[0071] [Preparation 1] Sodium demethylcantharidinate-egg yolk lecithin complex

[0072] Take 4g of sodium demethylcantharidinate (calculated as demethylcantharidin), 6g of egg yolk lecithin, add 50ml of acetone, compound at 60°C for 1 hour, remove the acetone by rotary evaporation, and dry in vacuum for more than 12 hours (20-30°C) , the drug-loaded egg yolk lecithin complex is obtained, which is airtightly packaged and stored in a refrigerator.

[0073] [Preparation 2] Sodium demethylcantharidinate-soybean lecithin complex

[0074] Take 2g of sodium demethylcantharidinate (calculated as demethylcantharidin) and 6g of soybean lecithin, add 100ml of ethyl acetate, compound at 60°C for 1 hour, remove the ethyl acetate by rotary evaporation, and dry in vacuum for more than 12 hours (20- 30°C), the drug-loaded soybean phospholipid complex was obtained, sealed and stored in a refrigerator.

[0075] 【Preparation 3】 Sodium dem...

Embodiment 3

[0083] Example 3 Preparation of sodium demethylcantharidinate phospholipid complex lipid microsphere injection

[0084] [Prescription 1] Demethylcantharidinate sodium phospholipid complex lipid microsphere injection (specification: 0.5mg / ml)

[0085] Sodium demethylcantharidate complex (calculated as demethylcantharidin) 0.05 % Soybean oil 10% Lecithin 1.2% glycerin 2.5% sodium oleate 0.03% Poloxamer 188 0.2% Edetate Calcium Sodium 0.02% Water for Injection Add to 100%

[0086] Preparation:

[0087] (1) Disperse glycerin for injection, poloxamer 188, sodium oleate and calcium sodium edetate in an appropriate amount of water for injection, heat to 70°C in a magnetic stirrer and stir until completely dissolved as the water phase;

[0088] (2) Add the phospholipid complex and lecithin for injection in [Preparation 4] into soybean oil for injection, heat to 80°C and stir until completely dissolved as the oil phase;

[00...

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