Preparation of 2-methoxyl group estradiol vena nano emulsions

Abstract

The invention relates to a preparation method of 2-methoxyestradiol nano-emulsion for intravenous injection, which radically eliminates residues of physiologically sensitive organic solvents in nano-emulsion final products and utilizes a high-pressure homogenizer to ensure the production of high-content 2-methoxyestradiol preparations. The technical proposal is that: firstly, a 2-methoxyestradiol micro-dispersion is prepared; emulsifiers, oil for injection and isoosmotic adjusting agent are added in the micro-dispersion and then stirred to form a primary emulsion; the primary emulsion is treated with the high-pressure homogenizer to form a nano-emulsion; and the nano-emulsion is further treated with pH regulators, filtered, sealed, sterilized and cooled down to room temperature. The invention can completely eliminate organic solvent residues in final products. The preparation method has good operation continuity, is suitable for industrialized production, ensures high drug content in final products, prevents blockage of the high-pressure homogenizer, and is easy to operate.

Description

1. Technical field

[0001] The invention relates to the field of medicine, in particular to a method for preparing 2-methoxyestradiol intravenous nanoemulsion without residual organic solvent, which can be used for the preparation of 2-methoxyestradiol intravenous nanoemulsion in pharmaceutical production, and Preparation of microdispersions of 2-methoxyestradiol, preparation of other formulations of 2-methoxyestradiol on the basis of microdispersions. 2. Background technology

[0002] 2-methoxyestradiol (1,3,5-triene-2,3,17β-trihydroxy-2-methyl ether sterol) is a physiological metabolite of estradiol in vivo (Schumacher G et al. J CancerRes Clin Oncol.127: 405-410, (2001)), has obvious anti-tumor activity, and its anti-cancer mechanism may be the induction of tumor and endothelial cell apoptosis (Lin HL et al. Cancer.92: 500-509 (2001)) , also has anti-tumor angiogenesis (Figg WD ​​et al. Invest New Drug. 20: 183-194 (2002)) and its ability to inhibit the proliferation of t...

Examples

Embodiment 1

[0031] Take 200 mg of 2-methoxyestradiol, 2.0 g of soybean lecithin, and 1 g of soybean oil for injection in a high-pressure chamber, and inject purified high-purity supercritical CO2 from the bottom of the high-pressure chamber. 2 Fluid, pressure 18Mpa, temperature 35°C, dissolve for 20min, get microdispersion of 2-methoxyestradiol from the bottom of the separation chamber; add microdispersion of 2-methoxyestradiol Mix 20 g of soybean oil for injection filtered through a membrane filter, add water for injection containing 4% glucose filtered through a 0.22 μm microporous membrane to 100 ml, stir to form colostrum, and pass through a high-pressure milk homogenizer three times at a pressure of 15k psi. Interrupt, use 0.1Mol / L hydrochloric acid or 0.1Mol / L sodium hydroxide to adjust the pH value to 5.5-8.0, filter through a 0.45μm microporous membrane, purify nitrogen flow protection, fill and repack, rotate the autoclave at 121°C, and sterilize Bacteria for 20 minutes, pour hot...

Embodiment 2

[0035] Take 600 mg of 2-methoxyestradiol and 4 g of soybean oil for injection filtered through a 0.22 microporous membrane and place it in a high-pressure chamber, and inject purified high-purity supercritical CO2 from the bottom of the high-pressure chamber. 2 Fluid, pressure 23Mpa, temperature 38°C, dissolve for 30min, get micro-oil dispersion of 2-methoxyestradiol from the bottom of the separation chamber; add the micro-dispersion of 2-methoxyestradiol to the Mix with 16 g of soybean oil for injection filtered through a microporous membrane, then add water for injection containing 2.5% glycerin and 0.9 g of poloxamer filtered through a 0.22 μm microporous membrane to 100 ml, stir to form colostrum, and Homogenizer three times, pressure 17kpsi, operation without interruption, use 0.1Mol / L hydrochloric acid or 0.1Mol / L sodium hydroxide to adjust the pH value to 5.5-8.0, filter with 0.45μm microporous membrane, purify nitrogen flow to protect filling and packaging , rotate the...

Embodiment 3

[0039] Take 800 mg of 2-methoxyestradiol, 2.0 g of egg yolk lecithin, and 8 g of olive oil for injection filtered through a 0.22 μm microporous membrane and place them in a high-pressure chamber, and inject purified high-purity supercritical CO2 from the bottom of the high-pressure chamber. 2 Fluid, pressure 26Mpa, temperature 35°C Dissolve for 40min, get microdispersion of 2-methoxyestradiol from the bottom of the separation chamber; add microdispersion of 2-methoxyestradiol Mix with 12g of olive oil for injection filtered through a membrane filter, then add water for injection filtered through a 0.22μm microporous membrane and contain 5% sorbitol and 0.5g poloxamer to 100ml, stir to form colostrum, and pass through high-pressure milk Homogenize three times, the pressure is 16k psi, the operation is uninterrupted, the pH value is adjusted to 5.5-8.0 with 0.1Mol / L hydrochloric acid or 0.1Mol / L sodium hydroxide, the 0.45μm microporous membrane is filtered, and the purified nitro...

1. Technical field

[0001] The invention relates to the field of medicine, in particular to a method for preparing 2-methoxyestradiol intravenous nanoemulsion without residual organic solvent, which can be used for the preparation of 2-methoxyestradiol intravenous nanoemulsion in pharmaceutical production, and Preparation of microdispersions of 2-methoxyestradiol, preparation of other formulations of 2-methoxyestradiol on the basis of microdispersions. 2. Background technology

[0002] 2-methoxyestradiol (1,3,5-triene-2,3,17β-trihydroxy-2-methyl ether sterol) is a physiological metabolite of estradiol in vivo (Schumacher G et al. J CancerRes Clin Oncol.127: 405-410, (2001)), has obvious anti-tumor activity, and its anti-cancer mechanism may be the induction of tumor and endothelial cell apoptosis (Lin HL et al. Cancer.92: 500-509 (2001)) , also has anti-tumor angiogenesis (Figg WD ​​et al. Invest New Drug. 20: 183-194 (2002)) and its ability to inhibit the proliferation of t...

Examples

Embodiment 1

[0031] Take 200 mg of 2-methoxyestradiol, 2.0 g of soybean lecithin, and 1 g of soybean oil for injection in a high-pressure chamber, and inject purified high-purity supercritical CO2 from the bottom of the high-pressure chamber. 2 Fluid, pressure 18Mpa, temperature 35°C, dissolve for 20min, get microdispersion of 2-methoxyestradiol from the bottom of the separation chamber; add microdispersion of 2-methoxyestradiol Mix 20 g of soybean oil for injection filtered through a membrane filter, add water for injection containing 4% glucose filtered through a 0.22 μm microporous membrane to 100 ml, stir to form colostrum, and pass through a high-pressure milk homogenizer three times at a pressure of 15k psi. Interrupt, use 0.1Mol / L hydrochloric acid or 0.1Mol / L sodium hydroxide to adjust the pH value to 5.5-8.0, filter through a 0.45μm microporous membrane, purify nitrogen flow protection, fill and repack, rotate the autoclave at 121°C, and sterilize Bacteria for 20 minutes, pour hot...

Embodiment 2

[0035] Take 600 mg of 2-methoxyestradiol and 4 g of soybean oil for injection filtered through a 0.22 microporous membrane and place it in a high-pressure chamber, and inject purified high-purity supercritical CO2 from the bottom of the high-pressure chamber. 2 Fluid, pressure 23Mpa, temperature 38°C, dissolve for 30min, get micro-oil dispersion of 2-methoxyestradiol from the bottom of the separation chamber; add the micro-dispersion of 2-methoxyestradiol to the Mix with 16 g of soybean oil for injection filtered through a microporous membrane, then add water for injection containing 2.5% glycerin and 0.9 g of poloxamer filtered through a 0.22 μm microporous membrane to 100 ml, stir to form colostrum, and Homogenizer three times, pressure 17kpsi, operation without interruption, use 0.1Mol / L hydrochloric acid or 0.1Mol / L sodium hydroxide to adjust the pH value to 5.5-8.0, filter with 0.45μm microporous membrane, purify nitrogen flow to protect filling and packaging , rotate the...

Embodiment 3

[0039] Take 800 mg of 2-methoxyestradiol, 2.0 g of egg yolk lecithin, and 8 g of olive oil for injection filtered through a 0.22 μm microporous membrane and place them in a high-pressure chamber, and inject purified high-purity supercritical CO2 from the bottom of the high-pressure chamber. 2 Fluid, pressure 26Mpa, temperature 35°C Dissolve for 40min, get microdispersion of 2-methoxyestradiol from the bottom of the separation chamber; add microdispersion of 2-methoxyestradiol Mix with 12g of olive oil for injection filtered through a membrane filter, then add water for injection filtered through a 0.22μm microporous membrane and contain 5% sorbitol and 0.5g poloxamer to 100ml, stir to form colostrum, and pass through high-pressure milk Homogenize three times, the pressure is 16k psi, the operation is uninterrupted, the pH value is adjusted to 5.5-8.0 with 0.1Mol / L hydrochloric acid or 0.1Mol / L sodium hydroxide, the 0.45μm microporous membrane is filtered, and the purified nitro...