TW201219055A - comprising chelation agent to help extending stability duration in an emulsion - Google Patents

Abstract

The present invention provides a taxane pharmaceutical solution containing chelation agent and a method for preparing same, and a combination usage of the pharmaceutical solution and emulsion. In clinic use, the pharmaceutical solution is dispersed in the emulsion and shaken uniformly and then applied through intravenous injection. Due to the inclusion of the chelation agent, the stability duration of the pharmaceutical solution dispersed in the emulsion is surprisingly extended and the surface oil problem of the dispersion liquid is also overcome, thereby helping improving clinically pharmaceutical security and effectiveness. The present invention also provides a method for preparing a taxane pharmaceutical solution, a composition containing taxane pharmaceutical solution and emulsion, a combined package composed of taxane pharmaceutical solution and emulsion, and an emulsion containing chelation agent.

Description

201219055 VI. Description of the Invention: [Technical Field] The present invention relates to a pharmaceutical preparation technique, and more particularly to an octataxane drug solution and a preparation method thereof. [Previous technique] Taxanes include paclitaxel (paclitaxd,

Taxol) and docetaxel (d〇cetaxei, trade name σ ° name approved by fda two kinds of yew-type anticancer drugs. Typical cytotoxic agents of taxanes, with broad-spectrum anti-tumor effect, on the mammary gland Cancer = nest cancer, small cell lung cancer, non-small cell lung cancer, head and neck squamous. Primary cancer and metastatic cancer such as malignant melanoma have strong inhibition $ and its anti-tumor mechanism is through stimulation of the catheter bundle Polymerization promotes the assembly of micro-tubules into microtubules, and causes microtubules to be ultra-stable and _(4) reticular = recombination, eventually stopping the proliferation of cancer cells in the quiescent stage of mitosis: achieving anti-tumor purposes. Paclitaxel and Dorsey Paclitaxel is very water-soluble, almost insoluble in the vehicle (4), 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 Zi Teng, the clinical application (4) Shanlu ejaculation is from palmitic ethylene The beneficial color of S sesame oil and absolute ethanol (50: 50, V/V) is a concentrated solution of the 'Weihe lion's lion's turn, but the injection contains polyoxygen which is easy to induce sensitization. Ethylene (four) oil, _ after breathing _, red, jump faster, Allergic reactions have brought safety concerns and pain to patients. Similar problems exist in the available docetaxel preparations. The clinical preparation of docetaxel is composed of two parts of Tween 8〇% ethanol solution. Dispersed in physiological saline / water intravenously, although the dissolution of docetaxel is solved, but = injection 3 / 42 201219055 liquid ^ has a solution A effect of Tween 8 〇 'clinical drug is prone to occur - a certain degree of hemolytic reaction' The safety is poor. #There are many existing clinical preparations. The research and development of the yew (4) drug injections are active. In recent years, the research on taxane injections is mainly liposome: fat milk, nano Particles, self-protein cross-linking precursors, cyclodextrin inclusion complexes, etc. are the research hotspots. The current technology key towels in the selection of materials biocompatibility, body (four) acceptability and dosage form stability: breakthrough, but Due to the low drug loading, the application of the wave is not limited.

Fortner et al. (Am. J. Hosp. Pharm. (1975) 32, 582-584) reported that 'transfer a poorly water-soluble drug to a suitable injection (iv) to form a drug bath' to disperse (iv) the length of the emulsion. This - the dosage form is gradually taken seriously. BS Anderson's "purine-transformed non-intestinal stable non-toxic preparation, (Chinese special and .97196934.5) in the drug solution part of the drug solvent is the ratio of polyethylene glycol 400 to dimercaptoacetamide to 3: i The composition, although dimethyl acetamide can improve the speed of the drug, but (4) also increased the role of pharmaceutical preparations. The research progress of toxic effects of Zhoulian (Diterpene B) [J]. Chinese occupational medicine , 2〇〇9,36(1): I wish 7) report that 曱-mercaptoamine can lead to weight loss, retinal atrophy, brain wave changes, and lung, stomach, liver, kidney and other damage treasures. In the "pharmaceutical composition containing a poorly water-soluble drug, (Chinese Patent Application: 2_8_7345.3), the drug solvent in the drug solution portion is mainly composed of polyethylene glycol 400 and oleic acid. RC. R()ehe et al. (Handbook of Medicinal Excipients, vol. 4, 476) showed that oleic acid can cause rupture of red blood cells, i.e., hemolyble, which is allowed in the primers. 4/42 201219055 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_8〇, Vesone, lecithin, etc. These surfactants all have some hemolytic and irritating properties. In order to make the medicinal and cedar drugs safer, more effective, stable and economical for clinical use and to better exert their anti-tumor effects, we have developed a group.

In the package, the solution package containing the taxane in the package and the medicinal emulsion package are separated and placed together. Before the administration, the drug is dissolved and dispersed in the (iv) towel ng卩 can be venous. The present invention adds a chelating agent to the combined agent, so that the k-dispersion in which the drug solution is dispersed in the emulsion is stably recorded (4), and the submarine float is overcome. Insufficient oil, improve = shai to the safety and effectiveness of the body. . SUMMARY OF THE INVENTION The present invention provides a yew 9 liming compound, which is made of yew:===, wherein the drug solution or 忒1% [coupon/said heart is 0.05~2% (g/ml) Preferably, it is 0.1~. The preparation is a mixture of 5 体积 in a volume ratio of 1: 1 G to 1: 100, preferably 1:1. After that, it shows strong stability. "The music is in combination with the emulsion for injection. The present invention provides a pharmaceutical solution of the yew (four), which contains preparation, cedar, chelating agent and solvent. Good, the ratio of each component 5/42 201219055 Taxanes 1~8% (g/ml) Chelating agent 0.05~2% (g/ml) The rest are solvents and other medicinal excipients added if necessary. Preferably, the ratio of each component is: taxane 1 to 6% (g / ml) chelating agent 0.1 to 1% (g / ml) The rest are solvents and other pharmaceutical excipients added if necessary. Other pharmaceutical excipients are added during the preparation of the solution, such as: co-solvent, etc., ginseng conditioner, surfactant, pH adjuster, etc. Whether or not to add these medicinal excipients depends on the taxanes The properties of the drug, the chelating agent and the solvent. In the drug solution of the present invention, the taxane drug is any taxane drug, preferably paclitaxel or docetaxel which has been marketed. Where the chelating agent is added to the drug In the liquid, wherein the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodium edetate, triamethylene edetate, and disodium citrate. Or a mixture of more than one, preferably citric acid, lactic acid, ethylenediaminetetraacetic acid, disodium edetate, preferably disodium edetate. The solvent selected in the pharmaceutical solution of the invention One or more mixtures of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, propylene glycol, glycerin, absolute ethanol, water for injection; preferably polyethylene glycol 400. The present invention also includes a process for preparing a solution of the present invention, comprising the steps of dissolving a taxane drug and a chelating agent in a solvent, and if necessary, adding other pharmaceutically acceptable excipients. 6/42 201219055 Fortunately, the present invention The preparation method comprises the steps of: weighing paclitaxel or docetaxel, a chelating agent into a solvent, heating or stirring or shearing and dissolving in 5 〇~] rc (r), and then diluting with a solvent; adding 0.01% to 33⁄4 g/ml ^ Needle with activated carbon, at 25 (10) C is adsorbed at a heating temperature of 15 to 120 minutes and then filtered, dispensed, sealed, and sterilized. The present invention also provides a pharmaceutical combination package which is packaged by the yew drug solution and the emulsion according to the present invention. The two kinds of medicaments are respectively loaded in the valley D. They are placed in a vertical position and are packaged together. The combination package of the present invention is to fill the taxane drug solution and the medicinal emulsion of the invention into the plastic bottle respectively. Or in a glass bottle, the two drugs are packaged in a ratio of 1:10 to 10:1, preferably in the ratio of i: ,, packaged in the same large packaging container. 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. Points. The present invention uses a venous > primary 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. It generally contains an injection oil, an emulsifier, an antioxidant, an isotonic regulator, a pH adjuster, water for injection, and the like. The present invention is characterized in that a chelating agent may be added to the emulsion of the present invention in an amount of 0.05 to 2% gram per liter, preferably (U to 1% gram per liter, and the chelating agent is selected from the group consisting of ethylenediamine). One or a mixture of tetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodium edetate, trisodium ethylenediaminetetraacetate, disodium citrate, preferably citric acid, lactic acid, Ethylenediaminetetraacetic acid, disodium edetate, preferably ethylenediaminetetraacetic acid 7/42 201219055 The emulsion of the present month, wherein the injection oil is selected from the group consisting of glyceryl octoate glycerol Self-purpose, octyl glycerin di g |, octanoic acid triglyceride, ganoderma lucidum, oil, glycerin, monoglyceride, glyceric acid, glycerin, glycerin, glycerin Duck gallbladder oil, artemisia oil, caprylic acid diglyceride, cowpea oil, fish oil, linseed oil, sunflower oil, evening primrose oil, ", oil, oil, safflower oil, sesame oil, corn oil, elemene a mixture of oils, garlic oils, or the like, in a mixture of 1 to 30% g/m The concentration of the oil in the emulsion is expressed in grams of oil per milliliter of emulsion. The preferred injection oil is selected from one or a mixture of caprylic acid triglyceride and soybean oil in an amount of 1 〇 3 〇% g / ml. wherein the emulsifier is selected from the group consisting of soybean phospholipids, egg yolk phospholipids, dimylocidin sera, two palm _ fat _ test, distearyl choline choline, diolein phosphatidylcholine a mixture of one or more of a base, palm olein, phospholipid choline, distearyl phospholipid, ethanolamine, poloxamer 188, containing 0.5% to 5% g/ml. Preferred emulsifier A mixture of one or two selected from the group consisting of soy sauce and egg yolk phospholipid in an amount of 〇8 to 3% g/ml. The concentration of the emulsifier in the emulsion is expressed in grams of emulsifier per ml of the emulsion. The antioxidant of the present invention is tocopherol, and its content is 〇~〇5% g/ml. The preferred content is 0-0.3% g/ml. The isotonicity adjusting agent of the present invention is selected from the group consisting of glycerin, One or more of sorbitol, mannitol, glucose, and sodium chloride, preferably glycerin. The guanidine regulator of the present invention is selected from the group consisting of citric acid, malic acid, citric acid, acetic acid, lactic acid, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, etc. Sodium, adjust the pH to 6 〇~9 〇. It is better to adjust the pH to 6.5~8.5.

The preparation method of the emulsion for intravenous injection is the prior art, such as mixing the injection oil and the antioxidant, heating to 5 〇 9 9 C, adding an emulsifier, stirring or shearing to dissolve the emulsifier to obtain an oil phase; The isotonicity adjusting agent and the stabilizer are added to an appropriate amount of water for injection, heated to 5 Torr to 9 Torr, and stirred to obtain an aqueous phase; the oil phase and the aqueous phase are at 50 to 9 Torr. Mix at 〇 temperature, emulsifie or emulsifie with a shear emulsifier for 5 to 60 minutes, and rotate at 5 〇〇〇 to 3 rpm for 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 oil for injection or dissolving the emulsifier in water. In the present invention, the further emulsification of the colostrum is carried out using a high pressure homogenizer at a pressure of 5 Torr to 250 psi. The disinfection in the preparation step of the emulsion is a sterilization and disinfection method using a rotary Koryo steam sterilization pot, a circulating steam or a microporous filter membrane, wherein the high temperature sterilization temperature is encouraged to be 12 Γ (:, time 8 to 45 minutes. The emulsion preparation method The over-manufactured m, but not limited to microporous _, sand filter rod, sintered transition funnel or capsule filter ϋ. The final milk white or class = liquid, with opalescence, average particle size 00~·nm, ρΗ The invention also provides a method for using a yew-like drug solution, which comprises adding a purple-type drug solution and an emulsion to a volume ratio of from 1 to 100, preferably 1:25. The ratio of the drug solution is dispersed in the emulsion, the vein is private, and the drug solution after the dispersion of the emulsion is added to the physiological saline or the i-sugar solution for injection. The following describes the experimental data by the experimental data. 9/42 201219055 1. Comparison of the stability of the dispersion containing the chelating agent (citric acid) and the yew containing no chelating agent, and the dispersion of the composition before the administration of the composition, in order to further embody the chelating agent in the present invention. Substance, j. Unexpected effects, we will compare the stability of the dispersion containing the chelating agent (citric acid) with the paclitaxel injection composition without the chelating agent. Formulation of the chelating agent (lemon) according to the embodiment described in Example 1. a drug solution of the acid), a test drug solution is obtained; according to the embodiment described in the embodiment, the citric acid is removed, a drug solution containing no chelating agent is prepared, and a control drug solution is obtained; and the test drug solution and the control drug are aspirated 4 ml of each solution was dispersed in 10 ml of the self-made emulsion described in Example 1, and shaken to obtain a test sample. The liquid crystal was prepared by a high performance liquid chromatograph and a particle size analyzer, respectively, at different time points. The drug content and particle size; in the determination of the content, first use a syringe to extract the appropriate amount of dispersion through the .45μιη microporous membrane 'determine the content of the drug in the liquid, calculate the percentage of the label, the content of this The drug was evaluated for crystallization; the particle size was directly measured, and the appearance was visually observed. The results are shown in Tables 1 and 2.

...... Paclitaxel injection composition I. Stability of a pre-dispersion solution. Emulsion) Time (days) 6 Content (%) 100.0 1012 inn -7 Γ υι, ζ 100·7 99.8 99.8 97.1 Particle size (nm) 148.0 150 7 n〇〇Γ 139.8 147.0 142.6 155.1 —^ Appearance is better __ Table 2 The stability of the dispersion before the administration of the paclitaxel injection composition containing no sonicating agent (calic acid) represented by Example I Dispersed milking is a homemade emulsion) '° 10/42 201219055 Time (days) Content (%) Particle size (nm) Appearance

More, and over time ^~: 'Looking at the poor results analysis of the chelating agent (citric acid) prepared from the comparison of the test results of Table 1 and Table 2: out of the same as the composition of the composition of Example 1 The paclitaxel injection containing the chelator %丨^\3 chelating agent does not contain the integrator, the dispersion containing the chelating agent is about 6 days; the dispersion from the outside without the integrator is more oil slick, , ^^,: good view" There is a drug precipitation day round ★ On the stable day _ little change, when the purple-white dispersion of the paclitaxel injection of the Cedar injection composition of Si white overcomes the deficiency of the dispersion oil slick f "" and do not think that the invention has a substantial excellent effect = this indicates that the chelating agent is the present 2, containing a chelating agent (ethylene diamine oxime = injection composition before the dispensing 1-liquid = two mixture More and two - effect: now I am: ^^^ (4) and does not contain § _ ^ 丨 丨 (B--- tetraacetic acid two liquid stability comparison. 4 cedar injection sword composition before dispersion According to the embodiment described in, the actual 2, the preparation of the chelation-containing office (B 11/42 201219055 disodium diamine tetraacetate) The docetaxel injection composition was obtained as a test sample; according to the embodiment described in Example 2, the integrator (diethylenediaminetetraacetic acid di-nano) was removed to prepare a chelating agent-free docetaxel injection combination, and a control sample was obtained. The sample solution of the above test and the lysate sample was separately dispersed in the respective ML emulsions prepared according to the embodiment described in the actual 2, and the test sample was obtained. The high-performance liquid color π was obtained. The granules and the granules are respectively measured for the drug content and particle size of the dispersion at different time points; when determining the content, the appropriate amount of the dispersion is firstly extracted by a syringe through a microporous 0.45 of 0.45 μm, and the content of the drug in the filtrate is determined. Calculate the percentage content 'to evaluate whether the drug precipitates crystals by this content;: directly loses' and visually observes the appearance. The results are shown in Table 3 and Table 4. Table 3 contains the integrator represented by Example 2. Docetaxel (diethylenediaminetetraacetate) Dosage time (days) 〇2 4 6 Content (%) 100.0 99.4 100.4 101.1 Particle size (nm) 140.0 135.1 143.6 145.6 . Appearance 1. 1_2 days without oil slick No chelating agent, the appearance of rape imperial 12 Table 4 «Example 2 is represented by (edetate disodium) is docetaxel West

Loose emulsion is a homemade emulsion) Time (days)

Content (%) Particle size (nm) From the comparison of the test results in Table 3 and Table 4, it is concluded that the prepared chelating agent is only a case of sputum sputum (disodium edetate) and chelating agent-free white.丨12/42 201219055 The dosage of docetaxel injection composition is up to half a time up to 3 3 ^ ^ ^ ^ ^ 7 蜊 dispersion is stable 6 夭 without chelation _ penny stable when asked, from the appearance Look, the phenomenon of oil slick containing chelating agent, outer 颧 _ cup ^ A 剞 7 knife month liquid + no sputum within the month (four) more slick-free oil slick n = extended, slick gradually increased, poor appearance = Within the 'intersection is not big', when there is a mature precipitation, the diameter becomes larger. The results show that the chelating agent (the ethylenediaminetetraacetic acid agent composition has a remarkable effect) has the advantage of 'and unexpectedly overcomes the deficiency of the dispersion oil slick'. The invention has the excellent effect of tf (4). 3. The stability comparison test between the present invention containing the g mixture (disodium edetate) and the methyl acetamide-containing patent embodiment is in the patent (Chinese patent) :971%934·5) indicates that the patent adds dimercaptoacetamide to polyethylene glycol 400, which has a ratio of 1:3 to polyethyl alcohol, and its drug loading is 25 mg. 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 the above, and the test drug solution is obtained; 2: 4 ml of the above reference drug solution and the test drug solution are taken. Diluted into the 1 mM commercial emulsion described in Example 18. Shake well to obtain the test product. The high-performance liquid chromatograph was used to determine the drug content of the dispersion at different times &points; When using the substance, first use a syringe to pump Appropriate amount of the dispersion was passed through a microporous membrane of 45 μm, and the content of the drug in the filtrate was measured. The percentage of the drug was measured by 瞀^, and the content was used to evaluate whether the drug precipitated crystals; and the appearance was observed by the naked eye, and the results are shown in Table 5. /42 201219055 Table 5 Stability of the dispersion of the preparation containing the chelating agent (disodium edetate) and the dispersion of the control patent preparation containing dimethylacetamide (dispersed emulsion is a commercially available emulsion) 6h 8h 10h 18h 24h Preparation of the invention 100.4% 99.2% 100.1% 101.0% 97.9% Control preparation 94.7% 90.2% 86.8% Appearance The preparation of the invention has no oil slick within 24 hours; the control preparation has more oil slick. Result analysis: by test It is concluded 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 dimercaptoacetamidine. The stability of the dispersion of the amine control preparation is less than 6 hours; from the appearance point of view, the dispersion of the preparation of the invention has no oil slick phenomenon, and the dispersion liquid containing the dimercaptoacetamide control preparation is more serious, The addition of the chelating agent unexpectedly solves the problem. It can be seen that the formulation scheme of the present invention has significant advantages and unexpected effects compared with the control patent. Therefore, it is indicated that the inclusion of the chelating agent is essential to the present invention. Characterization of the excellent effect of the invention. φ 4, the stability test of the present invention and the oleic acid-containing patent embodiment containing the chelating agent (ethylenediaminetetraacetic acid) is shown in the published patent application (Chinese Patent Application: 200680007345.3) The application is mainly to add oleic acid based on polyethylene glycol 400 in an amount of 0.01 to 5%. According to the embodiment, 0.3%, 1.0%, and 5.0% oleic acid polyethylene glycol 400 solution is separately prepared; A solution of paclitaxel having a paclitaxel content of 25 mg/ml was prepared as a control solution, and a drug solution was prepared according to the embodiment described in Example 19 to obtain a test solution; 4 ml of the above control solution and a test solution were respectively taken. 14/42 201219055 Disperse in 100 ml of the commercially available emulsion described in Example 19, and shake the sentence to obtain a test sample. The high-performance liquid chromatograph was used to determine the drug content of the dispersion at different time points. When measuring the content, the appropriate amount of the dispersion was firstly extracted by a syringe through a microporous membrane of 0.45 μm 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. ^ υ 3 The public agent (ethylenediaminetetraacetic acid) of the dispersion of the preparation of the invention and the stability of the dispersion of the control patent preparation containing oil sputum (dispersed emulsion is a commercially available emulsion) sample 6h 8h 10h preparation of the invention 101.5% 100.8 % 99.3% 0.3% oleic acid 93.1% 88.5% 81.1% 1.0% oleic acid 89.4% 82.6% 76.7% 5.0% oleic acid 81.6% 76.0% 72.5% Appearance - no oil slick in the hour;

Agent (ethylenediamine^=the same commercially available emulsion dispersion medium, including integration for more than 20 hours, ^: * dispersion stability time of the invention composition + hour, and with the two dispersion stability time (9) The series of oil rrr acid is two-way: it is not enough. Second: the addition of the second chelating agent means that the meal mixture is an unexpected effect. Therefore, the table s, containing meal mixture (# Λ# is excellent The characteristics of the effect. 3 The implementation of the _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Warm 80 (Tween-80), pototene, lecithin, injection vehicle composition, an embodiment similar to the present invention is Example 3, that is, paclitaxel 1.8g, phospholipid 22g, propylene glycol 40g 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 Example 20, respectively. Said Test samples were 'shakened' in 100 ml of commercially available emulsion. The liquid content of the dispersion was measured by liquid chromatography at different time points; when measuring the content, the appropriate amount of dispersion was firstly extracted with a syringe. .45μιη microporous membrane, the content of the drug in the filtrate was determined, the percentage of the label was calculated, and the content was used to evaluate whether the drug precipitated and crystallized; and the appearance was observed by the naked eye, and the results are shown in Table 7. Table 7 Containing a chelating agent (citric acid) The stability of the dispersion of the preparation of the invention and the dispersion of the control patent preparation containing the surfactant (dispersion emulsion is a commercially available emulsion) sample 6h 8h 10h 15h 20h 99.8% of the preparation of the invention 101.1% 100.8% 99.6% 98.4% Patented preparation 99.6% 94.4% Appearance The preparation of the invention has no oil slick within 20 hours; : The control preparation has more oil slick. Result analysis: It is found from the experiment that the chelating agent (citric acid) is contained in the same commercially available emulsion dispersion medium. The dispersion of the composition of the present invention has a stabilization time of up to 20 hours or more, and the dispersion containing the surfactant-controlled patent preparation has a stabilization time of less than 8 hours; Appearance angle evaluation, the composition dispersion of the present invention has no oil slick phenomenon, and the surfactant-containing control patent preparation dispersion liquid oil is serious, and there is a large amount of oil collapse wall. The addition of the chelating agent unexpectedly solves the 16/ 42 201219055 Advantages and unexpected effects. The characteristics of the present invention are substantially excellent. The '3 combination is the advantage of the present invention: Oxygen B good soil: any cosolvent with toxic side effects For example, the squid of yin, sputum, sputum, sputum, sputum, sputum

Sesame oil and vomiting (4) have severe hemolysis and allergic reactions; ^^^^^^^^^^^^^^^^^^^^^^^^^^ : Two: Ben: = =. _=.,' year-on-year LDs. It is dimethyl ethanoamine II: r: pre. .疋 - a safe solvent for injection; RC · Roche and other two (four) auxiliary materials hand Gang. The original fourth edition: 476) shows that oleic acid can lead:,, the breakage of the worker cells, that is, the narrative, = the preparation of the present invention Does not contain toxic side effects = 一大 a great advantage of the present invention; called / combined d also ❿ 2 good stability: 彳 (d) the stability of the dispersion of the hair solution obtained 2 significantly extended the dispersion敎Time, and the sound phase does not overcome the shortage of the sub-ship materials, and further improves the stability of the limbs. [Embodiment] The effect is the invention, the sexual advantage and the unexpected implementation of the yoke scheme are achieved, but the invention It is not limited to the preparation of the purple-static side and the combined packaged drug solution as in the first embodiment: 17/42 201219055 > 2.5 g of Izuol, 5 g of bismuth citrate, and added to the appropriate amount of polyethylene glycol 400 j ' 85 C heating shear dissolution, and then to a volume of 1 〇〇ml with polyethylene glycol lion; add 0.3 grams of needle with activated charcoal, adsorption at the temperature of the pit for 3 ,, 'then filtered with a capsule magnet, Dispense, seal, use the rotating Gaocheng steam to destroy _ urc Gu 15 minutes, that is, yew Solution. Preparation of the emulsion: Weigh 1 gram of left-handed soybean oil, 3 gram of octanoic acid glycerin, heat to 8G C, add 2Q grams of soy for injection, cut to dissolve, mix Na 'Oil oil phase; measure 74 liters of water for injection, add 1 gram of poise: " 188, 22.5 grams of glycerin, stir to dissolve, heat to 8 〇. .得水目=From the phase and the water phase at 8 (mixed at rc temperature, emulsified with a shear emulsifier; 隹 _! half ^ 15 GG)), get colostrum; high pressure homogenizer for colostrum: Lihua ([12]. (4), use the water for injection to make up to liter, adjust the pH of the liquid to 7, filter with a capsule filter, and divide it by 'rotating high-pressure steam pin 12rc for 15 minutes, pay To the determination of 'the average particle size of 148 faces, Yang is 712 wide glass bottles, and the money and (four) milk money (four) in the (four) bottle or glass 'muscle armor two kinds of music in the body packaged in the same - a large packaging container Packing together the ratio of the medium M, for example, the ratio of the cedar solution to the emulsion is 1:25. The solution of the music is dispersed in the milk, the drug solution is added to the emulsion, and the intravenous drip is also applied; The solution can be used for injection. Add a predetermined amount of normal saline or glucose =: paclitaxel intravenous injection and combination packaging to weigh 2.5 g of docetaxel, add appropriate amount of polyethylene glycol, 18/42 201219055 C force "', 苕切洛解' then fixed to 1 (nine) ml with polyethylene glycol 400; t two 1 gram of needle with activated carbon 'at 25 ° C temperature 30 minutes adsorption, membrane filtration consider two holes L, rape 'seal [sigma]' off by a rotary pressure steam sterilization granary steel 5 c 30 minutes, i.e., docetaxel emulsion was prepared:

,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Phase; take 74G of water for injection, add ethylenediamine, acetonitrile: one nano gram, 5 grams, 10 grams of poloxamer 188, glycerol 22.5 grams 'interference solution' 2 heat to the order of the water phase: (four) phase And the water phase at the thief temperature, this mouth 'emulsified with male cutlery for 8 minutes (speed 2 deleted 〇 turn / min), get colostrum; colostrum is further emulsified with high pressure homogenizer (pressure 12000psi), with the main shot Use glutinous rice to the milliliters, adjust the pH to H with sodium hydroxide solution. Fill the nitrogen with the capsule type rhyme® 'Nongnong', seal σ, and extinguish the a pin 121 with a rotating high-strength strip. . Sterilize 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 respectively filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a volume ratio of 丨:〗 ❸, and packaged in the same large packaging container. When the drug is administered and the emulsion is in a ratio of 1: Μ, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 3 Preparation of paclitaxel intravenous injection and combination packaging drug solution: Weigh 2.0 g of paclitaxel into 9 g of polyethylene glycol 4 ,, and dissolve at room temperature (4) to obtain a paclitaxel solution; Diurethane tetraacetate U gram 'dissolve it with 1G gram of water for injection to obtain a chelating agent solution; mix the whole 19/42 201219055 mixture solution with the drug solution (4), (4) Glycol condensate to ι〇〇 Γ tG · 8 grams of activated carbon, adsorbed at the temperature of thief 120 22 f filtered with microporous membrane, divided into agriculture, sealed π, with rotating high pressure H 烕囷 steel 121 C @ 8 minutes, that is, the paclitaxel solution . Preparation of the emulsion: Weigh 150 grams of soybean oil, Xin! Pure a ^. Brother 150 grams of citric acid triglyceride and mixed, water > Valley heated to 60 C 'Add 1 廿* /β θ for injection 12 Use 12 grams of egg phospholipid, cut to dissolve, pay oil phase; House: Take Water for injection 6 〇〇 Λ pen liter, add 25 grams of glycerin, stir to make the bath solution 'heated to 60 ° C to get the water phase; 肱, 丄丄人 々丄, the oil phase and the water phase at 60 ° C temperature Under mixing, emulsified with a shear emulsifier 3 〇 cylinder + knife Cui Li (speed 6000 rev / min), get colostrum; colostrum with high pressure homogenizer into a + boring knife) pay the initial hole ' ^ Lihua (pressure 22000pSi ), make up to 000 ml with water for injection, use P; ra ^ , a. Wind-emulsified steel solution to adjust its pH to 8.00, filter with capsule filter, dispense, right & fill the 'sealing, 闬 rotate High-pressure steam simmering pot 1]) C sterilized for 30 minutes, / $ is a salvage agent. It was determined to have an average particle diameter of 284.2 nm and a pH of 7.64. The sucrose/liquid mixture and the ritual are respectively poured into a plastic bottle or a glass bottle, and the two kinds of music are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container. At the time of administration, the ratio of the drug solution to the emulsion is 丨·· 2Q, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 4 Preparation of Docetaxel Intravenous Injection and Combination Packaging Drug Solution: Take 2:5 g of docetaxel and 3 g of citric acid, and add to the appropriate amount of polyethylene glycol 400 ^ ' 9 〇t heating Shear and dissolve, then make up to 100 ml with polyethylene glycol 4 ;; add 0.3 g of needle with activated carbon, absorb 45 points at 25 ° C temperature! Child, then use a capsule filter to sputum,帛〇.22 handsome micro 20/42 201219055 hole filtration, membrane sterilization, aliquoting, sealing 'that is much more paclitaxel solution. Preparation of the emulsion: Weigh 200g of large oil for weighing/main injection, heat to 8 (rc in the water bath, add 20g of soy 注射 曰 注射 注射 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 ; ; ; ; ; ; ; ; ; Losham 188, 22.5 g of glycerin, so that the water phase is dissolved, the oil phase and the water phase are mixed at 8 (TC temperature, and the colostrum is obtained in minutes (speed (9) rpm). The first = Tian-step emulsification (pressure job (four), with the injection of water to determine the oxidative sodium solution to adjust the yang to 8.53, sterilized in a micro-pot for 15 minutes, the mouse obtained rotary high-pressure steam sterilization w, pH is please. The average particle diameter was determined to be above the docetaxel solution and the emulsion = two drugs were combined in a ratio of 1:1 by volume = wrapped in the same large packaging container. With the emulsion, the drug solution is dispersed in the emulsion, and the ratio of '25% 'fertility' is intravenously instilled. Actually: Example 5 Preparation of sterol cisazin Shiping packaged music solution: Weighing paclitaxel 1.5 grams, B-& 400 constant volume money 〇 ml. Force into 'f shear dissolution, then use polyethylene glycol temperature adsorption 20 silly filter After the smashing, the smashing steam boots are extinguished for 8 45 minutes, that is, the preparation of the yew coffee ^ sealing emulsion: Weigh 75 grams of soybean oil, 75 grams of bismuth citrate triglyceride, water bath heating 21/42 From 201219055 to 60 C, obtain the oil phase; measure 750 ml of water for injection, add 12 g of egg yolk scales, 22.5 g of glycerin, stir to uniformly disperse and heat to 6 ° C to obtain an aqueous phase. The oil phase and water phase are 6 (mixed at TC temperature, emulsified by shear emulsifier 2 〇 (return 5 rpm), get colostrum; colostrum is further emulsified with high pressure homogenizer (pressure 12000 psi), with water for injection Capacitance to 1 00 ml, adjust the pH to 7.50 with sodium hydroxide solution, filter with a capsule filter, dispense, fill, seal, and use a rotary high-pressure steam sterilization pot 115. (: Sterilization for 30 minutes, that is The emulsion has an average particle size of 214.5 nm and a pH of 6.84. The above paclitaxel solution and the emulsion are respectively filled in a plastic bottle or a glass bottle. The two drugs are packaged together in a ratio of 1:1 by volume. , packaged in the same large packaging container. Evening - drug solution and emulsion The volume ratio is 1:80, the music solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 6 Preparation of docetaxel intravenous injection and combination packaging drug solution: Weighing docetaxel 6 0.7 grams of gram, citric acid, added to 8 grams; 2 grams of anhydrous ethanol in a mixed solution, 8 (rc heating, solution ..., and then with ♦ ethylene glycol 4 〇〇 to 1 liter; add 〇 5

The adsorption was carried out for 45 minutes at a temperature, and then sealed with a peach: y U 'knife', and fixed by rotary autoclaving for 30 minutes, i.e., a paclitaxel solution. Preparation of U emulsion: Weigh 5 grams of soybean oil, 5 grams of garlic oil, pure water r2 grams of water bath, shear dissolution: get oil phase:, heat to 7. . . Get the water phase; the oil phase and temperature =:: solution '22/42 201219055 etched emulsifier for 5 minutes (speed 3 rpm / min), get colostrum; colostrum with a pressure homogenizer further Emulsification (pressure 2 psi), make up to 1000 liters with water for injection, adjust the pH to 8.25 with sodium hydroxide solution, filter with microporous membrane, 'package H seal σ, job-high pressure The steam sterilization pin 117 C was sterilized 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 were respectively filled in a plastic bottle or a glass bottle, and the two drugs were packaged in a volume ratio of 1:1, and packaged in the same large packaging container. At the time of administration, the drug solution and the emulsion are in a ratio of 1:9 G by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 7 Intravenous injection of paclitaxel and combination packaging Preparation of drug solution: 7.0 g of paclitaxel was weighed, and 8 g of polyethylene glycol 4 〇〇, 85 was added. 〇 Heat shearing and dissolution, then make up to 1 〇〇ml with polyethylene glycol 400; add 2 gram of needle with activated carbon 'at 7G minutes at 3G ° C, filter with a capsule filter, Split, seal σ, circulation steam (10). The sputum was sterilized for 45 minutes to obtain a paclitaxel solution. Preparation of emulsion: #辛酸glycerin, 1 gram of vinegar, 5 grams of fish oil, 5 grams of sesame oil, 3.0 grams of raw phenol, mixed, heated to 83 水 in a water bath: stirred and mixed to obtain an oil phase; 7GG of water, adding 8 g of disodium edetate, 22.5 g of glycerin, 2 g of egg yolk phospholipid, 15 g of dimyristoyl phospholipid choline (DMPC), sheared and dispersed, heated to 83. The aqueous phase was obtained; the oil phase and the aqueous phase were mixed at a temperature of 83 ° C, and emulsified by a shear emulsifier for 27 minutes (speed 8000 rpm) to obtain colostrum; the colostrum was further emulsified by a high pressure homogenizer (pressure 23 /42 201219055 Force 21000psi) 'Condensate to 1 〇〇〇ml with water for injection, adjust the pH to 7.S6 with sodium hydroxide solution, filter with microporous membrane, dispense, nitrogen, seal, rotate The high pressure steam was extinguished (iv) 12 rC for 15 minutes to obtain an emulsion. It was measured to have an average particle diameter of 261 nm and a pH of 7 〇5. The above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle. The two drugs are packaged together in a ratio of 1: i by volume, and packaged in the same large packaging container. When administered, the ratio of the drug solution to the emulsion is 丨: 4 体积, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 8 Preparation of Docetaxel Intravenous Injection and Combination Packaging Drug Solution: Weigh 2.5 g of docetaxel and add a mixture of 6 g of anhydrous ethanol, 20 g of polyethylene glycol 200, and 10 g of propylene glycol to heat the mixture. Dissolve and dissolve, then make up to 10 〇 ml with absolute ethanol; add 〇 6 g of needle with activated carbon at 55. (: adsorption at temperature for 50 minutes, then filter with a capsule filter, dispense, seal, use a rotary high-pressure steam sterilization pot 121. 〇 sterilization for 15 minutes, that is, more paclitaxel solution. Preparation of the emulsion: weighing the coix seed 25 grams of oil, 25 grams of duck gallbladder oil, mixed, heated to 80 C in a water bath, stirred and mixed to obtain an oil phase; measuring 9 ml of water for injection, adding 10 g of egg wall grease, stuffed with distatin 2 g of ethanolamine (DSpE), 5 g of ethylene-amine tetraacetic acid, 5 g of glycerin, 22.5 g of glycerin, shear dispersion, heating to 60 C to obtain an aqueous phase; mixing the oil phase and the aqueous phase at 6 (rc temperature) Emulsification of the emulsifier for 3 minutes (rotation speed 20000 rpm), get colostrum; colostrum with a pressure homogenizer into the step emulsification (pressure 20000Psi), with injection water to a volume of 1000 ml 'sodium hydroxide solution Adjust the pH to 7.14, filter with the capsule type 24/42 201219055 ' filter, sub-package, nitrogen filling, sealing α, high-volume a a sterilization 12rC from the minute, that is, the emulsion is obtained. It is determined to be 134.5nm, pH It is 6·40. 卞呜拉 k The above docetaxel solution and emulsion are respectively filled in the glass bottle. The _ combination of two __ 胄 胄 1:1 is packaged in the same large packaging container at 4 t. When administered, the ratio of the drug solution to the emulsion is i: 5 (U disperses the drug solution in the emulsion) Shake well, intravenous drip, just fine.

Example 9 Preparation of paclitaxel intravenous injection and combined packaging drug solution: ▲ Weigh 8 g of paclitaxel, 3 g of ethylenediaminetetraacetic acid G, add mixed diol and no 7] c ethanol, and thief heat-shear and dissolve , immerse in anhydrous ethanol to a volume of 1.5 ml; add 15 grams of needle with active stone anti-' adsorption at 25 C for 90 minutes, then use a capsule filter to tear, dispense, seal, flow steam l〇 ( After TC sterilization for 45 minutes, the solution of paclitaxel was obtained. Preparation of emulsion: Weigh 10 g of decanted oil, 90 g of sunflower oil, 25 g of citric acid monoester, 25 g of octanoic acid diglyceride, 0.5 g of tocopherol and mix, water bath Heat to 60 C 'mix and mix to obtain the oil phase; measure 8 ml of water for injection, add 6 g of dipalmitoside phospholipid choline (DPPC), 4 g of distearyl phospholipid choline (DSPC), 25 g of glycerin, shear-dispersed, heated to 7 〇t:, to obtain an aqueous phase; the oil phase and the aqueous phase were mixed at 6 Torr. The mixture was emulsified for 6 minutes with a shear emulsifier (rotation speed 3 rpm) / min), get colostrum, colostrum with high pressure homogenizer into the step emulsification (pressure lOOOOpsi), with a note Make up to 1000 ml with water. Adjust the pH to 8.10 with sodium hydroxide solution, filter with microporous membrane, 25/42 201219055 subpackaged 'charge II, seal, surge high pressure steam off (four) 115. annihilate for 30 minutes' That is, the emulsion is obtained. The average particle size is determined to be 25 () 7.46. P is

The above paclitaxel solution and the emulsion were respectively filled in a plastic bottle or a broken glass bottle, and the two drugs were packaged together in a ratio of a volume ratio of 1:1, and the spoon was placed in the same large packaging container. When the L" is administered, the ratio of the solution to the emulsion is 1:9G, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 10 Preparation of Docetaxel Intravenous Injection and Combination Packaging Drug Solution: 6 g of docetaxel and 2.5 g of malic acid were weighed and added to a mixture of 50 g of polyethylene glycol 200 and 35 g of polyethylene glycol 6 〇〇. In the solvent, it is sheared and dissolved in seven yttrium and then fixed to 1 〇〇ml with polyethylene glycol _; the needle added with gram is adsorbed with activated carbon at the temperature of the pit for 12 ,, and then the capsule filter is used. Filtration, 'packing, sealing, circulation steam HKTC reduced bacteria for 45 minutes, that is, more paclitaxel solution. Knife Preparation of the emulsion: Weigh 100 grams of caprylic acid glycerin, 3 grams of elm oil, safflower oil. 34 grams, caprylic acid three cool 36 grams, 5 grams of fertility, water bath heated to 75 ° C, plus injection soybean fat 2 () grams, two oil _ fat brewing test (DOPC) 3.0 grams, palm stuffed Oil phosphatidylcholine choline (p〇pc) a gram, stirred to dissolve, to obtain an oil phase; measuring 73 liters of water for injection, adding 21.0 grams of glycerol. , heating to hunger 'infusion to dissolve, to obtain an aqueous phase; the oil phase and the aqueous phase, mixed at 75 ° C, emulsified for 25 minutes, obtained colostrum, colostrum with high pressure homogenizer into the step emulsification (pressure丨5_psi), make up to 1000 ml with water for injection, adjust the pH to 7.04 with sodium hydroxide solution, filter with a sintered 26/42 201219055 filter funnel, separate the mash, and sterilize the steel boots for 10 minutes, ie ^. The rotation was 219 nm with a rotary high pressure steam and the pH was 6.58. ^ Menstrual Determination' The average particle size of the above docetaxel solution and the glass bottle, the two drugs in the volume, in a plastic bottle or glass packaged in the same large envelope. The proportion of the combination of shocks in the - start, - medicine time

Disperse the drug solution in the ratio of emulsion = W 1 · 8G, real: Example 11 Preparation of paclitaxel intravenous injection and combination packaged music solution: = 1.2 g of cedar alcohol, citric acid called a scorpion 400, 85 t heating Shear dissolution, polyglycol to just ML; add 02 Gu 1 PEG 400 〇. 2 g of needle with activated carbon, at 25. 〇 = to: after the use of microporous membrane sputum, sub-package · = two;: _ boots sterilization 3 ° minutes 'have a paclitaxel solution. Weigh 10 grams of Artemisia annua oil, 1 gram of corn oil, heat to 6 (rc, into the water bath, shoot 2G grams of soybeans, cut to dissolve, stir and mix, get oil, ® take 810 ml of water for injection, Add 25 grams of glycerin, mix to dissolve, heat to 60 ° C to obtain the aqueous phase; mix the oil phase and the aqueous phase at 6 °t, emulsified with a shear emulsifier for 15 minutes (speed 23 rev / min) Get colostrum; further emulsification of colostrum with a surface pressure homogenizer (pressure 15 psi), set each to 1 liter with water for injection, and adjust the pH to 6.8 with sodium hydroxide solution. The microporous membrane was over; t 'packing' the seam, and the thief gave the steam sterilization pot 115 C for 45 minutes to obtain an emulsion. The average particle size was determined to be 232 nm and the pH was 6.56. 27/42 201219055 In the I fir alcohol solution and the milk ^ ^ ^ ^, the two drugs are in a large packaging container of "! and 4= bottle or glass bottle. j, and D are packaged together and packaged in the same drug. When the 'drug solution and emulsion drug = disperse in the emulsion, shake the ratio 'drug two:: paclitaxel intravenous injection and combination packaging" two: Γ 克 'Add to 80 grams of polyethylene glycol _ medium, m read, more paclitaxel solution = sodium 〇. 8 grams, with 8 New Zealand _ cut New solution, county combined constant volume and docetaxel solution mixed evenly, with polyethylene glycol 400 Combine the pen, add). 0g of needle with activated carbon, adsorption at 6〇t temperature: 20 minutes' then use microporous membrane to sputum, dispense, seal = high pressure steam off _121t sterilization 12 minutes , that is, more paclitaxel solution. '' Preparation of emulsion: ^ Weigh 50 g of caprylic acid triglyceride for injection, 20 g of soybean oil, 30 g of water of the scorpion oil to the thief' for injection Egg yolk oil gram, cut to dissolve, stir and mix to obtain oil phase; measure 85 liters of water for injection, add 22.5 grams of glycerin, stir to dissolve, heat until it gets water phase; oil phase and water The phase was mixed at 75 ° C, emulsified by a shear emulsifier for 1 Torr (speed 12000 rpm) to obtain colostrum; colostrum was further emulsified with a high pressure homogenizer (pressure 15000 psi) 'Condensation with water for injection to 1 〇〇〇ml, adjust the pH to 7.81 with sodium hydroxide solution, filter with microporous membrane, dispense, fill nitrogen, seal, use spin The rotary autoclave was sterilized at 121t for 1 minute to obtain an emulsion. The average particle size was 208 nm and the pH was 7.15. 28/42 201219055, the above docetaxel solution and emulsion were respectively filled in plastic bottles or glass bottles. In the case of 'two drugs in a volume ratio of 1:1 (four), the package is packaged in the same large packaging container. In the case of oral medicine, the ratio of the drug solution to the emulsion by volume ratio is i: The drug solution is dispersed in the emulsion, and the injection is given intravenously. f Example 13 Preparation of paclitaxel intravenous injection and combination packaging drug solution: ▲ Weighing, 2.5 g of cedar, and 0 2 g of citric acid, added to The right amount of polyethylene glycol alcohol =, 88. . Heat the shear solution, then dilute to 100 ml with polyethylene glycol 4 ;; add 3 gram of the needle with activated carbon, adsorption at 25 ° C temperature! 5 minutes, then filtered with a capsule filter, dispensed, sealed, and rotated with the same type of hot steam sterilization pot 121. The sputum was sterilized for 15 minutes to obtain a paclitaxel solution. Preparation of the emulsion: 5 g of soybean oil for injection and 5 g of tricaprylic acid triglyceride were weighed and heated to 55 with water cooling. (:, adding 12 g of egg yolk phospholipid for injection, shearing to dissolve, stirring and mixing to obtain an oil phase; measuring 800 ml of water for injection, adding 22.5 gram of glycerin, stirring to dissolve, heating to 55 to obtain an aqueous phase; The oil phase and the aqueous phase were mixed at 55 C, emulsified by a shear emulsifier for 15 minutes (rotation speed 22000 rpm) to obtain colostrum; the colostrum was further emulsified by a high pressure homogenizer (pressure • 20000 psi), with water for injection The volume was adjusted to 1000 ml, and the pH was adjusted to 6.54 with sodium hydroxide solution. The filter was filtered with a capsule filter, subpacked, nitrogen-filled, sealed, and sterilized by a rotary autoclave 12rc for 12 minutes to obtain an emulsion. The average grain edge is 179 nm and the pH is 6.00. The above paclitaxel solution and the emulsion are respectively 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 In a large packaging container. 29/42 201219055 ” When the drug solution and the emulsion are in a ratio of η 5 体积, the solution of the music is dispersed in the emulsion, shaken, and intravenously instilled. 14 docetaxel intravenous injection Preparation of injection and combination packaged drug solution: - Weigh 4.0 g of docetaxel, Q 3 of ethylenediaminetetraacetic acid, add to the appropriate amount of polyethylene glycol 400 towel, 85t heat shear and dissolve, silk with polyethylene glycol働Set the volume to the excitation milliliter; add 1 gram of needle to the activated carbon, adsorb it for 8Q minutes at 25 C's dish. 'Use the capsule filter to filter, dispense, seal 'use the suspected south pressure steam sterilization Pin 121. Quenching® 15 minutes, that is, more paclitaxel solution. Preparation of the emulsion: ,, weigh 1 gram of oil for injection, glycerin octyl citrate! (10) g, water / heat to 7GC 'Adding human egg yolk for injection 12 grams, shear to dissolve, mix and mix, get the oil phase; measure the water for injection 75 () soar, add 22.5 grams of glycerin, mix to dissolve, heat to the water The oil phase and the water phase were mixed at 70 ° C. Emulsified with a shear emulsifier for 1 Torr (rotation speed 18 rpm) to obtain colostrum; the colostrum was further emulsified by a high pressure homogenizer (pressure = 0 GpSI) 'Condensate to the milliliter with water for injection, adjust the pH to 6.5 〇 with sodium hydroxide solution. Filter with microporous membrane. Packing, filling, sealing, two-rotating high-pressure steam sterilization (2). C sterilization for 12 minutes, obtaining an emulsion. After testing, the average particle size is 227nm, pH is 6.01. The above docetaxel solution and emulsion are separately filled. In a plastic bottle or glass bottle, 'the two drugs are packaged in a ratio of 1:1 by volume, and packaged in the same large packaging container. When administered, the volume ratio of the drug solution to the emulsion is 丨: 6 〇 ratio, the drug solution is dispersed in the emulsion, shake the 'intravenous infusion, can be. 30/42 201219055 Example 15 Preparation of paclitaxel intravenous injection and combination packaging drug solution: ★ Weighing 6.0 g of paclitaxel, citric acid Gram, add to the appropriate amount of polyethylene glycol 400 ^ '84C heat shear dissolution, then dilute to 100 liters with polyethylene glycol 4 〇 0; add 2 grams of needle with activated carbon, at 25 ° C temperature Adsorption = 0 knife & 'then (four) pore filter minus, dispensing, circulating steam 1 〇叱 sterilization for 45 minutes, that is, the paclitaxel solution. Preparation of emulsion:

/ Dan shot with 150 grams of caprylic acid triglyceride, 150 grams of soybean oil, 7 & / σ, heated to 75c 'added egg yolk Wei μg for injection, shear to dissolve, disturbed and mixed, get the oil phase Measure the water for injection (four) ml, add 10 grams of polox " 188, glycerin, oil 22.5 grams, stir to dissolve, heat to 75 〇c to get water ^^ phase and water recording temperature mix, cut Emulsifier emulsification speed 11_rev / min) 'get colostrum; colostrum with high pressure homogenizer = ritual (pressure 2 〇 _ psi), with water for injection to the surface of the milliliter, ^ = steel solution to adjust its pH 7·5〇, use a capsule-type filter to pass through the sputum, and divide it into two minutes. Use a rotary high-pressure steam sterilizer to sterilize it. The average particle size is 400 nm and the pH is 703. In the middle, two: C fir two _ emulsions are respectively filled in plastic bottles or glass bottles "i large package ratio packaged in - from the package of drugs dissolved: two bodies: 6. ratio of 2 = two: paclitaxel intravenous injection And the combination package weighed 4.0 g of docetaxel, 0.05 g of ethylenediaminetetraacetic acid, added 31/42 201219055 to the appropriate amount of polyethylene glycol 400, dissolved at 95 ° C with stirring, and set the valley with polyethylene glycol 400 to 1 〇〇ml, add 1. gram of needle with activated carbon, adsorption at temperature for 30 minutes' filtered with microporous membrane, then filtered with 〇22μηι filter, aliquot, seal, much more paclitaxel Solution: Preparation of emulsion: Weigh 100 grams of soybean oil for injection, heat to 7 (rc in water bath, add 12 grams of egg yolk phospholipid for injection, cut to dissolve, stir and mix to obtain oil phase; measure 850 liters of water for injection 22.5 g of glycerin was added, stirred to dissolve, and heated to 75 ° C to obtain an aqueous phase; the oil phase and the aqueous phase were mixed at 75 Torr, and emulsified by a shear emulsifier for 10 minutes (rotation speed 12,000 rpm). Milk; further emulsification of colostrum with a high pressure homogenizer (pressure 17 psi) The volume of water was adjusted to 1 〇〇〇ml, the pH was adjusted to 6.88 with sodium hydroxide solution, filtered with a capsule filter, and the 'nitrogen-filled' seal was dispensed. The sterilized high-pressure steam sterilization pot 121 C was sterilized. In the minute, the emulsion was obtained. The average particle size was 194 nm and the pH was 6.58. The above docetaxel solution and the emulsion were respectively filled in a plastic bottle or a glass bottle, and the two drugs were 1:1 by volume. The proportions are packaged together 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/liquid mixture is dispersed in the emulsion, shaken, and intravenously. Note, can be. ^ Example 17 preparation of paclitaxel intravenous drug solution: Weigh 2.0 g of paclitaxel, add to 9 g of polyethylene glycol 400, 85 〇 $ heat to find dissolved paclitaxel solution; Take the disodium edetate, and dissolve it with 1 gram of water for injection to obtain a chelating agent solution; mix the chelating liquid with the drug solution uniformly, and make up to 1 〇〇 32 with polyethylene glycol 400. /42 201219055 ml, add 0.5g needle with activated carbon, at 2 Adsorb 45 at a temperature of 5 〇C, then filter with a microporous membrane, dispense, seal, and sterilize with a rotating high-pressure non-quenching steel 121 C for 15 minutes 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 ratio of the drug solution to the commercially available emulsion is 1:15. The solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 18 Intravenous injection of paclitaxel φ Preparation of drug solution: 2.5 g of paclitaxel is weighed and added to an appropriate amount of polyethylene glycol 4 ,, 8 〇 ° C Heat shearing and dissolving 'weigh 50 g of disodium edetate, dissolve it with 10 g of water for injection to obtain a chelating agent solution; mix the chelating agent solution with the drug solution uniformly, and make up to volume with polyethylene glycol 400 Up to 100 liters; add 5 grams of needle with activated carbon, adsorb at 45:50 for 45 minutes, then filter with a microporous membrane, dispense, seal, and sterilize at 121 °C with a rotary autoclave. In minutes, the paclitaxel solution is obtained. Lu marketed emulsion. [Specifications]: 100 ml ' 20 ° / 〇 medium / long chain fat emulsion; [batch number] · GM0809034 ’ [production waste business]: Guangzhou Baite Qiaoguang Medical Products Co., Ltd. When administered, the volume ratio of the drug solution to the commercially available emulsion is 1:25, - the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 19 Preparation of a pharmaceutical solution of paclitaxel intravenous injection: Weighing 2.5 g of cedarol, gram of ethylenediaminetetraacetic acid, adding to an appropriate amount of polyethylene glycol 400, stirring and dissolving at 85 ° C, using polyethylene glycol 4 〇〇 to a volume of 100 ml, add 0.5 gram of needle with activated carbon, at 25. 〇The temperature of 33/42 201219055 is divided, sealed, and adsorbed for 45 minutes with the solubility of paclitaxel, then filtered with a microporous membrane, and sterilized by a rotary autoclave at 121 °C for 12 minutes. 0 Commercial emulsion: [Specification]: 100 ml, 20% medium/long bond fat emulsion; [batch number]: GM0809034; [production Weishang]: Guangzhou Baite Qiaoguang Medical Products Co., Ltd. _ At the time of administration, the volume ratio of the drug solution to the commercially available emulsion is a ratio of 25:, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 20 Preparation of paclitaxel intravenous injection of a drug solution: ▲ Weigh 2.5 g of paclitaxel, 3 g of citric acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 85 ° C, then use polyethylene Alcohol 4 (8) to a volume of 1 〇〇 ml; add 0.3 gram of needle with activated carbon, adsorption at the temperature of the machine for 3 ,, then filter with a capsule filter, dispense, seal, use rotary high pressure steam to destroy _ After 121 Torr for 8 丨 5 minutes, a sterol solution was obtained. Commercially available emulsion: [Specification]: 100 ml, 2% by weight of medium/long-chain fat emulsion; ^Tiger]·GMG8G9G34; [Birth of money]: Guangzhou Baite Qiaoguang Medical Use--Drug solution and commercial sale The emulsion volume ratio is 丨: 25, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 21 Preparation of a pharmaceutical solution of paclitaxel intravenous injection: 3.0 g of lingsolic acid and M g of ethylenediaminetetraacetic acid were added to a suitable solvent of '75 C for heating and shearing, and then polyethylene glycol 4 ^ Capacitance to 100 ml; add 1 gram of needle with activated carbon, adsorb for 15 minutes under the thief's degree' then use the capsule filter rhyme, dispense, seal 34/42 201219055 15 minutes' to get paclitaxel with rotary high pressure Steam sterilized steel 121 sterilized solution. Commercially available emulsion: [Specification]: 250 ml, 20% ring/long chain fat emulsion; [batch number]: FG9_C2; [manufacturer]: Sichuan Kelun Pharmaceutical Co., Ltd.

When the ratio of the drug solution to the municipal agent is 1:6 g, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 22 Preparation of the drug solution of paclitaxel intravenous injection: X Take 2.5 g of paclitaxel and 5 g of ethylenediaminetetraacetic acid, add to the appropriate amount of poly-(tetra) 0, 80 C heat-shear and dissolve, and use polyethylene glycol to make up to 100 ml; add 2. The needle is activated with activated carbon, adsorbed in the pit, 'field for 15 minutes' and then filtered, packed, sealed, and rotated by two micro-pressure steam _ 115. 〇 sterilization 3 () minutes, the paclitaxel solution 〆

When the company is administered, the volume ratio of the drug solution to the commercially available emulsion is [:25 ratio, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 23 Preparation of paclitaxel intravenous injection drug solution: Weigh 6-0 grams of paclitaxel, 2. gram of citric acid, add appropriate amount of polyethylene glycol 400 =, m: heat the shear solution, then dilute with polyethylene glycol to 100 ml; add 1.2 g of needle with activated carbon., adsorb at the temperature of the machine for 20 minutes, then filter with microporous filter, dispense, seal σ, flow steam 35/42 201219055 steam l〇〇C sterilization for 45 minutes That is, a paclitaxel solution is obtained. Commercially available emulsion: [Specifications]·· 250 ml, 2〇% long-chain fat emulsion; [Batch 5 tiger] '0811212·〗; [Production shaft]: Zhejiang Kanglaite Pharmaceutical Co., Ltd. "Drug" drug; the ratio of the volume of the liquid to the commercially available emulsion is i · ·, the drug solution is dispersed in the emulsion, shaken, intravenous drip, then. Example 24 docetaxel intravenous drug Preparation of the solution: Weigh 2.5 g of docetaxel and 14 g of citric acid, add to the appropriate amount of poly 4 〇 " 'machine heat shear dissolution, then use polyethylene glycol to dilute to 100 ml; add 3 g of needle Using activated carbon, in production, rape, sealing, using gin to kill gl for 5 minutes, that is, much more than the commercial emulsion of paclitaxel. [Specification]: 1 〇〇 并 and % City: = = 1: -, Example 25 paclitaxel Preparation of intravenous drug solution: Weigh 2.5 g of paclitaxel, 400 tartaric acid alcohol, 70 〇c plus 敎 scissors] 适里水乙至至10) ml; Add.: 2 2: =diol _ constant volume adsorption for 90 minutes, Then use micropores _ over-reduction,: the temperature of the I steam sterilized for 45 minutes, that is, the paclitaxel solution., circulation Luo 36/42 201219055: sold ^ [Specification]: 25G ml '骂中 / long-chain fat emulsion; GM0810022 ; C ] : The ratio of the volume ratio of the drug solution to the commercially available emulsion at the time of administration is 丨:25 The fungus solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 26 Preparation of paclitaxel intravenous injection drug solution: 2.5 g of paclitaxel is weighed and added to 9 g of polyethylene glycol oxime, 9 〇 • °C heating and stirring to dissolve, to obtain a paclitaxel solution; weighed ethylenediaminetetraacetic acid di-n-1.0 g 'dissolved with 5 g of injection (iv) water to obtain a chelating agent solution; the integration, the solution and the drug solution are mixed evenly, Use polyethylene glycol hydrazine to make up to the pencil sharpening; add G.5 grams of needle riding material, adsorb for 3 minutes at the temperature of hunger' then use the microporous membrane to smash, split, seal, rotate High-pressure Qinqi sterilization pin sterilization for 12 minutes, that is, paclitaxel solution. Commercial gift. [Specification]: 250 ml, 30% long-chain fat emulsion; [batch number]: (10) delete) 022; [production waste business]: China Rui Pharmaceutical Co., Ltd. In spring, when the dosage ratio of the drug solution to the commercially available emulsion is i:25, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 27 Docetaxel Preparation of intravenous drug solution: Weigh 3.0 g of docetaxel, 1 gram of bismuth citrate, added to the appropriate amount of poly = alcohol _ in '7G ° C heating shear dissolution, money with polyethylene glycol 400 set to 100 ml; add 〇. 7 grams of needle with activated carbon, at 4 At the temperature of the study, absorb for 60 minutes, then filter with microporous membrane, dispense, seal, and sterilize with rotary autoclave pin 115 for 3 minutes, ie, more paclitaxel solution. 37/42 201219055 Commercial emulsion: [Specification]: 250 ml, 20% medium/long chain fat emulsion; [batch number]: 8192A181; [manufacturer]: German Braun Medical Co., Ltd. When administered, the volume ratio of drug solution to commercially available emulsion is 丨: 4 The ratio of bismuth, the drug solution is dispersed in the emulsion, shaken, intravenous drip, then. Example 28 Docetaxel intravenous injection Preparation of drug solution: 2.5 g of docetaxel and 25 g of ethylenediaminetetraacetic acid were weighed and added to a suitable polyethylene glycol 400, 80. 〇 Heat shearing and dissolution, then make up to ML with polyethylene glycol 400; add 〇.3g of needle with activated carbon, adsorb at 25 C for 30 minutes, then filter with microporous membrane, dispense , Sealed, sterilized with a rotary autoclave at 115 〇c for 3 , minutes, ie more paclitaxel solution. Commercially available emulsion. [Specifications]: 250 ml, 30% long-chain fat emulsion; [batch number] \GM0810022; [manufacturer]: Huarui Pharmaceutical Co., Ltd. When administered, the volume ratio of the drug solution to the commercially available emulsion is 丨:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled. Example 29 Docetaxel intravenous injection Preparation of drug solution: 2.5 g of docetaxel and 25 g of barium lactate were weighed and added to an appropriate amount of polyethylene glycol 400 t '80. The crucible is heated and sheared and dissolved, and then the solution is set to 100 liters with polyethylene glycol 4; and 3 g of the needle is added with activated carbon at 25. The mixture was adsorbed for 30 minutes at a temperature of krypton, then filtered through a microporous membrane, dispensed, sealed, and sterilized with a rotary autoclave. . Sterilize for 3 minutes, i.e., more paclitaxel solution. Commercially available emulsion: [Specification]: 250 ml, 3〇% long-chain fat emulsion; [batch number]: GM0810022; [manufacturer]: Huarui Pharmaceutical Co., Ltd. 38/42 201219055

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. [Simple description of the diagram] None [Key component symbol description] None 39/42

Claims (1)

201219055 VII Patent application scope: [A taxane drug solution, characterized in that the purple color contains yew wire, a chelating agent and a solvent. For example, the ratio of the sputum and the music solution to the yew-type drug solution of the patent scope is: , and each of them becomes a taxane 1 to 8% (g/ml) chelating agent 0.05 to 2% ( g/ml) The remainder are the aforementioned solvents and other pharmaceutical excipients which may be added if necessary. For example, the ratio of the Taxus Hospital drug solution in the second paragraph of the patent application is: 1 to 6% (grams per milliliter) of the chelating agent for each of the cleavage agents 〇·]~1% (g/ml) 4 It is the aforementioned solvent and other pharmaceutical excipients which are added as necessary. The taxanes dissolved in any of the third to third items: the scallops or the docetaxel. ', the yew-burning drug of any one of the items 1 to 3, the sodium, the sodium sulphate, the citric acid, the milk, the mixture of more than 7 kinds; or It is selected from the group consisting of lime, . ^ - aminic acid or disodium edetate. Such as the scope of patent application! 〇 _ , the liquid, wherein the solution is selected from the group consisting of a taxane medicinal glycol diol 300, a polyethylene glycol in water, Iti di glycerol, absolute ethanol, and a solution. A mixture of sputum, preferably a method for preparing a yew-burning drug 40/42 201219055 of the first to sixth items of the polyethylene glycol application (4), characterized in that the yew is burned. The drug and the infusion are dissolved in the solvent to add other pharmaceutical excipients as necessary. For example, the preparation method of the scope of application of the patent scope '1' is buried in the purple city paving and chelating agent and added to the note (4) the spray is sprayed at 5 〇 赖 或 or cut and donated, New (4) solvent to volume. Add 0.01% ~3% g / ml of the needle with activated carbon, adsorption at 25 ° heating temperature for 15 to 12G minutes, then county, sub-package, sealing σ disinfection, that is. The method of preparation of the seventh or eighth aspect of the invention, wherein the taxonomy product is paclitaxel or docetaxel. ', Yuan-species yew-burning pharmaceutical composition, which is prepared by the two parts of the purple-reducing material and the _ two-component agent as in the first to sixth items of the patent application; The ratio of J: 10 to i: 100 is used to mix the taxane drug solution with the emulsion. * A pharmaceutical combination package characterized by being packaged by a combination of a taxane drug solution and an emulsion as in the scope of claims ii to 6 of the patent application, the two agents being separately placed in a container and placed separately , the combination is packaged in one. A pharmaceutical combination package characterized in that a combination of a taxane drug solution and an emulsion is packaged, and the two agents are separately loaded in a container, placed separately, and packaged together, wherein the taxane drug solution or emulsion is Containing a chelating agent' content of 0.05 to 2% (g/ml). An emulsion containing a chelating agent, characterized in that the chelating agent is contained in an amount of 0.05 to 2% (g/ml). The chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, and ethylene. Mixture of one or more of disodium tetraamine, trisodium ethylenediaminetetraacetate and disodium citrate 41 /42 13 201219055 201219055 IV. Designation of representative drawings: (1) The representative representative of the case is: None (2) The symbol of the symbol of this representative figure is simple: 5. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: 2/42