TWI511725B - A taxane-containing drug solution containing chelating agent and a preparation method thereof - Google Patents

Description

Taxane drug solution containing chelating agent and preparation method thereof

The invention relates to a pharmaceutical preparation technology, in particular to a taxane-containing taxane drug solution and a preparation method thereof.

Taxanes include paclitaxel (trade name Taxol) and docetaxel (trade name Taxotem), two taxane-based anticancer drugs approved by the FDA. Taxanes are a typical class of cytotoxic agents with broad-spectrum anti-tumor effects, such as breast cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma and malignant melanoma. Both cancer and metastatic cancer have strong inhibitory effects. Its anti-tumor mechanism is to stimulate the polymerization of the catheter bundle, promote the assembly of microtubule dimer into microtubules, and cause the microtubule to be ultra-stable and inhibit the dynamic reorganization of the microtubule network, and finally stop the proliferation of cancer cells in the stationary phase of mitosis. Stage to achieve anti-tumor purposes.

Paclitaxel and docetaxel are very water-soluble, almost insoluble in water (about 4 μg/ml), and the oral absorption rate is only 2% to 4%, so it can only be administered intravenously. In order to improve the water solubility of paclitaxel, the clinical application of paclitaxel injection is a colorless viscous concentrated solution made of polyoxyethylene castor oil and absolute ethanol (50:50, V/V), which solves the dissolution of paclitaxel. The problem, but the injection contains polyoxyethylene castor oil which is easy to cause allergic reaction. After taking the medicine, it has allergic reactions such as difficulty in breathing, flushing, rapid heartbeat and rash, which brings safety concerns and pain to the patient. Similar problems exist with the available docetaxel formulations. The clinical preparation of docetaxel is composed of Tween 80 solution and 13% ethanol solution. When it is administered, it is dispersed intravenously in physiological saline. Although the dissolution of docetaxel is solved, the injection is The liquid contains Tween 80 with hemolysis, and the clinical drug is prone to a certain degree of hemolysis reaction, and the safety is poor. In view of the many shortcomings in clinical preparations, the research and development of taxane injections are active. In recent years, studies on taxane injections have focused on liposomes, fat emulsions, nanoparticles, albumin cross-linking precursors, and cyclodextrin inclusion complexes. The current technology focuses on the biocompatibility, in vivo tolerance, and stability of the formulation. Despite breakthroughs in some formulation studies, their use is still limited due to low drug loading and insufficient therapeutic drug concentrations.

Fortner et al. (Am. J. Hosp. Pharm. (1975) 32, 582-584) reported that a poorly water-soluble drug is dissolved in a suitable solvent for injection to prepare a drug solution, which is dispersed in an injectable emulsion for use in instillation. The dosage form is gradually taken seriously by everyone.

BS Anderson's "non-intestinal stable non-toxic preparation of paclitaxel" (Chinese patent: 97196934.5), the drug solvent part of the drug solution is composed of polyethylene glycol 400 and dimethyl acetamide in a ratio of 3:1, Although methyl ketamine can increase the dissolution rate of the drug, it also increases the toxic side effects of the drug preparation. Zhou Lianfang et al (research progress in the toxic effects of dimethylacetamide [J]. Chinese Occupational Medicine, 2009, 36 (1): 66-67) reported that dimethyl acetamide can cause weight loss in large mice , retinal atrophy, brain wave changes and lung, stomach, liver, kidney and other damage.

In the "pharmaceutical composition containing a poorly water-soluble drug" (Chinese Patent Application: 200680007345.3), the pharmaceutical solvent portion of the drug solution portion is mainly composed of polyethylene glycol 400 and oleic acid. R.C. Roche et al. (Medical Excipient Handbook [M]. Original 4th Edition: 476) showed that oleic acid can cause rupture of red blood cells, ie, it is hemolytic, and is only allowed in non-injectables in the UK.

Hu Yufang's "a concentrated emulsifier containing paclitaxel compound and its use method" (Chinese Patent Application: 200410025522.3), the drug solution part contains a surfactant, such as Tween-80, Pweenone, egg Phospholipids. These surfactants have certain hemolytic and irritating properties.

In order to make taxanes safer, more effective, stable and economical for clinical use and to better exert their anti-tumor effects, we have developed a combination package containing solution and drug for taxanes in combination packaging. Packed in emulsion, the two packages are separated and put together. Before the administration, the drug solution is dispersed in the emulsion, shaken, and then intravenously instilled. The chelating agent is added to the combination agent in the invention, so that the stability of the dispersion of the drug solution dispersed in the emulsion is remarkably improved, and the dispersion is overcome. The lack of oil slick improves the safety and effectiveness of the drug delivery system.

The invention provides a taxane pharmaceutical composition, which is prepared from a taxane drug solution and an emulsion two-part agent, wherein the drug solution or the emulsion contains a chelating agent, and the content is 0.05-2% (g/ml). It is preferably 0.1 to 1% (g/ml). The preparation is to mix the drug solution and the emulsion in a ratio of 1:10 to 1:100 by volume, preferably the volume ratio is 1:20 to 1:50, and the ratio is preferably 1:25. .

The composition of the present invention exhibits strong stability after being mixed with an injectable emulsion by adding a chelating agent to the taxane drug solution or emulsion prior to formulation.

To this end, the present invention provides a taxane drug solution containing a taxane, a chelating agent and a solvent.

Preferably, the ratio of the components is: Taxanes 1~8% (g/ml)

Chelating agent 0.05~2% (g/ml)

The rest are solvents and other pharmaceutical excipients added if necessary.

More preferably, the ratio of each component is: taxanes 1 to 6% (g/ml)

Chelating agent 0.1~1% (g/ml)

The rest are solvents and other pharmaceutical excipients added if necessary.

Wherein the other medicinal excipients are added during the preparation of the solution, such as: co-solvents, isotonic regulators, surfactants, pH adjusters, etc., whether or not to add these medicinal excipients depends on the yew The nature of alkanes, chelating agents and solvents.

In the pharmaceutical solution of the present invention, the taxane is any taxane, preferably paclitaxel or docetaxel which has been marketed.

In the pharmaceutical solution of the present invention, the chelating agent is added to the drug solution, wherein the chelating agent is selected from the group consisting of: ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodium edetate One or a mixture of one or more of trisodium edetate and disodium citrate, preferably citric acid, lactic acid, ethylenediaminetetraacetic acid, disodium edetate, preferably ethylenediamine Disodium tetraacetate.

The solvent in the pharmaceutical solution of the present invention is selected from one or more selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, propylene glycol, glycerin, absolute ethanol, and water for injection. a mixture; preferably polyethylene glycol 400.

The present invention also encompasses a process for the preparation of a solution of the present invention comprising the steps of dissolving a taxane-based drug and a chelating agent in a solvent, and if necessary, adding other pharmaceutically acceptable excipients.

Preferably, the preparation method of the present invention comprises the steps of: weighing paclitaxel or docetaxel, a chelating agent into a solvent, heating or stirring at 50 to 100 ° C or shearing and dissolving, and then diluting with a solvent; adding 0.01%~ The 3% g/ml needle is adsorbed with activated carbon at a heating temperature of 25 to 100 ° C for 15 to 120 minutes, and then filtered, dispensed, sealed, and sterilized.

The invention also provides a pharmaceutical combination package, which is packaged by the combination of a taxane drug solution and an emulsion according to the invention, wherein the two medicaments are respectively loaded in a container, placed separately, and packaged together. In the combined package of the present invention, the taxane drug solution and the medicinal emulsion of the present invention are respectively filled in a plastic bottle or a glass bottle, and the two drugs are combined in a volume ratio of 1:10 to 10:1. Packed together, preferably in a ratio of 1:1, packaged in the same large packaging container. It is advisable to pack in one use.

The emulsion of the present invention is an oil-water mixed emulsified preparation, which is a non-uniform dispersion system formed by dispersing an oil or an oil solution in a dispersion state in a dispersion medium, and has an oral emulsion and an intravenous emulsion. The present invention uses an intravenous emulsion, preferably a fat emulsion for intravenous injection, specifically, for example, a 20% medium/long-chain fat emulsion, a 20% long-chain fat emulsion, and the like.

The emulsion of the present invention is a commercially available emulsion product for injection or an emulsion product formulated according to the prior art. Generally, it contains an injection oil, an emulsifier, an antioxidant, an isotonic regulator, a pH adjuster, water for injection, and the like.

The invention is characterized in that a chelating agent may be added to the emulsion of the invention in an amount of 0.05 to 2% g/ml, preferably 0.1 to 1% g/ml, and the chelating agent is selected from the group consisting of: ethylenediaminetetraacetic acid, One or a mixture of citric acid, lactic acid, malic acid, tartaric acid, disodium edetate, trisodium ethylenediaminetetraacetate, disodium citrate, preferably citric acid, lactic acid, ethylenediamine Tetraacetic acid, disodium edetate, preferably ethylenediaminetetraacetic acid Disodium.

The emulsion of the present invention, wherein the oil for injection is selected from the group consisting of caprylic acid triglyceride, caprylic acid monoglyceride, caprylic acid diglyceride, caprylic acid triglyceride, ganoderma lucidum spore oil, capric acid monoglyceride, capric acid diglyceride , citric acid triglyceride, caprylic acid monoglyceride, coix seed oil, duck gall nut oil, artemisia oil, caprylic acid diglyceride, soybean oil, fish oil, linseed oil, sunflower oil, evening primrose oil, sea buckthorn oil, A mixture of one or more of oil, safflower oil, sesame oil, corn oil, elemene oil, garlic oil, etc., in an amount of 1 to 30% g/ml. The concentration of oil in the emulsion is expressed in grams of oil per milliliter of emulsion.

A preferred injectable oil is selected from the group consisting of one or a mixture of caprylic acid triglyceride and soybean oil in an amount of 10 to 30% g/ml.

Wherein the emulsifier is selected from the group consisting of soybean phospholipids, egg yolk phospholipids, dimyristoyl phospholipid choline, dipalmitoside phosphocholine choline, distearyl phospholipid choline, diolein phospholipid choline, palm eucalyptus oil One or more mixtures of phosphatidylcholine, bis-lipid phospholipid, ethanolamine, and poloxamer 188 in an amount of 0.5 to 5% g/ml. Preferred emulsifiers are selected from the group consisting of soybean phospholipids, egg yolk phospholipids, or a mixture of two, in an amount of from 0.8 to 3% g/ml. The concentration of the emulsifier in the emulsion is expressed in grams of emulsifier per ml of emulsion.

The antioxidant of the present invention is tocopherol, and its content is 0-0.5% g/ml. A preferred content is 0 to 0.3% g/ml.

Wherein the isotonicity adjusting agent of the present invention is one or more selected from the group consisting of glycerin, sorbitol, mannitol, glucose, and sodium chloride, preferably glycerin.

Wherein the pH adjusting agent of the present invention is selected from the group consisting of citric acid, malic acid, hydrochloric acid, acetic acid, lactic acid, sodium carbonate, sodium hydrogencarbonate, and sodium hydroxide. Or several, preferably sodium hydroxide, to adjust the pH to 6.0 to 9.0. It is preferred to adjust the pH to 6.5~8.5.

The preparation method of the intravenous emulsion is the prior art, such as mixing the injection oil and the antioxidant, heating to 50-90 ° C, adding an emulsifier, stirring or shearing to dissolve the emulsifier to obtain an oil phase; The adjusting agent and the stabilizer are added into an appropriate amount of water for injection, heated to 50-90 ° C to be stirred and dissolved to obtain an aqueous phase; the oil phase and the aqueous phase are mixed at a temperature of 50 to 90 ° C, and emulsified or stirred by a shearing emulsifier 5~ 60 minutes, the speed is 5000~30000 rev / min, get colostrum. The colostrum is further emulsified, then fixed to volume with water for injection, adjusted to pH 6.0-9.0 with a pH adjuster, filtered, dispensed, nitrogen-filled, sealed, and sterilized.

In general, the preparation step of the emulsion includes dissolving the emulsifier in the injectable oil or dissolving the emulsifier in the water. In the present invention, further emulsification of the colostrum is carried out using a high pressure homogenizer at a pressure of 5,000 to 25,000 psi. The disinfection in the preparation step of the emulsion is a sterilization method using a rotary high-pressure steam sterilization pot, a circulating steam or a microporous filter membrane, wherein the high temperature sterilization temperature is 100 to 121 ° C for 8 to 45 minutes. The filtration device in the preparation step of the emulsion includes, but is not limited to, a microporous membrane, a sand filter rod, a sintered filter funnel or a capsule filter. The final emulsion is a white or off-white emulsion liquid with opalescence, an average particle size of 100 to 500 nm, and a pH of 6.0 to 9.0.

The present invention also provides a method for using a taxane drug solution, which comprises administering a taxane drug solution and a medicinal emulsion in a ratio of 1:10 to 100, preferably 1:25 by volume. The solution is dispersed in the emulsion, shaken, and intravenously instilled; or, when used, the drug solution dispersed by the emulsion is added to a physiological saline solution or a glucose solution for injection.

The beneficial effects of the present invention are illustrated below by experimental data.

1. Comparison of stability of dispersions containing chelating agent (citric acid) and paclitaxel injection composition without chelating agent before administration

In order to further embody the substantial characteristics and unexpected effects of the chelating agent in the present invention, we compare the stability of the dispersion before the administration of the chelating agent (citric acid) and the chelating agent-free paclitaxel injection composition. .

Preparing a drug solution containing a chelating agent (citric acid) according to the embodiment described in Example 1 to obtain a test drug solution; according to the embodiment described in Example 1, removing citric acid, preparing a drug solution containing no chelating agent, The control drug solution was obtained; 4 ml of each of the above test drug solution and the control drug solution was aspirated, and dispersed in 100 ml of the self-made emulsion described in Example 1, and shaken to obtain a test sample. The content and particle diameter of the dispersion at different time points were measured by high performance liquid chromatography and particle size analyzer. When measuring the content, a proper amount of the dispersion was firstly extracted by a syringe through a microporous membrane of 0.45 μm. The content of the drug in the filtrate was measured, and the percentage of the label was calculated. The content was used to evaluate whether the drug precipitated crystals; the particle size was directly measured, and the appearance was visually observed. The results are shown in Tables 1 and 2.

Table 2 The stability of the dispersion before the administration of the paclitaxel injection composition containing no chelating agent (citric acid) represented by Example 1 (dispersed emulsion is a self-made emulsion)

Result analysis:

From the comparison of the test results of Table 1 and Table 2, it was found that the chelating agent-containing dispersion was stable under the premise of the chelating agent (citric acid) prepared in the same manner as in Example 1 and the paclitaxel injection composition containing no chelating agent. The time is up to 6 days, and the dispersion time of the dispersion containing no chelating agent is about 3 days; from the appearance, the dispersion containing the chelating agent has no oil slick within 6 days, and the appearance is better, and the chelating agent is not contained. The dispersion has more oil slick, and with the extension of time, the oil slick gradually increases, and the appearance is poor; the particle size does not change much during the stabilization time, and the particle size becomes larger when the drug is precipitated.

The results show that the paclitaxel injection composition containing a chelating agent (citric acid) has a remarkable effect, which is manifested in that the stability of the dispersion of the paclitaxel injection composition containing no chelating agent is remarkably improved, and the dispersion is unexpectedly overcome. Insufficient liquid slick. Therefore, it has been revealed that the inclusion of a chelating agent is a feature of the present invention having substantially excellent effects.

2. Stability evaluation of dispersion before administration of a chelating agent (disodium edetate) and a docetaxel injection composition containing no chelating agent

In order to further embody the substantial characteristics and unexpected effects of the chelating agent in the present invention, we will pre-administer the chelating agent (disodium edetate) and the chelating agent-free docetaxel injection composition. The stability of the dispersion is compared.

A docetaxel injection composition containing a chelating agent (disodium ethylenediaminetetraacetate) was prepared according to the embodiment described in Example 2 to obtain a test sample; according to the embodiment described in Example 2, the chelating agent was removed ( Ethylenediaminetetraacetic acid disodium) is prepared by preparing a docetaxel injection composition containing no chelating agent to obtain a control sample; and 4 ml of each of the drug solutions of the above test and control samples are aspirated, respectively, dispersed in respective ones according to Example 2. The embodiment of the homemade 100 ml emulsion was shaken to obtain a test sample. The content and particle diameter of the dispersion at different time points were measured by high performance liquid chromatography and particle size analyzer. When measuring the content, a proper amount of the dispersion was firstly extracted by a syringe through a microporous membrane of 0.45 μm. The content of the drug in the filtrate was measured, and the percentage of the label was calculated. The content was used to evaluate whether the drug precipitated crystals; the particle size was directly measured, and the appearance was visually observed. The results are shown in Tables 3 and 4.

Result analysis:

From the comparison of the test results of Table 3 and Table 4, under the premise of the chelating agent (disodium ethylenediaminetetraacetate) prepared in the same manner as in Example 2 and the docetaxel injection composition containing no chelating agent, The chelating agent-containing dispersion has a stabilization time of more than half a month, and the chelating agent-free dispersion has a stabilization time of about 6 days; from the appearance, the chelating agent-containing dispersion has no oil slick within half a month. The appearance is better, and there is more slick oil without chelating agent, and with the extension of time, the oil slick gradually increases, and the appearance is poor; the particle size does not change much during the stabilization time, and the particle size becomes larger when the drug is precipitated.

The results show that the docetaxel injection composition containing a chelating agent (disodium edetate) has a remarkable effect, which is advantageous in that the dispersion stability of the docetaxel injection composition containing no chelating agent is greatly improved. Improved, and unexpectedly overcome the shortcomings of the dispersion oil slick. Therefore, it has been revealed that the inclusion of a chelating agent is a feature of the present invention having substantially excellent effects.

3. Stability comparison test between the present invention containing a chelating agent (disodium edetate) and a patented embodiment containing dimethyl acetamide

In the patent (Chinese Patent: 97196934.5), it is indicated that the patent mainly adds dimethylacetamide to the polyethylene glycol 400, and its ratio to polyethylene glycol 400 is 1:3, and its drug loading amount It is 25 mg/ml. According to the embodiment, the drug solution is prepared as a control drug solution; the drug solution is prepared according to the embodiment described in Example 18, and the test drug solution is obtained; 4 ml of the above control drug solution and the test drug solution are respectively taken up and dispersed in the implementation. In a 100 ml commercial emulsion as described in Example 18. Shake well and test the sample. The content of the drug at different time points was determined by high performance liquid chromatography. When the content was determined, a proper amount of the dispersion was firstly extracted with a microporous membrane of 0.45 μm by a syringe to determine the content of the drug in the filtrate. The percentage content was marked, and the content was used to evaluate whether or not the drug precipitated crystals; and the appearance was visually observed, and the results are shown in Table 5.

Result analysis:

It has been experimentally found that in the same commercially available emulsion dispersion medium, the dispersion of the composition of the present invention containing a chelating agent (disodium edetate) is stable for up to 24 hours and contains dimethyl acetamidine. The stability of the dispersion of the amine control preparation was less than 6 hours; from the appearance point of view, the dispersion of the preparation of the invention had no oil slick phenomenon, and the dispersion liquid containing the dimethyl acetamide control preparation was more serious, and there was a large amount of oil stained wall. The addition of a chelating agent unexpectedly solved the problem. It can be seen that the formulation scheme of the present invention has significant advantages and unexpected effects compared to the control patent. Therefore, it has been revealed that the inclusion of a chelating agent is a feature of the present invention having substantially excellent effects.

4. Comparative test of the stability of the present invention and the oleic acid-containing patent embodiment containing a chelating agent (ethylenediaminetetraacetic acid)

It is indicated in the published patent application (Chinese Patent Application No. 200680007345.3) that the patent application mainly adds oleic acid to the polyethylene glycol 400 in an amount of 0.01 to 5%. Referring to the embodiment, 0.3%, 1.0%, and 5.0% oleic acid polyethylene glycol 400 solution was separately prepared; then, the solution was used to prepare a paclitaxel solution having a paclitaxel content of 25 mg/ml, respectively, as a control solution; In the embodiment, the drug solution is prepared to obtain a test solution; 4 ml of the above control solution and the test solution are respectively taken up. The samples were separately dispersed in 100 ml of the commercially available emulsion described in Example 19, and shaken to obtain a test sample. The content of the drug at different time points was determined by high performance liquid chromatography. When the content was determined, a proper amount of the dispersion was firstly extracted with a microporous membrane of 0.45 μm by a syringe to determine the content of the drug in the filtrate. The percentage content was indicated, and the content was used to evaluate whether the drug precipitated crystals; and the appearance was visually observed, as shown in Table 6.

Result analysis:

It has been experimentally found that in the same commercially available emulsion dispersion medium, the dispersion of the composition of the present invention containing a chelating agent (ethylenediaminetetraacetic acid) is stable for up to 20 hours, and the dispersion time of the oleic acid-containing control preparation dispersion is determined. Less than 6 hours, and the stability decreases with the increase of oleic acid; from the appearance point of view, the dispersion of the invention has no oil slick phenomenon, while the oleic acid-containing series of the controlled patent preparation dispersion slick oil is serious, and there is a large amount of oil stain wall hanging. . The addition of a chelating agent unexpectedly solved the problem. It can be seen that the formulation scheme of the present invention has significant advantages and unexpected effects compared to the control patent. Therefore, it has been revealed that the inclusion of a chelating agent is a feature of the present invention having substantially excellent effects.

5. Comparative test of stability of the present invention containing a chelating agent (citric acid) and a surfactant-containing patented embodiment

It is indicated in the published patent application (Chinese Patent Application No. 200410025522.3) that the patent application is mainly composed of paclitaxel, Tween-80, phoravirin, lecithin, and a vehicle for injection, and is similar to the present invention. The protocol is Example 3, that is, 1.8 g of paclitaxel, 22 g of phospholipid, and 40 g of propylene glycol are dissolved in absolute ethanol and made up to 100 ml. According to the solution, the drug solution was prepared as a control solution; the drug solution was prepared according to the embodiment described in Example 20 to obtain a test solution; 4 ml of the above control solution and the test solution were separately aspirated, and dispersed in the method described in Example 20, respectively. In 100 ml of a commercially available emulsion, shake it to obtain a test sample. The content of the drug at different time points was determined by high performance liquid chromatography. When the content was determined, a proper amount of the dispersion was firstly extracted with a microporous membrane of 0.45 μm by a syringe to determine the content of the drug in the filtrate. The percentage content was indicated, and the content was used to evaluate whether or not the drug precipitated crystals; and the appearance was visually observed, and the results are shown in Table 7.

Result analysis:

It has been experimentally found that in the same commercially available emulsion dispersion medium, the dispersion of the composition of the present invention containing a chelating agent (citric acid) has a stabilization time of up to 20 hours, and the surfactant-containing proprietary formulation dispersion is stable. It is less than 8 hours; from the appearance point of view, the dispersion of the composition of the invention has no oil slick phenomenon, and the dispersion of the control patent preparation dispersion containing the surfactant is more serious, and there is a large amount of oil stains hanging on the wall. The addition of a chelating agent unexpectedly solved the problem. It can be seen that the formulation scheme of the present invention has significant advantages and unexpected effects compared to the control patent. Therefore, it has been revealed that the inclusion of a chelating agent is a feature of the present invention having substantially excellent effects.

The advantages of the invention are:

Good safety: does not contain any co-solvent with toxic side effects, such as polyoxyethylene castor oil, Tween 80, dimethylacetamide, oleic acid, pravone, etc., so the toxic side effects of pharmaceutical preparations are correspondingly reduced Among them, polyoxyethylene castor oil and Tween 80 have severe hemolysis and allergic reaction, and the safety is poor; dimethyl acetamide mice have an oral LD ₅₀ of 4.620 g/kg, and the preferred injectable solvent of the present invention is Polyethylene glycol 400, non-toxic, non-irritating, its oral LD _{50 is} as high as 28.9g/kg, LD ₅₀ is 6.3 times that of dimethylacetamide, so polyethylene glycol 400 is a safe injection. Solvent; RC Roche et al. (Medical Excipient Handbook [M]. Original 4th Edition: 476) showed that oleic acid can cause rupture of red blood cells, ie, hemolysis, and is only allowed in non-injectables in the UK. Therefore, it is also a great advantage of the present invention that the preparation of the present invention does not contain a co-solvent having toxic side effects;

The stability is good: the stability of the dispersion using the solution of the invention is greatly improved, the stabilization time of the dispersion is remarkably prolonged, and the shortage of the dispersion oil is unexpectedly overcome, and the stability of the dispersion is further improved.

In order to further demonstrate the substantial advantages and unexpected effects of the present invention, we will achieve the following embodiments, but the present invention is not limited to the following embodiments.

Example 1 Paclitaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 2.5 g of paclitaxel and 0.5 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear dissolve at 85 ° C, then make up to 100 ml with polyethylene glycol 400; add 0.3 g of needle with activated carbon, The mixture was adsorbed at a temperature of 25 ° C for 30 minutes, then filtered with a capsule filter, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes to obtain a paclitaxel solution.

Preparation of emulsion:

Weigh 100 g of soybean oil for injection and 100 g of caprylic acid triglyceride, heat to 80 ° C in a water bath, add 20 g of soy lecithin for injection, dissolve to dissolve, stir and mix to obtain oil phase; measure water for injection 740 ML, add 10 grams of poloxamer 188, 22.5 grams of glycerin, stir to dissolve, heat to 80 ° C to obtain the aqueous phase; the oil phase and the aqueous phase are mixed at 80 ° C, emulsified with a shear emulsifier for 10 minutes (speed 15000 rpm, get colostrum; further emulsification of colostrum with high pressure homogenizer (pressure 12000 psi), make up to 1000 ml with water for injection, adjust pH to 7.86 with sodium hydroxide solution, filter with capsule filter The mixture was filled, nitrogen-filled, and sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes to obtain an emulsion. It was determined to have an average particle diameter of 148 nm and a pH of 7.12.

The above paclitaxel solution and the medicinal emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

In use, the paclitaxel solution and the emulsion are in a ratio of 1:25 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled; or the drug solution may be added to the emulsion first, and then a predetermined amount of physiological saline or A glucose solution is used for the injection.

Example 2 Docetaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 2.5 g of docetaxel, add to the appropriate amount of polyethylene glycol 400, heat shear at 90 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.3 g of needle with activated carbon at 25 ° C Adsorbed for 30 minutes at a temperature, then filtered through a microporous membrane, dispensed, sealed, and sterilized in a rotary autoclave at 115 ° C for 30 minutes, ie, a more paclitaxel solution.

Preparation of emulsion:

Weigh 100 g of soybean oil for injection and 100 g of caprylic acid triglyceride, heat to 80 ° C in a water bath, add 20 g of soy lecithin for injection, dissolve to dissolve, stir and mix to obtain oil phase; measure water for injection 740 ML, adding 0.5 g of disodium edetate, 10 g of poloxamer 188, 22.5 g of glycerin, stirring to dissolve, heating to 80 ° C to obtain an aqueous phase; mixing the oil phase and the aqueous phase at 80 ° C, Emulsified with a shearing emulsifier for 8 minutes (20000 rpm) to obtain colostrum; the colostrum was further emulsified by a high-pressure homogenizer (pressure: 12,000 psi), and the volume was adjusted to 1000 ml with water for injection, and the solution was adjusted with sodium hydroxide solution. The pH was 7.56, filtered with a capsule filter, subpacked, nitrogen-filled, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes to obtain an emulsion. It was determined to have an average particle diameter of 140 nm and a pH of 7.04.

The above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:25 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 3 Paclitaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 2.0 g of paclitaxel, add it to 90 g of polyethylene glycol 400, dissolve it by heating and stirring at 90 ° C to obtain a paclitaxel solution; weigh 1.2 g of disodium edetate, and dissolve it with 10 g of water for injection to obtain a chelate. Mixture solution; mix the chelating agent solution and the drug solution uniformly, and make up to 100 ml with polyethylene glycol 400; add 0.8 g of needle with activated carbon, adsorb at 120 ° C for 120 minutes, then use microporous membrane Filter, dispense, seal, and sterilize in a rotary autoclave at 121 ° C for 8 minutes to obtain a paclitaxel solution.

Preparation of emulsion:

Weigh 150 grams of soybean oil, 150 grams of caprylic acid triglyceride and mix, heat to 60 ° C in a water bath, add 12 grams of egg yolk phospholipid for injection, shear to dissolve, get oil phase; measure 600 ml of water for injection, add glycerin 25 g, stirred to dissolve, heated to 60 ° C to obtain an aqueous phase; the oil phase and the aqueous phase were mixed at 60 ° C, emulsified with a shear emulsifier for 30 minutes (speed 6000 rev / min), to obtain colostrum; The milk is further emulsified (pressure 22000 psi) with a high-pressure homogenizer, adjusted to 1000 ml with water for injection, adjusted to pH 8.00 with sodium hydroxide solution, filtered with a capsule filter, packed, nitrogen-filled, sealed, and rotated. The autoclave was sterilized at 115 ° C for 30 minutes to obtain an emulsion. It was determined to have an average particle diameter of 284.2 nm and a pH of 7.64.

The above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:20 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 4 Docetaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 2.5 g of docetaxel and 0.3 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 90 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.3 g of needle for activity The carbon was adsorbed at a temperature of 25 ° C for 45 minutes, then filtered through a capsule filter, sterilized by filtration through a 0.22 μm microporous membrane, and dispensed, and sealed, that is, a much more paclitaxel solution.

Preparation of emulsion:

Weigh 200 g of soybean oil for injection, heat to 80 ° C in a water bath, add 20 g of soy lecithin for injection, stir to dissolve the oil phase; measure 700 ml of water for injection, add 10 g of poloxamer 188, 22.5 g of glycerin, Stirring to dissolve, heating to 80 ° C to obtain an aqueous phase; mixing the oil phase and the aqueous phase at a temperature of 80 ° C, emulsified with a shear emulsifier for 15 minutes (speed 10,000 rev / min), to obtain colostrum; high pressure for colostrum The homogenizer is further emulsified (pressure 15000 psi), adjusted to 1000 ml with water for injection, adjusted to pH 8.53 with sodium hydroxide solution, filtered through a microporous membrane, packed, nitrogen-filled, sealed, and sterilized by rotary high-pressure steam. The pot was sterilized at 121 ° C for 15 minutes to obtain an emulsion. The average particle diameter was determined to be 181 nm and the pH was 8.01.

The above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:25 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 5 Paclitaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 1.5 g of paclitaxel and 0.05 g of ethylenediaminetetraacetic acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 90 ° C, then dilute to 100 ml with polyethylene glycol 400; add 1.0 g of needle The activated carbon was adsorbed at a temperature of 50 ° C for 20 minutes, then filtered with a sand filter, dispensed, sealed, and sterilized by circulating steam at 100 ° C for 45 minutes to obtain a paclitaxel solution.

Preparation of emulsion:

Weigh 75 grams of soybean oil, 75 grams of caprylic acid triglyceride, heated to 60 ° C in a water bath to obtain an oil phase; measure 750 ml of water for injection, add 12 g of egg yolk phospholipid, 22.5 g of glycerin, stir to evenly disperse, heat to The aqueous phase was obtained at 60 °C. The oil phase and the aqueous phase were mixed at a temperature of 60 ° C, emulsified by a shear emulsifier for 20 minutes (speed: 5000 rpm) to obtain colostrum; the colostrum was further emulsified by a high pressure homogenizer (pressure: 12,000 psi), with water for injection The volume was adjusted to 1000 ml, the pH was adjusted to 7.50 with sodium hydroxide solution, filtered with a bag filter, subpacked, nitrogen-filled, sealed, and sterilized by a rotary autoclave at 115 ° C for 30 minutes to obtain an emulsion. It was determined to have an average particle diameter of 214.5 nm and a pH of 6.84.

The above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:80 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 6 Docetaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 6 g of docetaxel and 0.7 g of citric acid, add to a mixed solution of 80 g of polyethylene glycol 400, 10 g of absolute ethanol, dissolve at 80 ° C with stirring, and then make up to 100 ml with polyethylene glycol 400. Add 0.5 g of needle with activated carbon, adsorb at 45 ° C for 45 minutes, then filter with a capsule filter, dispense, seal, and sterilize in a rotary autoclave at 115 ° C for 30 minutes, ie much Paclitaxel solution.

Preparation of emulsion:

Weigh 50 g of soybean oil for injection, 50 g of garlic oil, heat to 70 ° C in a water bath, add 12 g of egg yolk phospholipid for injection, and shear to dissolve to obtain an oil phase; measure 850 ml of water for injection, add 22.5 g of glycerin, stir Dissolved, heated to 70 ° C to obtain an aqueous phase; the oil phase and the aqueous phase were mixed at 70 ° C, emulsified by a shear emulsifier for 5 minutes (rotation speed of 30,000 rpm) to obtain colostrum; high pressure homogenizer for colostrum Further emulsification (pressure 20,000 psi), make up to 1000 ml with water for injection, adjust the pH to 8.25 with sodium hydroxide solution, filter with microporous membrane, dispense, nitrogen, seal, use rotary high pressure steam sterilization pot 117 Sterilize at °C for 20 minutes to obtain an emulsion. It was determined to have an average particle diameter of 175.6 nm and a pH of 7.53.

The above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:90 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 7 Paclitaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 7.0 g of paclitaxel, add 80 g of polyethylene glycol 400, heat and shear dissolve at 85 ° C, then dilute to 100 ml with polyethylene glycol 400; add 2 g of needle with activated carbon at 30 ° C temperature Adsorption for 70 minutes, then filtration with a capsule filter, dispensing, sealing, and steaming at 100 ° C for 45 minutes to obtain a paclitaxel solution.

Preparation of emulsion:

100 g of octanoic acid monoester, 50 g of fish oil, 50 g of sesame oil, 3.0 g of tocopherol and mixed, heated to 83 ° C in a water bath, stirred and mixed to obtain an oil phase; 700 ml of water for injection was added, and ethylenediaminetetraacetic acid was added. Sodium 0.8 g, glycerin 22.5 g, egg yolk phospholipid 20 g, dimyristoyl phospholipid choline (DMPC) 15 g, shear dispersion, heated to 83 ° C, to obtain an aqueous phase; oil phase and aqueous phase at 83 ° C temperature Under mixing, emulsified by shear emulsifier for 27 minutes (speed 8000 rev / min), get colostrum; colostrum is further emulsified with high pressure homogenizer (pressure 21000 psi), with water for injection to 1000 ml, with sodium hydroxide The solution was adjusted to have a pH of 7.56, filtered through a microporous membrane, packed, filled with nitrogen, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes to obtain an emulsion. The average particle diameter was determined to be 261 nm and the pH was 7.05.

The above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:40 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 8 Docetaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 2.5 g of docetaxel, add to a mixed solvent of 60 g of absolute ethanol, 20 g of polyethylene glycol 200, 10 g of propylene glycol, dissolve at 55 ° C with stirring, then dilute to 100 ml with absolute ethanol; add 0.6 g The needle was adsorbed with activated carbon at a temperature of 55 ° C for 50 minutes, then filtered with a capsule filter, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes, i.e., a paclitaxel solution.

Preparation of emulsion:

Weigh 25 grams of coix seed oil, 25 grams of duck gallbladder oil, mix, heat to 80 ° C in a water bath, stir and mix to obtain the oil phase; measure 900 ml of water for injection, add 10 g of egg yolk phospholipid, distearyl phospholipid 醯 ethanolamine ( DSPE) 2 g, disodium edetate 0.5 g, glycerin 22.5 g, shear dispersion, heating to 60 ° C to obtain an aqueous phase; mixing the oil phase and the aqueous phase at 60 ° C, emulsified with a shear emulsifier 13 minutes (20000 rpm), get colostrum; further emulsification of colostrum with high pressure homogenizer (pressure 20,000 psi), make up to 1000 ml with water for injection, adjust the pH to 7.14 with sodium hydroxide solution, with capsule The filter is filtered, subpacked, nitrogen-filled, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes to obtain an emulsion. It was determined to have an average particle diameter of 134.5 nm and a pH of 6.40.

The above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When administered, the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:50 by volume, shaken, and intravenously instilled.

Example 9 Paclitaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 8 g of paclitaxel and 0.3 g of ethylenediaminetetraacetic acid, add a proper amount of polyethylene glycol 400 and absolute ethanol in a mixed solvent, heat and shear at 70 ° C, then dilute to 100 ml with absolute ethanol; add 1.5 g The needle was adsorbed with activated carbon at a temperature of 25 ° C for 90 minutes, then filtered with a capsule filter, dispensed, sealed, and steamed at 100 ° C for 45 minutes to obtain a paclitaxel solution.

Preparation of emulsion:

Weigh 10 grams of oil, 90 grams of sunflower oil, 25 grams of citric acid monoglyceride, 25 grams of caprylic acid diglyceride, 0.5 grams of tocopherol and mix, heat to 60 ° C in a water bath, stir and mix to obtain the oil phase; 800 ml of water for injection, 6 g of dipalmitoside phospholipid choline (DPPC), 4 g of distearyl phospholipid choline (DSPC), 25 g of glycerin, shear-dispersed, heated to 70 ° C to obtain an aqueous phase; The oil phase and the aqueous phase were mixed at a temperature of 60 ° C, emulsified by a shear emulsifier for 6 minutes (rotation speed of 30,000 rpm) to obtain colostrum, and the colostrum was further emulsified by a high-pressure homogenizer (pressure 10000 psi) with water for injection. The volume was adjusted to 1000 ml, the pH was adjusted to 8.10 with sodium hydroxide solution, filtered through a microporous membrane, subpacked, nitrogen-filled, sealed, and sterilized by a rotary autoclave at 115 ° C for 30 minutes to obtain an emulsion. It was determined to have an average particle diameter of 250 nm and a pH of 7.46.

The above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:90 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 10 Docetaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 6 g of docetaxel and 2.5 g of malic acid, add 50 g of polyethylene glycol 200, 35 g of polyethylene glycol 600 in a mixed solvent, heat and shear at 75 ° C, and then set with polyethylene glycol 600. Capacitance to 100 ml; adding 0.05 g of needle with activated carbon, adsorption at 25 ° C for 120 minutes, then filtering with a capsule filter, dispensing, sealing, circulating steam at 100 ° C for 45 minutes, that is, more paclitaxel Solution.

Preparation of emulsion:

100 g of caprylic acid diglyceride, 30 g of elemene oil, 34 g of safflower seed oil, 36 g of caprylic triglyceride, 5.0 g of tocopherol, heated to 75 ° C in a water bath, and 2.0 g of soybean phospholipid for injection were added. Diolein phospholipid choline (DOPC) 3.0 g, palm oyster oil phosphatidylcholine (POPC) 1.0 g, stir to dissolve, obtain the oil phase; measure 730 ml of water for injection, add 21.0 g of glycerin, heat to 75 °C, stirring to dissolve, to obtain an aqueous phase; the oil phase and the aqueous phase are mixed at 75 ° C, stirred and emulsified for 25 minutes to obtain colostrum, and the colostrum is further emulsified by a high-pressure homogenizer (pressure 15000 psi), and water for injection is used. The volume was adjusted to 1000 ml, the pH was adjusted to 7.04 with sodium hydroxide solution, filtered through a sintered filter funnel, packed, nitrogen-filled, sealed, and sterilized by a rotary autoclave at 121 ° C for 10 minutes to obtain an emulsion. It was determined to have an average particle diameter of 219 nm and a pH of 6.58.

The above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:80 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 11 Paclitaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 2.5 g of paclitaxel and 0.05 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear dissolve at 85 ° C, then make up to 100 ml with polyethylene glycol 400; add 0.2 g of needle with activated carbon, The mixture was adsorbed at a temperature of 25 ° C for 30 minutes, then filtered through a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 30 minutes to obtain a paclitaxel solution.

Preparation of emulsion:

Weigh 10 grams of Artemisia annua oil, 100 grams of corn oil, heat to 60 ° C in a water bath, add 20 grams of soy lecithin for injection, cut to dissolve, stir and mix to obtain oil phase; measure 810 ml of water for injection, add 25.0 of glycerin Gram, stir to dissolve, heat to 60 ° C to obtain an aqueous phase; the oil phase and the aqueous phase are mixed at 60 ° C, emulsified with a shear emulsifier for 15 minutes (rotation speed 23000 rev / min), get colostrum; colostrum Further emulsification (pressure 15000 psi) with high pressure homogenizer, make up to 1000 ml with water for injection, adjust the pH to 6.88 with sodium hydroxide solution, filter with microporous membrane, dispense, nitrogen, seal, use rotary high pressure The steam sterilization pot was sterilized at 115 ° C for 45 minutes to obtain an emulsion. It was determined to have an average particle diameter of 232 nm and a pH of 6.56.

The above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:30 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 12 Docetaxel intravenous injection and combination packaging

Preparation of drug solution:

Weighed 4.0 g of docetaxel, added to 80 g of polyethylene glycol 400, dissolved and dissolved at 95 ° C, and more paclitaxel solution; weighed 0.8 g of disodium edetate, and used 8 g of water for injection. Dissolve, obtain a chelating agent solution; mix the chelating agent solution with the docetaxel solution uniformly, and make up to 100 ml with polyethylene glycol 400; add 1.0 g of the needle with activated carbon and adsorb at a temperature of 60 ° C for 20 minutes. Then, it was filtered with a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 12 minutes, that is, a much more paclitaxel solution.

Preparation of emulsion:

Weigh 50 g of caprylic acid triglyceride for injection, 20 g of soybean oil, 30 g of ganoderma lucidum spore oil, heat to 70 ° C in a water bath, add 12 g of egg yolk phospholipid for injection, shear to dissolve, stir and mix, and obtain oil phase. Measure 850 ml of water for injection, add 22.5 g of glycerin, stir to dissolve, and heat to 75 ° C to obtain an aqueous phase; mix the oil phase and the aqueous phase at 75 ° C, and emulsify with a shear emulsifier for 10 minutes (rotation speed 12000 rpm) /min), get colostrum; further emulsification of colostrum with high pressure homogenizer (pressure 15000 psi), make up to 1000 ml with water for injection, adjust the pH to 7.81 with sodium hydroxide solution, filter with microporous membrane, divide The mixture was filled with nitrogen, sealed, and sterilized by a rotary autoclave at 121 ° C for 10 minutes to obtain an emulsion. It was determined to have an average particle diameter of 208 nm and a pH of 7.15.

The above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:70 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 13 Paclitaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 2.5 g of paclitaxel and 0.2 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 88 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.3 g of needle with activated carbon, The mixture was adsorbed at a temperature of 25 ° C for 15 minutes, then filtered with a capsule filter, dispensed, sealed, and sterilized at 121 ° C for 15 minutes in a rotary autoclave to obtain a paclitaxel solution.

Preparation of emulsion:

Weigh 50 g of soybean oil for injection and 50 g of caprylic acid triglyceride, heat to 55 ° C in a water bath, add 12 g of egg yolk phospholipid for injection, shear to dissolve, stir and mix to obtain oil phase; measure water for injection 800 ML, adding 22.5 g of glycerin, stirring to dissolve, heating to 55 ° C to obtain an aqueous phase; mixing the oil phase and the aqueous phase at 55 ° C, emulsified with a shear emulsifier for 15 minutes (rotation speed 22000 rev / min), at the beginning Milk; colostrum is further emulsified by a high-pressure homogenizer (pressure 20,000 psi), made up to 1000 ml with water for injection, adjusted to pH 6.54 with sodium hydroxide solution, filtered with a capsule filter, packed, nitrogen-filled, sealed The mixture was sterilized by a rotary autoclave at 121 ° C for 12 minutes to obtain an emulsion. It was determined to have an average particle diameter of 179 nm and a pH of 6.00.

The above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When administered, the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:50 by volume, shaken, and intravenously instilled.

Example 14 Docetaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 4.0 g of docetaxel and 0.3 g of ethylenediaminetetraacetic acid, add to the appropriate amount of polyethylene glycol 400, heat and shear dissolve at 85 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.1 g The needle was adsorbed with activated carbon at a temperature of 25 ° C for 80 minutes, then filtered with a capsule filter, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes, that is, a more paclitaxel solution.

Preparation of emulsion:

Weigh 100 g of soybean oil for injection and 100 g of caprylic acid triglyceride, heat to 70 ° C in a water bath, add 1.2 g of egg yolk phospholipid for injection, dissolve to dissolve, stir and mix to obtain oil phase; measure water for injection 750 ML, add 22.5 g of glycerin, stir to dissolve, heat to 70 ° C to obtain an aqueous phase; the oil phase and the aqueous phase are mixed at 70 ° C, emulsified with a shear emulsifier for 10 minutes (rotation speed 18000 rev / min), at the beginning Milk; colostrum is further emulsified by high-pressure homogenizer (pressure 17000 psi), made up to 1000 ml with water for injection, adjusted to pH 6.50 with sodium hydroxide solution, filtered with microporous membrane, packed, nitrogen-filled, sealed It was sterilized by rotary autoclaving at 121 ° C for 12 minutes to obtain an emulsion. The average particle diameter was determined to be 227 nm and the pH was 6.01.

The above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:60 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 15 Paclitaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 6.0 g of paclitaxel and 1.5 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear dissolve at 84 ° C, then dilute to 100 ml with polyethylene glycol 400; add 2 g of needle with activated carbon, The mixture was adsorbed at a temperature of 25 ° C for 30 minutes, then filtered through a microporous membrane, and dispensed, and steamed at 100 ° C for 45 minutes to obtain a paclitaxel solution.

Preparation of emulsion:

Weigh 150 g of caprylic acid triglyceride for injection, 150 g of soybean oil, heat to 75 ° C in a water bath, add 20 g of egg yolk phospholipid for injection, shear to dissolve, stir and mix to obtain oil phase; measure water for injection 650 ML, add 10 grams of poloxamer 188, 22.5 grams of glycerin, stir to dissolve, heat to 75 ° C to obtain the aqueous phase; the oil phase and the aqueous phase are mixed at 75 ° C, emulsified with a shear emulsifier for 16 minutes (speed 11000 rpm, get colostrum; further emulsification of colostrum with high pressure homogenizer (pressure 20,000 psi), make up to 1000 ml with water for injection, adjust pH to 7.50 with sodium hydroxide solution, filter with capsule filter , sub-packaging, nitrogen filling, sealing, sterilization in a rotary high-pressure steam sterilization pot at 121 ° C for 15 minutes, to obtain an emulsion. It was determined to have an average particle diameter of 400 nm and a pH of 7.03.

The above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:60 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 16 Docetaxel intravenous injection and combination packaging

Preparation of drug solution:

Weigh 4.0 g of docetaxel and 0.05 g of ethylenediaminetetraacetic acid, add to the appropriate amount of polyethylene glycol 400, dissolve at 95 ° C with stirring, and make up to 100 ml with polyethylene glycol 400; add 1.0 g of needle The activated carbon was adsorbed at a temperature of 25 ° C for 30 minutes, filtered through a microporous membrane, and then sterilized by filtration through a 0.22 μm filter membrane, and the mixture was sealed and sealed, that is, a much more paclitaxel solution.

Preparation of emulsion:

Weigh 100 g of soybean oil for injection, heat to 70 ° C in a water bath, add 12 g of egg yolk phospholipid for injection, dissolve to dissolve, stir and mix to obtain an oil phase; measure 850 ml of water for injection, add 22.5 g of glycerin, stir Dissolved, heated to 75 ° C to obtain an aqueous phase; the oil phase and the aqueous phase were mixed at 75 ° C, emulsified with a shear emulsifier for 10 minutes (rotation speed 12000 rev / min), to obtain colostrum; high pressure homogenizer for colostrum Further emulsification (pressure 17000 psi), make up to 1000 ml with water for injection, adjust the pH to 6.88 with sodium hydroxide solution, filter with a capsule filter, dispense, nitrogen, seal, and use a rotary high pressure steam sterilization pot 121 Sterilize for 10 minutes at °C to obtain an emulsion. It was determined to have an average particle diameter of 194 nm and a pH of 6.58.

The above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.

When the drug solution and the emulsion are in a ratio of 1:40 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 17 Paclitaxel intravenous injection

Preparation of drug solution:

Weigh 4.0 g of paclitaxel, add it to 90 g of polyethylene glycol 400, dissolve it by heating and stirring at 85 ° C to obtain a paclitaxel solution; weigh 0.5 g of disodium edetate, and dissolve it with 10 g of water for injection to obtain a chelate. Mixture solution; mix the chelating agent solution with the drug solution uniformly, and make up to 100 ml with polyethylene glycol 400; add 0.5 g of needle with activated carbon, adsorb at 45 ° C for 45 minutes, then use microporous membrane Filtration, aliquoting, sealing, and sterilizing at 121 ° C for 15 minutes in a rotary autoclave to obtain a paclitaxel solution.

Commercially available emulsion: [Specification]: 250 ml, 20% medium/long chain fat emulsion; [batch number]: 80BM072; [manufacturer]: Huarui Pharmaceutical Co., Ltd.

When administered, the volume ratio of the drug solution to the commercially available emulsion is 1:15, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 18 Paclitaxel intravenous injection

Preparation of drug solution:

Weigh 2.5 g of paclitaxel, add to the appropriate amount of polyethylene glycol 400, heat and shear at 80 ° C, dissolve 0.5 g of disodium edetate, and dissolve it with 10 g of water for injection to obtain a chelating agent solution; The chelating agent solution is uniformly mixed with the drug solution, and the volume is adjusted to 100 ml with polyethylene glycol 400; 0.5 g of the needle is added with activated carbon, and adsorbed at 25 ° C for 45 minutes, then filtered with a microporous membrane, and dispensed. , sealed, sterilized in a rotary autoclave at 121 ° C for 15 minutes to obtain a paclitaxel solution.

Commercially available emulsion: [Specification]: 100 ml, 20% medium/long chain fat emulsion; [batch number]: GM0809034; [manufacturer]: Guangzhou Baite Qiaoguang Medical Products Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 19 Paclitaxel intravenous injection

Preparation of drug solution:

Weigh 2.5 g of paclitaxel and 0.1 g of ethylenediaminetetraacetic acid, add to the appropriate amount of polyethylene glycol 400, dissolve at 85 ° C with stirring, and dilute to 100 ml with polyethylene glycol 400; add 0.5 g of needle for activity The carbon was adsorbed at a temperature of 25 ° C for 45 minutes, then filtered through a microporous membrane, packed, sealed, and sterilized by a rotary autoclave at 121 ° C for 12 minutes to obtain a paclitaxel solution.

Commercially available emulsion: [Specification]: 100 ml, 20% medium/long chain fat emulsion; [batch number]: GM0809034; [manufacturer]: Guangzhou Baite Qiaoguang Medical Products Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 20 Paclitaxel intravenous injection

Preparation of drug solution:

Weigh 2.5 g of paclitaxel and 0.3 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear dissolve at 85 ° C, then make up to 100 ml with polyethylene glycol 400; add 0.3 g of needle with activated carbon, The mixture was adsorbed at a temperature of 25 ° C for 30 minutes, then filtered with a capsule filter, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes to obtain a paclitaxel solution.

Commercially available emulsion: [Specification]: 100 ml, 20% medium/long chain fat emulsion; [batch number]: GM0809034; [manufacturer]: Guangzhou Baite Qiaoguang Medical Products Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 21 Paclitaxel intravenous injection

Preparation of drug solution:

Weigh 3.0 g of paclitaxel and 0.8 g of ethylenediaminetetraacetic acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 75 ° C, then dilute to 100 ml with polyethylene glycol 400; add 1.0 g of needle The activated carbon was adsorbed at a temperature of 60 ° C for 15 minutes, then filtered with a capsule filter, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes to obtain a paclitaxel solution.

Commercially available emulsion: [Specification]: 250 ml, 20% medium/long chain fat emulsion; [batch number]: F090203C2; [manufacturer]: Sichuan Kelun Pharmaceutical Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:60, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 22 Paclitaxel intravenous injection

Preparation of drug solution:

Weigh 2.5 g of paclitaxel and 0.5 g of ethylenediaminetetraacetic acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 80 ° C, then dilute to 100 ml with polyethylene glycol 400; add 2.0 g of needle The activated carbon was adsorbed at 25 ° C for 15 minutes, then filtered through a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 115 ° C for 30 minutes to obtain a paclitaxel solution.

Commercially available emulsion: [Specification]: 250 ml, 20% medium/long chain fat emulsion; [batch number]: F090203C2; [manufacturer]: Sichuan Kelun Pharmaceutical Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 23 Paclitaxel intravenous injection

Preparation of drug solution:

Weigh 6.0 g of paclitaxel and 2.0 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 80 ° C, then dilute to 100 ml with polyethylene glycol 400; add 1.2 g of needle with activated carbon, The mixture was adsorbed at a temperature of 25 ° C for 20 minutes, then filtered through a microporous membrane, dispensed, sealed, and sterilized by circulating steam at 100 ° C for 45 minutes to obtain a paclitaxel solution.

Commercially available emulsion: [Specification]: 250 ml, 20% long-chain fat emulsion; [batch number]: 0811212-1; [manufacturer]: Zhejiang Kanglaite Pharmaceutical Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:100, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 24 Docetaxel intravenous injection

Preparation of drug solution:

Weigh 2.5 g of docetaxel and 1.4 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 70 ° C, then dilute to 100 ml with polyethylene glycol 400; add 3 g of needle for activity The carbon was adsorbed at 25 ° C for 15 minutes, then filtered through a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes, i.e., a paclitaxel solution.

Commercially available emulsion: [Specification]: 100 ml, 20% medium/long chain fat emulsion; [batch number]: GM0809034; [manufacturer]: Guangzhou Baite Qiaoguang Medical Products Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 25 Paclitaxel intravenous injection

Preparation of drug solution:

Weigh 2.5 g of paclitaxel and 0.8 g of tartaric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 70 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.06 g of needle with activated carbon, The mixture was adsorbed for 90 minutes at a temperature of 25 ° C, then filtered through a microporous membrane, dispensed, sealed, and sterilized by circulating steam at 100 ° C for 45 minutes to obtain a paclitaxel solution.

Commercially available emulsion: [Specification]: 250 ml, 20% medium/long-chain fat emulsion; [batch number]: GM0810022; [manufacturer]: Guangzhou Baite Qiaoguang Medical Products Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 26 Paclitaxel intravenous injection

Preparation of drug solution:

Weigh 2.5 g of paclitaxel, add to 90 g of polyethylene glycol 400, dissolve at 90 ° C with stirring, and obtain paclitaxel solution; weigh 1.0 g of disodium edetate, dissolve it with 5 g of water for injection, and obtain a chelate Mixture solution; mix the chelating agent solution and the drug solution uniformly, and make up to 100 ml with polyethylene glycol 400; add 0.5 g of needle with activated carbon, adsorb at 25 ° C for 30 minutes, then use microporous membrane Filtration, aliquoting, sealing, sterilization in a rotary autoclave at 121 ° C for 12 minutes, to obtain a paclitaxel solution.

Commercially available emulsion: [Specification]: 250 ml, 30% long-chain fat emulsion; [batch number]: GM0810022; [manufacturer]: Huarui Pharmaceutical Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 27 Docetaxel intravenous injection

Preparation of drug solution:

Weigh 3.0 g of docetaxel and 0.1 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 70 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.7 g of needle for activity The carbon was adsorbed at a temperature of 45 ° C for 60 minutes, then filtered through a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 115 ° C for 30 minutes, i.e., a paclitaxel solution.

Commercially available emulsion: [Specification]: 250 ml, 20% medium/long chain fat emulsion; [batch number]: 8192A181; [manufacturer]: Berenger Medical AG, Germany.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:40, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 28 Docetaxel intravenous injection

Preparation of drug solution:

Weigh 2.5 g of docetaxel and 0.25 g of ethylenediaminetetraacetic acid, add to the appropriate amount of polyethylene glycol 400, heat to shear at 80 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.3 g The needle was adsorbed with activated carbon at a temperature of 25 ° C for 30 minutes, then filtered through a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 115 ° C for 30 minutes, i.e., a paclitaxel solution.

Commercially available emulsion: [Specification]: 250 ml, 30% long-chain fat emulsion; [batch number]: GM0810022; [manufacturer]: Huarui Pharmaceutical Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Example 29 Docetaxel intravenous injection

Preparation of drug solution:

Weigh 2.5 g of docetaxel and 0.25 g of lactic acid, add to the appropriate amount of polyethylene glycol 400, heat to shear at 80 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.3 g of needle with activated carbon It was adsorbed for 30 minutes at a temperature of 25 ° C, then filtered through a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 115 ° C for 30 minutes, ie, a paclitaxel solution.

Commercially available emulsion: [Specification]: 250 ml, 30% long-chain fat emulsion; [batch number]: GM0810022; [manufacturer]: Huarui Pharmaceutical Co., Ltd.

When administered, the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

Claims (11)

A taxane drug solution characterized in that the taxane drug solution is composed of a taxane drug, a chelating agent, a solvent, and other medicinal excipients added as necessary, wherein the ratio of each component is: taxane 1~8% (g/ml) of the drug; 0.05~2% (g/ml) of the chelating agent; the rest are the aforementioned solvents and other medicinal excipients added if necessary; among them, other medicinal auxiliary materials added if necessary And a pH adjusting agent and/or an isotonicity adjusting agent, wherein the chelating agent is selected from the group consisting of citric acid, lactic acid and/or tartaric acid, wherein the solvent is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400. a mixture of one or more of polyethylene glycol 600, propylene glycol, glycerin, absolute ethanol, and water for injection, wherein the pH adjusting agent is selected from the group consisting of citric acid, malic acid, hydrochloric acid, acetic acid, lactic acid, sodium carbonate, and hydrogen carbonate. One or more of sodium, sodium hydroxide, the isotonicity adjusting agent is one or more selected from the group consisting of glycerin, sorbitol, mannitol, glucose, and sodium chloride. For example, in the taxane solution of claim 1, the proportion of each component is: taxanes 1 to 6% (g/ml); chelating agent 0.1 to 1% (g/ml); It is the aforementioned solvent and other pharmaceutical excipients added as necessary. The taxane drug solution according to any one of claims 1 to 2, wherein the taxane drug is paclitaxel or docetaxel. A taxane drug solution according to claim 1, wherein the solvent is polyethylene glycol 400. A method for preparing a taxane drug solution according to any one of claims 1 to 4, characterized in that the taxane drug and the chelate are combined The agent is dissolved in the solvent, and if necessary, other pharmaceutically acceptable excipients are added, the other pharmaceutically acceptable excipients being selected from the group consisting of pH adjusters and/or isotonicity modifiers, wherein the chelating agent is selected from the group consisting of citric acid, lactic acid and/or tartaric acid, wherein The solvent is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, propylene glycol, glycerin, absolute ethanol, water for injection, or a mixture of one or more, wherein the pH is The regulator is selected from one or more of citric acid, malic acid, hydrochloric acid, acetic acid, lactic acid, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, and the isotonicity adjusting agent is selected from the group consisting of glycerin, sorbitol, mannitol, glucose, and chlorine. One or more of sodium. The preparation method of claim 5, comprising the steps of: weighing a taxane drug and a chelating agent and adding the solvent to the injection, heating or stirring at 50 to 100 ° C or shearing and dissolving, and then using The solvent is fixed to volume; 0.01% to 3% g/ml of the needle is added to the activated carbon, and adsorbed at a heating temperature of 25 to 100 ° C for 15 to 120 minutes, and then filtered, dispensed, sealed, and sterilized. The preparation method of claim 5 or 6, wherein the taxane is paclitaxel or docetaxel. A taxane-type pharmaceutical composition, which is characterized in that it is prepared from a taxane drug solution and an emulsion two-part agent according to any one of claims 1 to 4; the formulation is in a volume ratio of 1 The ratio of 10 to 1:100 is mixed with the taxane drug solution and the emulsion. A pharmaceutical combination package, which is characterized in that it is packaged by a combination of a taxane drug solution and an emulsion according to any one of claims 1 to 4, wherein the two agents are respectively placed in a container, placed separately, and combined. Packed together. A pharmaceutical combination package characterized by a taxane drug solution and The emulsion is packaged in a package, and the two medicaments are respectively placed in a container, placed separately, and packaged together, wherein the taxane drug solution or the emulsion contains a chelating agent in an amount of 0.05 to 2% (g/ml). The pharmaceutical combination package of claim 10, wherein the emulsion comprises a chelating agent, the chelating agent is contained in an amount of 0.05 to 2% (g/ml), and the chelating agent is selected from the group consisting of citric acid, lactic acid, and tartaric acid. Or a mixture of more than one.