Alprostadil lipid nanosphere freeze-drying injection and preparation method thereof

Abstract

The invention discloses an alprostadil lipid nanosphere freeze-drying injection and a preparation method thereof, and belongs to the technical field of medicines. The alprostadil lipid nanosphere freeze-drying injection is prepared from the following raw materials in part by weight: 0.0005 to 0.1 part of alprostadil, 15 to 60 parts of medium-chain oil, 3.0 to 35 parts of emulsifier, 8.5 to 48 parts of polyethylene glycol-12-hydroxy stearate, 22 parts of glycerol, 20 to 200 parts of trehalose, and 20 to 300 parts of cyclodextrin. The particle size of the alprostadil lipid nanosphere freeze-drying injection after redissolution is less than 100nm; and an aseptic filtration way can be used for sterilization, so that the disadvantage of thermal instability of the alprostadil is overcome, and the stability of products is improved. Meanwhile, lipid nanospheres have smaller particle sizes which are less than 100nm, so the alprostadil lipid nanosphere freeze-drying injection is more favorable for the distribution of the alprostadil in in-vivo non-reticuloendothelial system (RES) tissues, reduces pulmonary circulation inactivation and blood clearance, is favorable for circulating in vivo for a long time, and is suitable for the treatment of cardiac and neurosurgical diseases.

Description

Technical field [0001] The present invention involves a prefixed lipid -quality microsphere frozen -drying injection and its preparation methods. This preparation is mainly used for injection of administration, for the treatment of cardiovascular and brain neurosurgery, which belongs to the field of drug technology. Background technique [0002] The front of the front is an exact effect of vascular dilatation, a human physiological substance, which is widely used in the clinical treatment of coronary heart disease, vasculitis, sequelae of cerebral thrombosis, severe hepatitis, thrombosis, and erectile disorders.For ulcerous diseases, such as diabetic ulcer, ulcers caused by ischemia at the end of the limbs also have a good effect. [0003] The chemical properties of the front ground are extremely unstable, and it is easy to degrade with water and heat.The intravenous administration of the front ground, and the blood can be extinguished by more than 90%at a time after the lung cir...

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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