CN114129519A

CN114129519A - Docetaxel nano fat emulsion injection and preparation method thereof

Info

Publication number: CN114129519A
Application number: CN202111207575.7A
Authority: CN
Inventors: 甘周阳; 刘振东; 喻颖利; 薛卉茹; 甘文飞
Original assignee: Hubei Halfsky Pharmaceuticals Co ltd
Current assignee: Hubei Halfsky Pharmaceuticals Co ltd
Priority date: 2021-10-18
Filing date: 2021-10-18
Publication date: 2022-03-04

Abstract

The invention discloses a docetaxel nano fat emulsion injection, which comprises the following raw materials in proportion: 1 part of docetaxel, 15-30 parts of hydrophilic phase, 0.5-5 parts of oil phase, 0.5-40 parts of emulsifier and 0.1-2 parts of stabilizer. The preparation method comprises the following steps: 1) weighing a hydrophilic phase, heating to 30-60 ℃, adding a stabilizer, stirring for dissolving, and filtering by a filter for later use; 2) crushing and sieving docetaxel, weighing, adding the docetaxel into the hydrophilic phase, and stirring and dissolving the docetaxel under the condition of nitrogen filling; 3) weighing the oil phase according to the above amount, adding an emulsifier, heating to 30-60 ℃, uniformly stirring, and filtering through a filter; 4) adding the oil phase into the hydrophilic phase, performing high-speed shearing to obtain primary emulsion, performing high-pressure homogenization, filtering, filling, nitrogen filling, tamponade and capping to obtain the docetaxel nano fat emulsion injection.

Description

Docetaxel nano fat emulsion injection and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, and in particular relates to a docetaxel nano fat emulsion injection and a preparation method thereof.

Background

Docetaxel (Docetaxel) is developed and marketed by Sanofi-Aventis, France, is a plant antitumor drug, plays an antitumor role by interfering a microtubule network necessary for cell mitosis and interphase cell functions, and has the characteristics of good curative effect, wide antitumor spectrum and the like.

Compared with paclitaxel, docetaxel has unique advantages in the aspect of tumor resistance: the affinity of docetaxel is 2 times that of paclitaxel, and the activity of docetaxel can reach 10 times that of paclitaxel in an in vitro anticancer activity test. Docetaxel also has better bioavailability, higher intracellular concentration, better water solubility and excellent anticancer broad spectrum, and has good curative effect on breast cancer and lung cancer and better therapeutic effect on patients with head and neck cancer, gastric cancer, pancreatic cancer and soft tissue tumor. Docetaxel in combination with certain antitumor drugs also has synergistic antitumor effects. In addition, docetaxel has less extracellular flux and has significant apoptosis inducing effect at low dose. Many in vitro and clinical studies have demonstrated that docetaxel has radiosensitizing effects on a variety of tumor cells without exacerbating the radiation damage of normal tissues.

Because docetaxel is insoluble in water, polysorbate 80 is mostly adopted as a solubilizer to improve the solubility of docetaxel, and injection which can be used for intravenous drip is prepared. However, the docetaxel injection on the market in China has the following defects:

(1) excessive adverse reactions. Polysorbate 80 is often used as a solubilizer of insoluble drugs, and the quality and dosage of polysorbate 80 obviously affect the clinical safety of pharmaceutical preparations. The national adverse reaction monitoring center and a plurality of documents report that polysorbate 80 can cause severe adverse reactions such as allergy, hemolysis and the like, and the quality of the polysorbate 80 should be strictly controlled when the polysorbate is clinically used especially for intravenous injection. At present, although many medicinal polysorbates 80 on the market at home have approved literature, the quality is obviously great, and the polysorbates 80 of most manufacturers have darker color and even approximate brown color, so that great potential safety hazards exist. In the traditional docetaxel injection, the dosage of polysorbate 80 is large (25ml/1g of main drug), and adverse reactions caused by the dosage are frequently reported. In addition, 6 months 2014, the FDA (the U.S. food and drug administration) issued a safety warning that docetaxel treatment may cause ethanol poisoning. At present, the docetaxel injection on the market at home mostly uses ethanol as a solvent, and has larger risk of adverse reaction of a central nervous system.

(2) The product quality is not high. Docetaxel is unstable, is sensitive to pH value, temperature and the like, and is easy to degrade in the production and storage processes. Research reports that 7-epi-docetaxel, the main degradation impurity of docetaxel, is one of the causes of drug resistance of tumor cells. Many domestic docetaxel injection solutions have poor treatment effect, which is attributed to high impurity content.

(3) It is inconvenient for clinical use. The traditional docetaxel injection is viscous liquid, needs a special solvent for dilution before clinical use, and easily generates foam in the preparation process, thereby influencing the accuracy of the dosage.

The defects greatly limit the clinical application of docetaxel, and the innovation of the key technology for improving the safety and the effectiveness of the clinical use of docetaxel is always a research hotspot of domestic and foreign institutions.

Chinese application patent CN 101584659B discloses a docetaxel pharmaceutical composition injection, which consists of docetaxel, absolute ethyl alcohol and polysorbate-80, wherein the weight ratio of docetaxel, absolute ethyl alcohol and polysorbate-80 is 15-25:10-15: 550-: slowly adding docetaxel into polysorbate-80 of a prescribed amount under stirring, uniformly stirring, adding anhydrous ethanol of a prescribed amount, stirring to obtain a mixed solution, filtering the mixed solution through a microporous filter membrane, and subpackaging the obtained filtrate, wherein the docetaxel composition uses a mixed solution of ethanol and water for injection as a diluent, and the volume ratio of 95% ethanol to the water for injection is 1: 6.4-8.5. The invention contains ethanol and a large amount of polysorbate-80, and can cause adverse reactions such as allergy, hemolysis, central nervous system toxicity and the like.

Chinese application patent CN 105534904B discloses a docetaxel composition for injection, which contains docetaxel, oil for injection, an emulsifier and a stabilizer. When preparing oil phase, mixing docetaxel, emulsifier and absolute ethanol, stirring to clarify, adding injectable oil and stabilizer, further stirring to clarify, and vacuum volatilizing ethanol to obtain oil phase. The ethanol is volatilized in vacuum, the production process is complex, and the industrial production difficulty is high.

Chinese application patent CN 104224710B discloses a docetaxel nano-micelle, comprising: 1 part by weight of docetaxel; 10-100 parts by weight of a carrier material; 0-10 parts of oil. Wherein the carrier material is a mixture of polyethylene glycol 1000-vitamin E succinate, pluronic L61 and polyethylene glycol-15-hydroxystearate, and the oil is medium chain triglyceride. The average particle size of the docetaxel nano-micelle is 10-200 nm.

Chinese application patent CN 101810574B discloses a method for preparing docetaxel submicron emulsion injection and lyophilized emulsion. The main active component of the submicron emulsion is docetaxel, and the auxiliary materials are oil for injection, an emulsifier, a stabilizer, an isoosmotic adjusting agent, a freeze-drying supporting agent and water for injection. The oil for injection is as follows: caprylic capric fatty acid triglycerides; the used emulsifiers were: one or more of poloxamer, soybean phospholipid and lecithin PC-98T; the used stabilizers are: oleic acid. The content of docetaxel is: 1-10 mg/ml. The particle size range of the submicron emulsion injection and the freeze-dried emulsion after redissolution is as follows: 100 and 200 nm.

In conclusion, despite the obvious progress of research on new formulations and dosage forms of docetaxel, the problem of drug resistance of docetaxel clinically is not effectively improved, and some inventions do not meet the requirements of medication safety, effectiveness, quality controllability and easy industrial production. To this end, the docetaxel composition of the present invention is proposed in view of the above-mentioned drawbacks of the docetaxel injection of the prior art.

Disclosure of Invention

The invention aims to provide a docetaxel composition, which has a reasonable formula and is convenient to use, can effectively overcome the defects of the existing preparation that the adverse reactions such as allergy, hemolysis, central nervous system toxicity, drug resistance and the like are easily caused, and improves the safety of the drug.

In order to achieve the purpose, the invention provides a docetaxel nano fat emulsion injection, which comprises the following raw materials in proportion:

preferably, the docetaxel nano fat emulsion injection contains the following raw materials in proportion:

further preferably, the docetaxel nano fat emulsion injection contains the following raw materials in proportion:

still more preferably, the docetaxel nano fat emulsion injection contains the following raw materials in proportion:

preferably, the oil phase is rich in polyunsaturated fatty acids.

Further preferably, the oil phase is selected from one or more of fish oil, omega-3-fatty acid triglycerides, omega-3-fatty acid ethyl esters, alpha-linolenic acid triglycerides, alpha-linolenic acid ethyl esters, linoleic acid, ethyl linoleate, olive oil and soybean oil.

Preferably, the hydrophilic phase is selected from a mixture of one or more of glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400.

Preferably, the emulsifier is selected from a mixture of one or more of sodium oleate, egg yolk lecithin, soybean lecithin and polysorbate 80.

Preferably, the stabilizer is selected from one or more of organic acid, cysteine hydrochloride, edetate disodium, edetate calcium sodium, vitamin C and vitamin E.

The invention also aims to provide a preparation method of the docetaxel composition, which is simple and convenient to operate, easy for industrial production, good in stability of the prepared product, capable of being stored at room temperature and free of docetaxel precipitation in the long-term storage process.

The preparation method of the docetaxel nano fat emulsion injection provided by the invention comprises the following steps:

1) weighing the hydrophilic phase in the amount, heating to 30-60 ℃, adding the stabilizer in the amount, stirring for dissolving, and filtering by a filter for later use;

2) crushing and sieving docetaxel, weighing the above parts by weight, adding the weighed docetaxel into the hydrophilic phase, and stirring and dissolving the docetaxel under the condition of nitrogen filling;

3) weighing the oil phase in the above amount, adding the emulsifier in the above amount, heating to 30-60 ℃, uniformly stirring, and filtering through a filter;

4) adding the oil phase into the hydrophilic phase, performing high-speed shearing to obtain primary emulsion, performing high-pressure homogenization, filtering, filling, nitrogen filling, tamponade and capping to obtain the docetaxel nano fat emulsion injection.

The beneficial technical effects are as follows:

compared with the prior art, the invention has the following advantages:

1) selecting one or more of fish oil rich in polyunsaturated fatty acid, omega-3-fatty acid triglyceride, omega-3-fatty acid ethyl ester, alpha-linolenic acid triglyceride, alpha-linolenic acid ethyl ester, linoleic acid ethyl ester, olive oil and soybean oil. The polyunsaturated fatty acid has anti-inflammatory effect, and can improve tolerance of organism, thereby improving safety of clinical medication of docetaxel.

2) The injection is a non-aqueous and non-ethanol system, has good stability, does not precipitate docetaxel in the long-term storage process, and has low impurity content.

3) The invention is suitable for treating breast cancer, non-small cell lung cancer, hormone refractory prostate cancer, gastric cancer and head and neck squamous cell carcinoma. When the nano fat emulsion is clinically used, the nano fat emulsion can be directly added into 0.9% sodium chloride or 5% glucose infusion and is self-emulsified to form the nano fat emulsion with the average particle size of 10-100 nm. The tumor passive targeting effect is achieved through an EPR effect (enhanced penetration retention effect), and the drug treatment effect is improved. The polyunsaturated fatty acid has anti-inflammatory effect, and can improve the safety of docetaxel in clinical application.

The invention does not need special solvent for dilution, can be directly added into 0.9 percent sodium chloride or 5 percent glucose infusion solution during clinical use, forms nano fat emulsion with the average particle size of 10-100 nm through self-emulsification, and plays a role in passive targeting of tumors through an EPR effect (enhanced osmotic retention effect).

Detailed Description

For a better understanding and for the purpose of carrying out the invention, reference is made to the examples, which are not intended to limit the invention in any way.

Example 1:

the preparation method comprises the following steps:

1) weighing 22 parts by weight of polyethylene glycol 300, heating to 45-55 ℃, adding 0.5 part by weight of organic acid, stirring for dissolving, and filtering by a 0.22 mu m filter for later use;

2) crushing and sieving docetaxel, weighing 1 part by weight, adding the docetaxel into the hydrophilic phase, and stirring and dissolving the docetaxel under the condition of nitrogen filling;

3) weighing 1.375 parts by weight of fish oil, adding 29.25 parts by weight of sodium oleate, heating to 45-55 ℃, uniformly stirring, and filtering by a 0.22-micron filter;

Example 2:

the preparation method comprises the following steps:

1) weighing 15 parts by weight of glycerol, heating to 40-50 ℃, adding 0.1 part by weight of cysteine, stirring for dissolving, and filtering by a 0.22 mu m filter for later use;

3) weighing 0.5 part by weight of omega-3-fatty acid ethyl ester, adding 2 parts by weight of egg yolk lecithin, heating to 40-50 ℃, uniformly stirring, and filtering by a 0.22 mu m filter;

Example 3:

the preparation method comprises the following steps:

1) weighing 30 parts by weight of polyethylene glycol 400, heating to 50-60 ℃, adding 1.0 part by weight of calcium disodium edetate, stirring for dissolving, and filtering by a 0.22 mu m filter for later use;

3) weighing 2 parts by weight of alpha-ethyl linolenate and 0.5 part by weight of olive oil, adding 30 parts by weight of soybean lecithin, heating to 50-60 ℃, uniformly stirring, and filtering by a 0.22 mu m filter;

Example 4:

the preparation method comprises the following steps:

1) weighing 15 parts by weight of polyethylene glycol 200, heating to 30-50 ℃, adding 2 parts by weight of edetate disodium, stirring for dissolving, and filtering by a 0.22-micron filter for later use;

3) weighing 3 parts of alpha-linolenic acid triglyceride and 2 parts of ethyl linoleate, adding 40 parts of polysorbate 80, heating to 30-50 ℃, uniformly stirring, and filtering by using a 0.22 mu m filter;

Example 5:

the preparation method comprises the following steps:

1) weighing 20 parts by weight of propylene glycol, heating to 45-55 ℃, adding 1 part by weight of cysteine hydrochloride, stirring for dissolving, and filtering by a 0.22 mu m filter for later use;

3) weighing 2 parts by weight of linoleic acid, 2 parts by weight of omega-3-fatty acid triglyceride and 1 part by weight of soybean oil, adding 0.5 part by weight of sodium oleate, heating to 45-55 ℃, uniformly stirring, and filtering by a 0.22 mu m filter;

Example 6:

the preparation method comprises the following steps:

1) weighing 15 parts by weight of glycerol and 15 parts by weight of polyethylene glycol 300, heating to 50-60 ℃, adding 1 part by weight of vitamin C, stirring for dissolving, and filtering by a 0.22 mu m filter for later use;

3) weighing 0.5 part by weight of fish oil and 0.5 part by weight of linoleic acid, adding 0.5 part by weight of sodium oleate, 10 parts by weight of polysorbate 80 and 1 part by weight of vitamin E, heating to 30-40 ℃, uniformly stirring, and filtering by a 0.22 mu m filter;

The invention is further illustrated by the following tests:

the product prepared in example 1 is placed at 25 ℃ +/-2 ℃ for 24 months, and the detection results are shown in table 1.

TABLE 1

From the test results in the table above, it can be seen that the related substances of the composition of the present invention are slightly increased during the long-term storage, but the quality of the composition is still far lower than the quality standard requirement of the current docetaxel formulation, and the product quality is stable.

The product obtained in example 2 was subjected to an allergy test, the test results being shown in table 2.

TABLE 2

The test result shows that the docetaxel nano fat emulsion can not cause anaphylactic reaction under the condition of normal medication and has good clinical safety.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. The docetaxel nano fat emulsion injection is characterized by comprising the following raw materials in proportion:

2. the docetaxel nano fat emulsion injection as set forth in claim 1, which comprises the following raw materials in proportion:

3. the docetaxel nano fat emulsion injection as set forth in claim 2, which comprises the following raw materials in proportion:

4. the docetaxel nano fat emulsion injection as set forth in claim 3, which comprises the following raw materials in proportion:

5. the docetaxel nano fat emulsion injection of claim 1, wherein the oil phase is enriched in polyunsaturated fatty acids.

6. The docetaxel nano fat emulsion injection of claim 2, wherein the oil phase is selected from the group consisting of fish oil, omega-3-fatty acid triglyceride, omega-3-fatty acid ethyl ester, alpha-linolenic acid triglyceride, alpha-linolenic acid ethyl ester, linoleic acid ethyl ester, olive oil and soybean oil.

7. The docetaxel nano fat emulsion injection of claim 1, wherein the hydrophilic phase is selected from the group consisting of glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 300 and a mixture of one or more of polyethylene glycol 400.

8. The docetaxel nano fat emulsion injection of claim 1, wherein the emulsifier is selected from the group consisting of sodium oleate, egg yolk lecithin, soybean lecithin and a mixture of one or more of polysorbate 80.

9. The docetaxel nano fat emulsion injection of claim 1, wherein the stabilizer is selected from the group consisting of one or more of organic acids, cysteine hydrochloride, edetate disodium, edetate calcium sodium, vitamin C and vitamin E.

10. The method for preparing docetaxel nano fat emulsion injection as set forth in any one of claims 1 to 9, which comprises the steps of: