CN102600077B - Gemcitabine or gemcitabine salt nano-emulsion injecta and preparation method thereof - Google Patents

Abstract

The invention relates to a gemcitabine or gemcitabine salt nano-emulsion injecta and a preparation method of the gemcitabine or gemcitabine salt nano-emulsion injecta. The injecta specifically includes gemcitabine or a gemcitabine salt, oil for injection, a surface active agent and water for injection, wherein the weight ratio of gemcitabine or the gemcitabine salt to the oil for injection to the surface active agent is 1:(10-100):(10-100), and the average particle size of an emulsion droplet in the emulsion is 1-100nm. The injecta provided by the invention is high in entrapment efficiency and stability and low in side effect.

Description

Gemcitabine or its salt nanoemulsion injection and preparation method thereof

technical field

The invention relates to a novel preparation of gemcitabine or a salt thereof and a preparation method thereof, in particular to a nanoemulsion injection of gemcitabine or a salt thereof and a preparation method thereof.

Background technique

Gemcitabine is a difluoronucleoside antimetabolite anticancer drug that disrupts cell replication. It is a water-soluble analog of deoxycytidine and is an inhibitory substrate for ribonucleotide reductase. , this enzyme is critical for the generation of deoxynucleotides required during DNA synthesis and repair. It has the characteristics of broad anti-tumor spectrum, unique mechanism of action, no cross-resistance with other chemotherapy drugs, and no superposition of toxic reactions.

As a prodrug, gemcitabine is a good substrate for deoxythymidine kinase phosphorylation in the cell, and is converted into the following metabolites under the action of the enzyme: gemcitabine monophosphate (dFdCMP), gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate Phosphate (dFdCTP) where dFdCDP and dFdCTP are active products. dFdCDP inhibits ribonucleotide reductase, thereby reducing the amount of deoxynucleotides needed for repair of DNA synthesis (especially dCTP), and low levels of dCTP reverse the normal negative feedback inhibition of deoxyglycoside kinases, resulting in more dFdCTP accumulation. At the same time, dFdCDP inhibits the deamination of dFdCMP by dCTP-induced deoxycytidine enzyme, and dFdCTP directly inhibits deoxycytidine dease, thereby converting more dFdCMP into the active metabolite dFdCMP deamination, and dFdCTP directly inhibits deoxygenation Cytidine deaminase, so that more dFdCMP is converted into active metabolites dFdCDP, dFd-CTP and dFdCTP competes with dCTP to enter the DNA chain, inserts into the site of deoxycytidine in the DNA chain, and allows guanosine to interact with it After pairing, the gemcitabine molecule is "masked" by this guanosine to prevent it from being removed and repaired by exoribonuclease, and then the DNA chain synthesis stops, and then the DNA breaks and the cell dies.

It has been confirmed that gemcitabine has a significant therapeutic effect on a variety of solid tumors, especially for non-small cell lung cancer, pancreatic cancer and breast cancer, and has achieved high efficacy either as a single drug or in combination with other anticancer drugs. The intracellular half-life of gemcitabine is relatively short (between 32 and 94 min), and it must be given in large doses (the recommended dose is 1000 mg/m2) and continuously administered intravenously to maintain its effective medicinal concentration and toxicity to cancer cells. Toxicity also affects normal tissues, and this dose-limiting toxicity affects clinical efficacy. In addition, gemcitabine lacks tissue specificity, has large systemic side effects, rapid metabolism in the body, short plasma half-life, and tumor drug resistance.

Therefore, finding a drug delivery method that can make the drug more targeted and less toxic and side effects is the focus and difficulty of current research. Drug-loaded nanoparticles containing effective drugs is a new type of sustained-release system, which can change the conventional drug delivery method and has a very broad prospect. It has become a research hotspot in the field of medicine in recent years. Slow release in the target area to reduce adverse drug reactions.

Huang Lesong, Wang Chunxia, Chen Zhiliang et al. "Targeted distribution of gemcitabine poly(n-butyl cyanoacrylate) nanoparticles in mouse brain" (Chinese Journal of Hospital Pharmacy, 2008, 28(16): 1332), and Huang Lesong, Wang Chunxia, Chen Zhiliang, etc. "Research on the influence of gemcitabine polycyanoacrylate n-butyl cyanoacrylate nanoparticles on mouse brain transplanted glioma" (Chinese Pharmacy, 2009, 20 (19): 1457) introduced a kind of gemcitabine nanoparticles and its effect on animals. Influence. Huang Junqin, Kong Liwen "Preparation of Gemcitabine Hydrochloride Liposome and Determination of Content and Encapsulation Efficiency" (Chinese Journal of Antibiotics, 2010, 35(1): 30) introduced a preparation and content determination method of gemcitabine liposome . CN101444485B discloses a kind of gemcitabine liposome, and this liposome comprises gemcitabine, phospholipid, cholesterol, but the encapsulation efficiency and dispersibility of this liposome all perform poorly, all have unfavorable to the stability of medicine and bioavailability Influence. CN101926779A discloses a gemcitabine solid lipid nanoparticle and a preparation method thereof. The preparation still has the problems of low drug encapsulation efficiency and poor stability, and the drug is partially degraded after storage for about 3 months. Although the liposome or nano drug research of some drugs has made great progress and has even been applied in clinical practice. However, due to differences in the physicochemical properties and pharmacological effects of drugs, no breakthrough has been made in the technology of applying liposomes or nano-medicines in the field of gemcitabine.

Judging from the current research results, gemcitabine liposomes or nano-microspheres prepared by existing methods have problems such as poor stability, easy aggregation in aqueous solution, overall erosion or surface degradation, and cannot be practically applied in clinical practice.

Contents of the invention

The purpose of the present invention is to solve the above technical problems, to provide a kind of gemcitabine that can enhance drug targeting, improve drug encapsulation efficiency and stability, reduce the side effects of gemcitabine or its salt in clinical application, and be suitable for clinical wide application Or its salt nanoemulsion injection.

The object of the present invention is to provide a kind of nanoemulsion injection of gemcitabine or its salt, described injection contains gemcitabine or its salt, injection oil, tensio-active agent and water for injection, wherein gemcitabine or its salt, injection oil, surface The weight ratio of the active agent is 1:10-100:10-100, and the average particle diameter of the emulsion droplets in the emulsion is 1-100nm.

The nanoemulsion injection is an oil-in-water type, wherein the weight ratio of gemcitabine or its salt, injection oil and surfactant is 1:20-50:10-20.

The salt of gemcitabine is hydrochloride.

The oil for injection is selected from one or more of mineral oil, vegetable oil, animal oil or synthetic oil; the vegetable oil is selected from soybean oil, peanut oil, corn oil, sesame oil, safflower oil, castor oil, palm oil, cottonseed One or more in oil, coconut oil, medium-chain fatty acid triglycerides, preferably one or more in soybean oil, peanut oil, sesame oil or medium-chain fatty acid triglycerides; The animal oil is selected from fish oil, spermaceti oil or mixtures thereof.

The surfactant is selected from phospholipids, nonionic surfactants or mixtures thereof.

Described phospholipid is selected from lecithin, soybean lecithin or its mixture, preferred lecithin or soybean lecithin; Described nonionic surfactant is selected from polyoxyethylene and polyethylene glycol nonionic surfactant, and described polyoxyethylene Ethylene nonionic surfactants are selected from Tween 20, Tween 40, Tween 60, Tween 80, Tween 85, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer 188 or mixtures thereof , preferably Tween 80 or Poloxamer 188, the polyethylene glycol nonionic surfactant is selected from the group consisting of polyethylene glycol polyhexadecyl cyanoacrylate, polyethylene glycol stearic acid, polyethylene glycol Alcohol vitamin E succinate or mixtures thereof.

The average particle size of the emulsion droplets in the emulsion is 1-70 nm, preferably 1-50 nm, more preferably 1-20 nm.

The injection of gemcitabine or its salt also contains one or more of antioxidants or stabilizers.

The antioxidant is selected from water-soluble antioxidants or oil-soluble antioxidants, wherein the water-soluble antioxidants are selected from sodium sulfite, sodium bisulfite, sodium pyrosulfite, sodium ascorbate, L-cysteine or mixtures thereof; The soluble antioxidant is selected from BHA (tert-butyl p-hydroxyanisole), BHT (2,6-di-tert-butylated hydroxytoluene), vitamin E, ascorbyl palmitate or mixtures thereof, preferably ascorbyl palmitate, wherein The antioxidant accounts for 0%-1w/v% of the injection.

The stabilizer is selected from oleic acid, sodium oleate, cholic acid, sodium cholate, dextran-70, deoxycholic acid, sodium deoxycholate or a mixture thereof, wherein the stabilizer accounts for 0% to 10% of the injection 1.5w/v%.

The object of the present invention is also to provide a kind of method for preparing above-mentioned gemcitabine or its salt nanoemulsion injection, comprise the steps:

Under the protection of inert gas, stir the injection oil evenly to form an oil phase;

Add the surfactant to an appropriate amount of water for injection, and stir evenly to form a water phase;

Under high-speed stirring, the oil phase and the water phase are mixed evenly, and then homogenized by a high-pressure homogenizer to produce colostrum;

adding gemcitabine or a salt thereof to colostrum;

Adjust the pH value to 4-9, continue to add water to the full volume, fully stir or homogenize with a high-pressure homogenizer to make the average particle size of emulsion droplets reach the required nanometer size.

The present invention also provides another method for preparing the above-mentioned gemcitabine or its salt nanoemulsion injection, comprising the following steps:

Under the protection of inert gas, stir the oil for injection and oil-soluble antioxidant to form an oil phase;

Add water-soluble antioxidant stabilizer and surfactant to an appropriate amount of water for injection, and stir evenly to form a water phase;

Under high-speed stirring, the oil phase and the water phase are mixed evenly, and are homogenized by a high-pressure homogenizer to produce colostrum;

adding gemcitabine or a salt thereof to colostrum;

Adjust the pH value from 4 to 9. Continue to add water to make up the volume to the full amount, fully stir or homogenize with a high-pressure homogenizer until the average particle size of emulsion droplets reaches the required nanometer size.

According to the inventor's research, it is especially good when the pH value is between 4 and 7.

The above-mentioned preparation has opened up a new way of administering gemcitabine or its salt, and the encapsulation efficiency and stability of the drug have been greatly improved through the screening of the content ratio of each component in the composition and the nano-scale treatment of the emulsion droplet size, reducing the The toxic and side effects of the medicine in use relieve the pain of the patient.

Detailed ways

In order to describe the invention more specifically, the invention will be further illustrated below in conjunction with specific examples, but the content of the present invention is not limited to the specific examples.

Embodiment one

Preparation method: under the protection of an inert gas, stir 200g of soybean oil for injection to form an oil phase, add 200g of soybean lecithin to 500ml of water for injection, stir to form a water phase, and mix the oil phase and water phase evenly under high-speed stirring , and homogenized by a high-pressure homogenizer to make colostrum, add 10 g of gemcitabine hydrochloride, adjust the pH value to 5.0, add water to set the volume to 1000 ml, and transfer to a high-pressure homogenizer to fully stir until the average particle size is below 40 nm; Packed with nitrogen gas.

Embodiment two

Preparation method: under the protection of an inert gas, stir 200g of peanut oil for injection to form an oil phase, add 200g of soybean lecithin to 500ml of water for injection, stir to form a water phase, and mix the oil phase and water phase evenly under high-speed stirring. And homogenized by a high-pressure homogenizer to make colostrum, add gemcitabine hydrochloride 10g, adjust the pH value to 5.0, add water to make it 1000ml, transfer it to a high-pressure homogenizer and stir well until the average particle size is below 40nm; filling , Nitrogen-filled packaging.

Embodiment Three

Preparation method: under the protection of an inert gas, stir 200g of sesame oil for injection to form an oil phase, add 200g of soybean lecithin to 500ml of water for injection, stir to form a water phase, and mix the oil phase and water phase evenly under high-speed stirring. And homogenized by a high-pressure homogenizer to make colostrum, add gemcitabine hydrochloride 10g, adjust the pH value to 5.0, add water to make it 1000ml, transfer it to a high-pressure homogenizer and stir well until the average particle size is below 40nm; filling , Nitrogen-filled packaging.

Embodiment four

Preparation method: under the protection of an inert gas, stir 200g of soybean oil for injection to form an oil phase, add 200g of soybean lecithin to 500ml of water for injection, stir to form a water phase, and mix the oil phase and water phase evenly under high-speed stirring , and homogenized by a high-pressure homogenizer to make colostrum, add 10 g of gemcitabine hydrochloride, adjust the pH value to 5.0, add water to constant volume to 1000 ml, transfer to a high-pressure homogenizer and stir well until the average particle size is below 20 nm; Packed with nitrogen gas.

Embodiment five

Preparation method: under the protection of an inert gas, stir 225g soybean oil for injection into an oil phase, preheat to 60°C, add 125g soybean lecithin and 4g sodium sulfite to 600ml water for injection, stir evenly to form a water phase, and preheat to 60°C ℃, under high-speed stirring, mix the oil phase and the water phase evenly, and homogenize through a high-pressure homogenizer to make colostrum, add 10g of gemcitabine hydrochloride, adjust the pH to 6.0, add water to 1000ml, and transfer it to a high-pressure Continue to emulsify in the homogenizer until the average particle size is about 20nm; fill and seal with nitrogen gas.

Embodiment six

Preparation method: under the protection of an inert gas, mix and stir 225g soybean oil for injection and 6g oleic acid to form an oil phase, preheat to 60°C, add 125g soybean lecithin and 4g sodium sulfite to 600ml water for injection, stir well to form a water phase , preheat to 60°C, mix the oil phase and the water phase evenly under high-speed stirring, and homogenize through a high-pressure homogenizer to make colostrum, add 10g of gemcitabine hydrochloride, adjust the pH value to 6.0, add water to 1000ml, Transfer it to a high-pressure homogenizer and continue to emulsify until the average particle size is about 15nm; fill it and fill it with nitrogen to melt seal.

Embodiment seven

Preparation method: under the protection of an inert gas, mix and stir 300g soybean oil for injection and 5g oleic acid to form an oil phase, preheat to 60°C, add 200g soybean lecithin and 5g sodium sulfite to 650ml water for injection, stir well to form a water phase , preheat to 60°C, mix the oil phase and the water phase evenly under high-speed stirring, and homogenize through a high-pressure homogenizer to make colostrum, add 10g of gemcitabine hydrochloride, adjust the pH value to 5.0, add water to make up to 1000ml, Transfer it to a high-pressure homogenizer and continue to emulsify until the average particle size is about 15nm; fill it and fill it with nitrogen to melt seal.

Embodiment eight

Preparation method: under the protection of an inert gas, mix and stir 450g soybean oil for injection and 12g oleic acid to form an oil phase, preheat to 60°C, add 150g soybean lecithin and 8g sodium sulfite to 650ml water for injection, stir well to form a water phase , preheat to 60°C, mix the oil phase and the water phase evenly under high-speed stirring, and homogenize through a high-pressure homogenizer to make colostrum, add 10g of gemcitabine hydrochloride, adjust the pH value to 5.0, add water to 1000ml, Transfer it to a high-pressure homogenizer and continue to emulsify until the average particle size is about 15nm; fill it and fill it with nitrogen to melt seal.

Embodiment nine

Preparation method: under the protection of inert gas, mix and stir 300g soybean oil for injection and 10g oleic acid to form an oil phase, preheat to 60°C, add Tween 80135g and sodium ascorbate 5g to 600ml water for injection, stir well to form water phase, preheat to 60°C, mix the oil phase and the water phase evenly under high-speed stirring, and homogenize through a high-pressure homogenizer to make colostrum, add 10g of gemcitabine hydrochloride, adjust the pH value to 5.0, add water to volume to 1000ml , transfer it to a high-pressure homogenizer and continue to emulsify until the average particle size is about 20nm; fill it, fill it with nitrogen and melt it.

Embodiment ten

Preparation method: under the protection of inert gas, mix and stir 300g soybean oil for injection and 10g oleic acid to form an oil phase, preheat to 60°C, add Tween 80135g and sodium ascorbate 5g to 600ml water for injection, stir well to form water phase, preheat to 60°C, mix the oil phase and the water phase evenly under high-speed stirring, and homogenize through a high-pressure homogenizer to make colostrum, add 10g of gemcitabine hydrochloride, adjust the pH value to 5.0, add water to volume to 1000ml , transfer it to a high-pressure homogenizer and continue to emulsify until the average particle size is about 50nm; fill it, fill it with nitrogen and melt it.

Embodiment Eleven

Preparation method: under the protection of an inert gas, mix and stir 300g of soybean oil for injection to form an oil phase, preheat to 60°C, add 135g of Tween 80, 5g of sodium ascorbate and 10g of sodium oleate into 600ml of water for injection, and stir evenly to form an oil phase. For the water phase, preheat to 60°C, mix the oil phase and the water phase evenly under high-speed stirring, and homogenize through a high-pressure homogenizer to make colostrum, add 10g of gemcitabine hydrochloride, adjust the pH value to 5.7, add water to volume 1000ml, transfer it to a high-pressure homogenizer and continue to emulsify until the average particle size is about 50nm; fill it, fill it with nitrogen and melt it.

Embodiment 12

Preparation method: under the protection of an inert gas, mix and stir 250g of medium-chain fatty acid triglycerides to form an oil phase, preheat to 70°C, add 150g of Tween 80, 7g of sodium ascorbate and 13g of sodium oleate into 650ml of water for injection, stir Uniformly form a water phase, preheat to 70°C, mix the oil phase and water phase evenly under high-speed stirring, and homogenize through a high-pressure homogenizer to make colostrum, add gemcitabine hydrochloride 10g, adjust the pH value to 6.0, add water to set When the volume reaches 1000ml, transfer it to a high-pressure homogenizer and continue to emulsify until the average particle size is about 20nm; fill it and seal it with nitrogen gas.

Embodiment Thirteen

Preparation method: under the protection of inert gas, mix and stir 300g soybean oil for injection and 5g ascorbyl palmitate to form an oil phase, preheat to 60°C, add Tween 80135g and sodium oleate 10g to 600ml water for injection, stir Uniformly form a water phase, preheat to 60°C, mix the oil phase and water phase evenly under high-speed stirring, and homogenize through a high-pressure homogenizer to make colostrum, add 10g of gemcitabine hydrochloride, adjust the pH value to 5.7, add water to set When the volume reaches 1000ml, transfer it to a high-pressure homogenizer and continue to emulsify until the average particle size is about 20nm; fill it and seal it with nitrogen gas.

Experimental Example One Encapsulation Efficiency Determination

Drug content determination method: chromatographic column: Diamonsil ^TM C ₁₈ (4.6mm*250mm, 5μm); mobile phase: 0.05mol/L ammonium acetate buffer solution (take 3.85g of ammonium acetate, add 800ml of water to dissolve, adjust the pH to 5.7, add water to 1000ml)-methanol (90:10); detection wavelength: 268nm; flow rate: 1.0ml/min; column temperature 40°C, injection volume: 20μL.

Encapsulation efficiency determination method: take 1 sample, accurately draw 2.0ml and place it in a 10ml measuring bottle, add water to dilute to the mark, use an 8010 type ultrafilter (MILLIPORE company) for ultrafiltration, discard the initial filtrate, and take the subsequent filtrate as the Test solution. Draw 20 μL of the test solution and the reference solution into the liquid chromatograph, record the chromatogram, and calculate the drug content in the aqueous phase of the preparation by the external standard method, which is recorded as W; in addition, calculate the total drug content of this product according to the method under the content determination item , recorded as W ₀ . Calculate the encapsulation efficiency of the sample according to the formula.

Encapsulation rate En=(W ₀ -W)/W ₀ *100%

Measure the encapsulation efficiency of three batches of samples by the above-mentioned method and take the average value as E, and the measurement results are as shown in Table 1:

Table 1 Gemcitabine Hydrochloride Injection Encapsulation Efficiency Determination

Example name E(%) Embodiment 1 95.8 Example 2 93.5 Example three 94.6 Embodiment four 96.9 Example five 97.7 Embodiment six 99.3 Embodiment Seven 99.1 Embodiment eight 98.9 Embodiment nine 99.5 Embodiment ten 98.7 Embodiment Eleven 99.1 Embodiment 12 99.6 Embodiment Thirteen 99.8

Conclusion: From the above results, it can be seen that the drug encapsulation effect of the injection solution of the invention is very good, meets the national drug quality requirements, and has good clinical application value.

Experimental example 2 Stability test

Determine the stability data of the injection solution of the present invention as follows.

Measuring method: take 1ml samples of each embodiment and place them in special centrifuge tubes, put them into a desktop high-speed centrifuge and centrifuge at 2000rpm, and after centrifuging for 15 minutes, take out the centrifuge tubes. Drop an appropriate amount of the sample into a small beaker from the bottom, draw 50.0 μL with a micro sampler and add it to a 25ml measuring bottle, dilute to the mark with water for injection, and mix well. Use the water level blank at a wavelength of 500nm to detect its absorbance value (A). Then take 50.0μL of the original sample and place it in a 25ml measuring bottle, dilute it with water for injection, and detect its absorption value (A ₀ ) at the same wavelength. According to the mathematical formula K _E =(|A ₀ −A|/A ₀ )*100%, the stability parameter K _E of the emulsion is calculated. The smaller the _KE , the more stable the emulsion. The experimental results are shown in Table 2:

Table 2 Gemcitabine Hydrochloride Injection Stability Determination

Example name KE _value Sample Appearance Embodiment 1 0.451 No oil drop seen Example 2 0.469 No oil drop seen Example three 0.416 No oil drop seen Embodiment four 0.446 No oil drop seen Example five 0.421 No oil drop seen Embodiment six 0.403 No oil drop seen Embodiment Seven 0.412 No oil drop seen Embodiment eight 0.432 No oil drop seen Embodiment nine 0.451 No oil drop seen Embodiment ten 0.415 No oil drop seen Embodiment Eleven 0.406 No oil drop seen Embodiment 12 0.408 No oil drop seen Embodiment Thirteen 0.408 No oil drop seen

In addition, the long-term stability of the samples was measured by conventional methods. After the samples were stored at room temperature for 6 months, the emulsion integrity rates in all examples were measured. The results showed that the emulsion integrity rates of the samples in each example reached more than 92%.

Conclusion: After determination, the sample has good stability and is suitable for clinical application and can be stored for a long time.

Claims (6)

1. a gemcitabine or its salt nanoemulsion injection, it is characterized in that described injection contains gemcitabine hydrochloride, injection oil, tensio-active agent and water for injection, and described injection is oil-in-water type, wherein gemcitabine hydrochloride, injection The weight ratio of oil and surfactant is 1:20～50:10～20, the average particle diameter of emulsion droplets in the emulsion is 1-50nm, and the oil for injection is selected from soybean oil, peanut oil, sesame oil or medium-chain fatty acid Triglyceride; The surfactant is selected from soybean lecithin or Tween 80, and the nanoemulsion injection is prepared through the following steps: Under the protection of inert gas, stir the injection oil evenly to form an oil phase; Add the surfactant to an appropriate amount of water for injection, and stir evenly to form a water phase; Under high-speed stirring, the oil phase and the water phase are mixed evenly, and then homogenized by a high-pressure homogenizer to produce colostrum; Adding gemcitabine hydrochloride to colostrum; Adjust the pH value to 4-9, continue to add water to the full volume, fully stir or homogenize with a high-pressure homogenizer to make the average particle size of emulsion droplets reach the required nanometer size. 2. The gemcitabine or its salt nanoemulsion injection according to claim 1, characterized in that the average particle diameter of the emulsion droplets in the emulsion is 1-20 nm. 3. The gemcitabine or its salt nanoemulsion injection according to any one of claims 1-2, further comprising one or more of antioxidants or stabilizers. 4. gemcitabine or its salt nanoemulsion injection according to claim 3, is characterized in that, described antioxidant is selected from water-soluble antioxidant or oil-soluble antioxidant, and wherein water-soluble antioxidant is selected from sodium sulfite, Sodium bisulfite, sodium pyrosulfite, sodium ascorbate, L-cysteine or mixture thereof; oil-soluble antioxidant selected from BHA, BHT, vitamin E, ascorbyl palmitate or mixture thereof, wherein said antioxidant It accounts for 0%~1w/v% of the injection. 5. gemcitabine or its salt nanoemulsion injection according to claim 3, is characterized in that, described stabilizer is selected from oleic acid, sodium oleate, cholic acid, sodium cholate, dextran-70, deoxycholic acid . Sodium deoxycholate or a mixture thereof, wherein the stabilizer accounts for 0% to 1.5w/v% of the injection. 6. a method for preparing gemcitabine or its salt nanoemulsion injection according to claim 4, comprising the steps of: Under the protection of inert gas, stir the oil for injection and oil-soluble antioxidant to form an oil phase; Add water-soluble antioxidant stabilizer and surfactant to an appropriate amount of water for injection, and stir evenly to form a water phase; Under high-speed stirring, the oil phase and the water phase are mixed evenly, and are homogenized by a high-pressure homogenizer to produce colostrum; Adding gemcitabine hydrochloride to colostrum; Adjust the pH value to 4-9, continue to add water to make up to the full volume, fully stir or homogenize with a high-pressure homogenizer until the average particle size of the milk droplets reaches the required nanometer size.