Alprostadil lipid nanosphere freeze-drying injection and preparation method thereof

Abstract

The invention discloses an alprostadil lipid nanosphere freeze-dried injection and a preparation method thereof, belonging to the technical field of medicines. Alprostadil lipid nanosphere freeze-dried injection, which is prepared from the following raw materials in parts by weight: alprostadil 0.0005-0.1, medium-chain oil 15-60, emulsifier 3.0-35, polyethylene glycol Alcohol lauryl hydroxystearate 8.5-48, glycerin 22, trehalose 20-200, cyclodextrin 20-300. The particle size of the reconstituted alprostadil lipid nanosphere freeze-dried injection of the present invention is less than 100nm, can be sterilized by sterile filtration, overcomes the shortcoming of alprostadil thermal instability, and increases the stability of the product. At the same time, because the lipid nanospheres have a smaller particle size below 100nm, it is more conducive to the distribution of alprostadil in non-RES tissues, reducing the inactivation of pulmonary circulation and blood clearance, which is conducive to long-term circulation in the body, and is suitable for the heart and brain. Treatment of neurosurgical diseases.

Description

technical field [0001] The invention relates to an alprostadil lipid nanosphere freeze-dried injection and a preparation method thereof. The preparation is mainly used for injection administration and for the treatment of cardiovascular and cranial neurosurgery diseases, and belongs to the technical field of medicines. Background technique [0002] Alprostadil is a vasodilator with definite curative effect and a human physiological substance, which is widely used clinically in the treatment of coronary heart disease, vasculitis, sequelae of cerebral thrombosis, severe hepatitis, thrombosis, and erectile dysfunction. It also has a good effect on ulcerative diseases, such as diabetic ulcers and ulcers caused by extremity ischemia. [0003] Alprostadil is extremely unstable chemically, is unstable to water and heat, and is easy to degrade. Alprostadil is administered intravenously in the body, and the blood can be inactivated by more than 90% once it passes through the pulmona...

AI Technical Summary

Problems solved by technology

Because alprostadil is extremely heat-labile, the product may be completely degraded by autoclaving. Even if a short-term high temperature method is used, the product will produce degradation products that may be as high as 60%, and the phospholipid degradation products due to high heat will continue to affect the main drug. stability, which shortens the shelf life of the product. For example, the products that are already on the market are produced in this way, and the technical defects of the products shown have greatly affected the clinical application of the product.

Chinese patent 201010168597.2, a kind of alprostadil freeze-dried emulsion for injection and its preparation method, although part of the disclosed technical scheme involves the injection oil, emulsifier, freeze-drying protective agent cyclodextrin and sugar of this patent, but the patent The content only involves the formulation and preparation process of traditional fat emulsion and submicron emulsion, which belongs to ordinary emulsion, and does not involve the formulation and process of preparing lipid nanospheres below 100nm, although the specification mentions that its particle size ranges from 50-500nm, But from the technical scheme and the examples described, its emulsion particle diameter can not be less than 100nm, and the actual emulsion particle diameter disclosed in its description of the invention has exceeded 100nm substantially, although the technical scheme particle diameter disclosed in embodiment 1 is 85nm, its content It shows that olive oil and soybean lecithin are prepared by high-pressure homogenization method. According to the common knowledge of emulsion preparation, this technical scheme belongs to the preparation of ordinary emulsion, and it is impossible to prepare emulsion with a particle size of less than 100nm

The technical solutions of the examples disclosed in this patent are basically the combination of medium and long-chain triglycerides and phospholipids commonly used in traditional fat emulsions and submicron emulsions. It is difficult to form an emulsion below 100nm due to the emulsification of the combination of agents

In addition, as for how the lyoprotectant protects the prepared emulsion to maintain a small particle size after reconstitution, according to its patent, sugar and cyclodextrin are used, but the cyclodextrin added in its technical solution is only for inclusion. Leaked alprostadil effect, due to the low addition amount (maximum 0.3%), it is difficult to achieve freeze-drying protection, such a technical solution cannot achieve the effective effect of maintaining particle size

The preparation of the patented emulsion must be obtained through high-pressure homogenization and external energy acquisition. The emulsion system is a thermodynamically unstable system. The technical solution of this patent is only suitable for the preparation of submicron emulsions (lipid microspheres) with a particle size of more than 100nm, etc. Common Emulsion Preparations

The Chinese patent is a patent previously declared by the inventor. Through the compounding of medium chain oil, phospholipid and HS-15, the particle size of nanospheres below 100nm can be achieved, but because it is an aqueous solution, the stability and transportation of the main drug , The storage is still affected, and the application has certain limitations. The patent does not involve its freeze-dried preparation formula

The currently published patents on lyophilized emulsions of alprostadil mainly relate to common emulsions such as fat emulsions and submicron emulsions. No lyophilized preparations involving microemulsions or nanospheres have been found, and the lyoprotectants are mainly carbohydrates. , there are many types, but it is difficult to protect the particle size of the emulsion for one emulsion formula, and it does not reveal the essential technical content of the freeze-drying protectant

[0005] In summary, the above-mentioned patented technical solutions that have been disclosed do not involve the technical solution of alprostadil lipid nanosphere freeze-dried injection, and do not disclose the technical solution of the present invention

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