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...

AI Technical Summary

Problems solved by technology

The conventional oral preparations of 2-methoxyestradiol have poor bioavailability due to the low solubility of the drug. The results of phase I clinical studies of 2-methoxyestradiol show that 2-methoxyestradiol Oral administration of alcohol is irregular and lacks correlation between pharmacokinetics and dose (James J et al., Invest New Drugs, 25:41-48 (2006))

[0003] 2-Methoxyestradiol is a poorly soluble drug in water, and its solubility in water is less than 5 mg / L. The injection of this type of drug can be an injection suspension, which requires the drug to have a high pharmacological Active, that is, there is a small dosage, and it can only be injected intramuscularly and subcutaneously, but the conventional dosage of 2-methoxyestradiol needs to reach more than 400mg; the second is to use organic solvents as solvents, or use ethanol Polyoxyethylene hydrogenated castor oil is added to the solvent as a solubilizer. The fatal flaw of the injection solution solubilized by organic solvents and surfactants is that it is easy to cause hemolysis and allergic reactions, and lacks sustained release and targeting, such as products already on the market It is clearly stipulated that corticosteroids and antihistamines should be used for desensitization before clinical use

[0004] In order to solve the problem of intravenous administration of 2-methoxyestradiol, the applicant has studied 2-methoxyestradiol intravenous nanoemulsion, but in the preparation process, organic solvents need to be used first, such as chloroform and other dissolved drugs and phospholipids In order to make the drug form a microdispersion before the preparation of the intravenous emulsion, although the applicant is very aware of the hazards of organic solvents such as chloroform, and uses a vacuum distillation method to remove the solvent as much as possible in its preparation, everyone knows that phospholipids are a kind of two It is very difficult to completely remove chloroform from the hydrophilic substance

In order to solve the problem of organic solvent residues, Akkar A etc. directly added the drug into colostrum when studying itraconazole injection emulsion, and then repeatedly used a high-pressure milk homogenizer to homogenize to obtain intravenous injection emulsion (Akkar A et al., European Journal of Pharmaceutics and Biopharmaceutics.56: 29-36 (2003)), this method exists that the wearing and tearing of the high-pressure homogenizer is relatively severe, and the high-pressure homogenizer is often blocked so that the operation process is often interrupted, and equipment exclusion is carried out. Production of injections with high quality requirements is very unfavorable