TWI246927B - One kind of concentrated emulsion containing Paclitaxel (taxane) - Google Patents

Abstract

This invention is aimed at an improvement of the Paclitaxel intravenous injection preparation (Taxol) approved by the United States FDA, and provides a product with less side effects and more convenience when being used. The product is an anhydrous concentrated injection without containing Cremophor EL. The formula only contains nontoxic organic solvent and surfactant. When being used, first it is injected into a lipid emulsion capable of being injected to make the active ingredient (Paclitaxel) inlay into the original drip fat nucleus, and thus an injection emulsion containing Paclitaxel is formed.

Description

1246927

, invention description (A7 B7 10 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 Pacific paclitaxel (pacmaxe_ approved by ten people in 1992, through the new molecular species for the anti-mineral foods, Ρ indicates that The competent authority prioritized the review and confirmed that there is a significant outlook on 1. The development and listing of paclitaxel, '= the most exciting achievement in anti-cancer drug research in the past 10 years. It's: The era is groundbreaking, so far there is still no changeable color in the music, which is commonly known as cranberry (doxorubicin), and the main component is platinum (dsplatin). ^ In fact, Pacific paclitaxel whispered as early as 196 years The bark of the yew bar records the growth zone of L-Pacific yew. The New Zealand is on the northwestern shore of the Pacific Ocean. In western Canada, the source is very limited. It is estimated that it takes an average of two to six sides to treat the patient. The tree grows and takes time. It takes 30 to 100 years. In addition, the felling of the yew is quite controversial by environmentalists. Although these difficulties are;,,:: After the X, the bruises are improved, but also The time to market for this anticancer drug has been slowed down. The alternative source of paclitaxel has been a concern of many people. Later, it was found that the yew grown in mainland China can also extract the same ingredients. The development of paclitaxel in the early days has not been smooth. After overcoming the problem of the source of the drug, during the first-stage human trial, the drug was almost terminated in the first phase of the clinical trial (Phase J) due to the discovery of a severe allergic reaction. Symptoms of this allergic reaction include difficulty in breathing, Hypotension, angioedema, and systemic urticaria are similar to those caused by blood-stained contrast agents. Later, multiple drugs are used beforehand (please read the notes on the back and fill out this page) - order, 3⁄4 ^ paper scale applies to Chinese national standards (CNS) A4 size (210X297 public sauce) 1246927 A7

V. Description of invention (2) The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative printed and prevented the injection rate of the drug, which reduced the incidence of this allergic reaction. As for the allergen, it was the solvent used in the preparation, not Pacific purple cedar itself. Pacific paclitaxel has a very high water repellency and is very difficult to dissolve in water (1) at 1〇# g/rnL. Therefore, special cosolvents must be used to make injections. This difficulty is also one of the obstacles to the initial development of drugs. The only approved prescription is an intravenous injection (Taxol@) developed by Bristol-Myers Squibb, and the 10 co-solvent in this product is ethanol and Crem〇ph〇r EL mixed in a ratio of 50:5. The remophor EL is - Non-ionic strong interface activity is Qi!, so it is also a mother 〖Beibei.> After the main shot will cause severe allergic reactions, there have been reports of death. In order to prevent these side effects, users must do pre-drug treatment and preventive treatment That is, taking corticosteroid, dipllenhydramine, blocker, etc., and then injecting paclitaxel intravenously after 30 minutes. In addition to causing severe allergic reactions, it It also makes the preparation, administration, stability and compatibility of drugs a challenge for physicians, nurses and pharmacists. For example, to prevent it from toxic plasticizers from PVC The plastic is dissolved out. No pvc-containing utensils can be used during the injection. The package 20 contains a drug container, an IV sleeve, a transition film inside the tube (must be used for the purpose of preventing nits) and an intravenous insertion device. For medical personnel, this It is a drug that is difficult to serve. Obviously, the shortcomings of paclitaxel injections mainly come from Crem〇ph〇r EL. Therefore, this disadvantage should be removed by replacing different solvents.

Aw Μ--------tr----------Aw. (Please read the notes on the back and fill out this page) 3 1246927 A7 V. Inventions (3) B7 10 15 Economy Department of Intellectual Property Bureau employee consumption cooperatives printed 20 rations of the production of P, L cited rabbits. This can make patients do not need to do pre-drugs f: f f increases the convenience of drug use 四 四 (4) I, there are quite a number of scientists and research units to carry out this type of preparation efforts. In the method of paclitaxel injection, the most well-known is the liposome agent: but there are reports that the yew _ old in a few weeks of storage _ the production of the sacred temple / so progress to the micro-lipid into a powder of the crystal, For storage. The complicated 1 body plus the time-consuming and resource-consuming cold and thorns makes the product cost high and loses its pre-modification significance. Tian Ran's simple process and improvement methods have also been proposed by researchers. For example, some organic solvents are substituted for C 峨 EL, such as dimethylacetamidc (DMA) > N-methylpyr〇〇lidinone (NMP) #^l ★ 曰 (10) alcohol solubility 1,2. Miscellaneous has a simple manufacturing advantage, but these organic solvents are still quite toxic and, therefore, are not widely accepted. A more specific method is to make paclitaxel and other non-toxic substances into a complex such as Neil Desai et al. to adsorb paclitaxel by human plasma protein to obtain a non-toxic and water-soluble paclitaxel injection 3. Compounds such as paclitaxel, which are poorly soluble, are often formulated as emulsions in pharmacy. Therefore, a considerable number of scientists are focusing on this approach. For example, Panagyi〇tis, ρ· et al, Kaufman, Rj· et al., chu, ρΜ—all have very outstanding research results 4'5,6. However, the preparation of the emulsion is relatively complicated compared to the liquid solution of Tax1®, and the cost is relatively high. In addition, the emulsion usually contains the size of the staple paper. _ Home Standard (CNS) A4 Regulation (10) X Norman Hair) 1246927 A7 B7 V. Invention Description (Doo) A considerable proportion of water, which causes the long-term preservation of paclitaxel Lowering, and also like the liposome dosage form, the product has crystallized doubts during the shelf life. (Please read the notes on the back and fill out this page) 5 References 1. Andersson, B, Parenteral Paclitaxel in a Stable Non-toxic Formulation, USP 5,877,205, March 2, 1999 2. Hausheer, FH·, Murali, D And, Seetharamulu, P., USP 6,040,330 Pharmaceutical Formulations of Taxanes, March 21, 2000 3. Desai, NP·, and Soon-Shiong, P., USP 6,096,331 Methods and Compositions Useful for Administration of Chemotherapeutic Agents, Aug. 1, 2000 15 4. Panayiotis, P. et al? W002/26208 Emulsion Vehicle for Pooly Soluble Drugs, April 4, 2002 5· Kaufman, JR, and Richard, TJ, USP 5,616,330 Stable Oil-In-Water Emulsions Incorporating a Taxine (Taxol) and Method of Making Same, April 1? 1997 6. Chu, IM, and Wang, TR, USP 6, 348, 491 Oil-In-Water Emulsion for Encapsulation Paclitaxel, Feb. 19, 2002 25 SUMMARY OF THE INVENTION It is to create a modified paclitaxel and its near-injection injection without Cremophor EL, which makes the toxicity and side effects greatly reduced, and it is more convenient to take. More important It has the simple manufacturing characteristics to increase the feasibility of the printing and manufacturing of the consumer cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Such inventions will be able to benefit patients and improve the quality of medical care. The present invention is directed to the original The FDA approved paclitaxel intravenous preparation (Taxol0) has been improved to become a product with fewer side effects and more convenient use. 5 The paper size is based on the standard of the country (CNS) A4 specification 121〇x 297 public)) — ----- 1246927 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (5) Due to the inclusion of Cremophor EL in Taxd@, the side effects and inconvenience of the product are caused, and the present invention is Design a new formulation of 5 paclitaxel injection preparation without Cremophor EL. Other pharmaceutically acceptable excipients are used in the prescription. The product of the present invention will be an anhydrous concentrated paclitaxel solution which, when administered, will be diluted with the injectable intravenous solution to the use concentration, except that the product is diluted with an intravenous lipid emulsion. At the same time, like Taxol®, the product will have similar ideal stability with an anhydrous solution. In addition, in the process, 10 is like TaxoH^, but the solvent is simply mixed, and the difficulty of production should be similar. However, such a Cremophor-free EL product will significantly reduce the side effects of the original paclitaxel injection formulation Taxd® and increase its ease of use. Paclitaxel or other taxanes are mostly water-repellent compounds and therefore are poorly soluble in water but soluble in organic solutions or mixtures thereof. For example, 15 Cremophor EL, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), ethanol, Tween, polyethyleneglycd (PEG), propylene glycol (propyiene giyc〇1) , PG) and so on. However, once mixed with water, the paclitaxel compound precipitates from the solvent and precipitates. Even in a commercial product of TaxoP containing the nonionic strong surfactant Crem〇ph〇r 20 EL, precipitation occurred after 27 hours of dilution in the intravenous infusion. Further, since the paclitaxel compound is a water repellent substance, it can be dissolved in an oily solvent. For example, 〇leic acid, saffl〇wer oils, corn oil, SOybeen oil, and the like. The present invention is an anhydrous mixture of a paclitaxel compound dissolved in an organic solvent and an emulsifier. When the paper size is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) — — — — — — — — — — I --------1T---------- (Please read the notes on the back and fill out this page) 1246927 A7 V. INSTRUCTIONS (έ 5 10 15 20 Re-injection when in use The dilution and mixing of the intravenous lipid emulsion product enables the paclitaxel compound to form an injectable emulsion containing paclitaxel by substituting the emulsified fat in the human venous fat-fed emulsion product. Lipid emulsion products are very common, for example, Lip〇syn@, Soyacaf, Travemulsbn, IntraHpid@. These products can be used as intravenous emulsions for the preparation of the present invention. The present invention utilizes the above principle to develop a Crem-free (3ph) 〇r乩 intravenous injection prescription. Firstly, organic solvent or interface activity to dissolve paclitaxel compounds. Re-dissolved into auxiliary surfactants, such as K〇md〇n, P_nic acid, egg fat ( Leci Thin) or other stone _ (ca _ _ _ mouth mouth, etc.. These mixed agent manufacturing process only needs a general simple search device, no need to shut down any special equipment. Because this no water test does not contain Moisture, therefore, the paclitaxel compound can be stored therein. According to the accelerated stability test of the towel of the present invention, the product can be stored at a temperature of room temperature, and can be stored for more than one year. The liquid can be directly injected into the humanized lipid chyle, which can be used in the injection of paclitaxel. Within a few hours after the adjustment, paclitaxel is very stable in this emulsion without any degradation or crystallization. The droplet size has not been changed due to the addition of paclitaxel concentrated emulsifier. In fact, paclitaxel is a light-sensitive substance, and the emulsion dosage form can provide the resistance of this product. The thief is more stable in use. And the product of the invention can have a paclitaxel concentration of up to 30 mg/mL, which is easy to order. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1246927

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, diluted with α3~i · 2 mg/mL using an intravenous lipid emulsion. This range covers the doses required for paclitaxel to treat cancer patients. From this, it can be seen that the product of the present invention will be comparable to the original Taxol® product in the production and clinical adjustment of the product, but the side effect is lower and the paclitaxel injection is improved. DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is to design a new formulation of Pacliphor EX-free paclitaxel injection 10 formulation to make the new prescription product safer and more convenient. Paclitaxel is a very low solubility compound, so the nonionic strong surfactant 〇Γεηι〇ρΗ〇Ι· el is added to the commercially available Tax〇p formulation to increase its solubility. However, Cremophor EL itself is a toxic substance. It can cause abnormal electrophoresis mode of liposuction and lipoprotein (lip0pr〇tein), 15 degrees of blood viscosity change, dyspnea, hypotension, angioedema and whole body after injection. Sexual acne, even without prophylactic shock, is not suitable for use in pharmaceutical preparations. The use of low solubility compounds as emulsions is a common practice in the absence of safer solvents. In addition, paclitaxel is a pair of light-sensitive compounds, and the emulsion dosage form will provide a light-blocking function. Therefore, paclitaxel should be used as an emulsion, which should be an appropriate choice in pharmacy 20 . Making a stable intravenous emulsion formulation is not an easy task. First, the size of the droplets must be considered, whether it can be injected into the body; whether the volume of the particles changes during the storage and the phenomenon of creaming. At the same time, the production process of the emulsion is cumbersome and time consuming, and it is more expensive in terms of manufacturing cost. Whether the drug is suitable for 25 paper quality standards (CNS) A4 specification (210 X 297 public) ' ---~: --- 丨—-------.—丨丨—tr---------- (Please read the notes on the back and fill out this page) 1246927 A7 B7 Ministry of Economic Affairs Intellectual Property Office Consumer Cooperatives Print 5, Invention Description (times) Factors such as positive value in economics should be carefully considered. The invention utilizes a concentrated emulsifier to dissolve and carry the paclitaxel medicine. When the emulsifier in the concentrate is used, the paclitaxel is originally implanted in the emulsion of the intravenous lipid emulsion. The intravenous lipid emulsions used have a number of commercial products that are very convenient to purchase and do not require complicated homemade engineering or additional conditioning. In fact, the process and the difficulty of the preparation of the product of the present invention and the original commercially available product Tax 〇 1@ formulation are not at all ambiguous. Therefore, the present invention has a relatively high feasibility in mass production and commercialization. EXAMPLE 1 This example illustrates the preparation of a concentrated paclitaxel-free solution using the formulation system of the present invention, which is listed in Table 1. 15 Table 1 Paclitaxel concentrated solution composition prescription

Compound dose Paclitaxel Paclitaxel 1.8g DSPC lOg Tween 80 45 g Kollidon 2g PEG 200 Ethanol qs· 100 mL DSPC Abbreviation for Udiacyl-sn-glyceroUphosphocholine This paper scale applies to China National Standard (CNS) ST^ (21〇x 297 mm) _ 〜----- ------------·装------丨---------AW (Please read the notes on the back and fill out this page } 1246927 A7 B7 V. INSTRUCTIONS (In the production, DSPC, Tween 80, Kollidon, PEG 200, Ethanol, etc. can be mixed and placed in an 8 cc water bath to sway to dissolve all the excipients. When the above mixture is completely After dissolution, the main component, paclitaxel, is added to the mixture and shaken in a water bath at 80 ° C for 2 hours to obtain a paclitaxel anhydrous concentrated solution. The paclitaxel is stored in the concentrate at 25 ° C ± 2 ° C and 40 ° C. At ±2°C, there is no obvious degradation in June (see Table 2;). 10 Time concentration mg/mL 25°C±2°C 40°C±2°C Start 1831+0,22 1831+0 , 22 first month 18,91+0*15 18*60+031 second month 18.11+037 18.46+0.25 fourth month 1844+0.13 18,81+0.29 sixth month 18.48+0.21 18.0 7 Earth 0.23 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed the above-mentioned 25 mL concentrated solution into a 250 mL intravenous lipid emulsion (Intralipid® 20%) and shaken for about 1 minute to allow the product to be completely mixed. In order to study the stability and crystallization rate of paclitaxel in this product, the paclitaxel intravenous emulsion was filtered through a 〇.45_ filter, and the difference in product concentration before and after filtration was detected to detect the rate of crystallization. This test proved that after modulation 24 There is no crystallization in the hour (see Table 3). It can also be seen from Table 3 that the particle size of the droplets in the product has remained at 150 to 2 〇〇 nm for 24 hours and has not increased significantly. Or the trend of reduction. In fact, there is no significant difference between the size of the emulsion droplets of the original intravenous lipid emulsion. This product can be administered to patients by intravenous drip. 15 —1—!—丨— ·Install·--------1T---------- (Please read the notes on the back and fill out this page) 10 1246927 A7 B7 V. Invention Description (> Table 3 Time Start : 4 hours 8 hours L2 hours 18 hours 24 hours purple Emulsion stability test results of the concentration of alcohol

Mg/mL particle size before filtration 1.71±0.02 NA NA 1.73±0.04 NA 1.77±0.07 After filtration 1.79+0.04 1.74±〇.〇8 1.77±0.12 1.72±〇.〇6 1.70±〇〇9 1.72±0.12

Intralipid® 20% 164.2 ± 30.9 171.4 ± 53.0 178.4 ± 51.7 158.4 ± 63.4 164.1 ± 71.4 158.4 ± 61.4 Paclitaxel emulsion ' 152.8 ± 73.1 161.3 ± 61.8 166.1 ± 42.4 172.8 ± 51.3 155.4 ± 81.4 177.0 ± 58.4 * with laser scattering ( Laser scattering) to detect (please read the back note first and then fill out this page) 5 Example 2 This embodiment is not necessary to use a single grease (phospholipid) in the prescription system of the present invention, and different kinds of phospholipid can also be used. Mixtures (such as CentiOphase31) to prepare a concentrated solution of anhydrous paclitaxel. The prescriptions are listed in Table 10. 4 ► Pack---------Booking i Boxing Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed

Compound dose Paclitaxel 3g Ccntrophase 31 20 g Tween 80 30 g Ethanol- 100 mL 11 1246927 A7 B7 V. Description of the invention (u 5 Preparation method Centrophase 3 Bu Tween 8〇, Ethan〇1, etc. can be mixed and placed at 80 ° C Shake in a water bath to dissolve. After completely dissolving, put it into the 叩 ( (4) 〉, 丨 液 solution to prepare a paclitaxel anhydrous concentrated solution ^ The purple transfer concentrate is stored at 25 ° C ± 2 ° C and 40 ° C ± 2 There is no obvious degradation in °C within 6 months (refer to Table 5). 10 Time concentration mg/mL 25°C±2°C 40°C±2°C Start 3231+0,22 3231+0.22 First Month 32*91±035 32.60+031 Second month 33·11±0·30 3246+0,25 Fourth month 32.44+0.13 32.01+0.29 Sixth month 32,48+0.21 32.17+0.23 (please first Read the notes on the back and fill out this page) ••装·

· IIII Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 5 mL of the emulsified concentrated solution of the above-mentioned configured Yuancheng into 5 mL of Jingyue Injection Lipid Emulsion (Intralipicf 10%), shaken for about 1 minute to enable the product to 15 mixed. In order to study the stability and crystallization rate of each cedarol in this product, the crystallization rate was determined by using the 过渡45 丨 membrane transition preparation, the cedar alcohol intravenous emulsion, and then measuring the difference in product concentration before and after the transition. This test proved that no crystallization occurred within 24 hours after preparation (see Table 6). In addition, it can be seen from Table 6 that the particle size of the droplets in the product has been maintained at 150 to 200 nm for 24 hours, and there is no tendency to increase or decrease slightly. This product can be administered to patients by intravenous drip. 12 The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1246927 A7 B7 V. Invention description (U) Color hexaerythritol emulsion stability test result OQ —- concentration mg/mL particle size ran lucky filter Pre-filtered Intralipid® 20% paclitaxel emulsion starts 0.28±0.02 0.28±0.02 174.2138.1 165.6±35.8 4 hours NA 0.29±0.03 151.4±53.7 181.3±46.1 8 hours NA 0.29±0.02 184.1±74.1 158.6±32.8 12 hours 0.29± 0.04 0.29±0.03 177.2±48.0 178.3±48.8 18 hours NA 0.29+0.02 156.8±37_1 159.2±68.1 24 hours 0.29±0.03 〇.28±0.04 178.7±68.3 164.0±38.8 Laser scattering to detect (please Read the notes on the back and fill out this page.)

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives This embodiment is a method for preparing a concentrated paclitaxel-free solution of non-enhancing agent (Hlb>1 〇) using the prescription system of the present invention, and the final product still has excellent stability. The 10 prescription details are listed in Table 7. Table 7 Paclitaxel emulsified concentrated solution composition prescription

Compound content Paclitaxel 1.8 g Phospholipon 90G 22 g Propylene Glycol 40g Ethanol q, s. 100 mL Formulated as mixed Phospholipon 9〇G, Pn) pylene oiyco 卜 Ethanol This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) 1246927 A7 B7 V. Invention description (13 ------ etc. Mix and put in 8 (arc in the rc water bath and mix the mixture to prepare anhydrous purple (4) concentrated miscellaneous. t solution, then put people in paditaxel At 25 °C ± 2 °C and 40 °C ± 2 cc, within 6 months, the ratio of < ^ paclitaxel concentrate is stored in VIII. U month shows the phenomenon of degradation (see Table 8 for the first month of the first month) Month of the fourth month of the fourth month of the month 10 cedarol emulsification concentrated solution>^ concentration^"i〇^C 17·58±0,30 17·4〇±〇·31 18*63±〇ji 18*25 ±〇,58 ϋ^7±0.73 25°C±2°C 17.58+030 18.01+0.57 17.15+033 18.29+034 18.13+0.69 Please read the notes of the back © and then fill out the page binding 15 Ministry of Economics Printed by the Bureau of Property and Staff of the Property Bureau. 20 Inject the above-mentioned 20 mL emulsified concentrated solution into the intravenous injection. Spray the lipid emulsion (Int aging age), shake for about 丨 minutes to make the product completely complete this a research |, the stability and crystallization rate of cedar in this product, using the intravenous transfusion of recorded drug The emulsion was tested for the rate of crystallization before detecting the difference in product concentration before and after filtration. This test proved that no crystallization occurred within 24 hours after preparation (see Table 6). The milk in the product can also be seen from Table 9. The particle size of the droplets has remained at 150 to 200 nm for 24 hours, and there is no obvious increase or decrease. This product can be applied to patients by intravenous drip. 14 This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) # 1246927 A7 B7 V. Invention description (viuse) Table IX Paclitaxel emulsion stability test results concentration mg/mL particle size nm^ time filtered before filtration Intralipid® 20% paclitaxel emulsion Start 0.73±0.03 0.73±0.06 155.0±51.6 167.2±58.1 4 hours NA 0.74±0.04 159.4±67.3 171.9±76.3 8 hours NA 0.76±0.04 164.8±46.3 182.7±38.8 12 hours 0.74±0.03 0.74±0.06 157.9±51 .8 158.0±58.1 18 hours NA 0.74±0.05 178.6±33.9 165.5±44.0 24 hours 0.74±0.05 0.74±0.07 166.2±58.7 171.4±52.6 5 *Detecting the spirit and scope of the invention by laser scattering It is only limited by the scope of the following patent application, and is not limited to the above specific examples. 10 (Please read the notes on the back and fill out this page) I --------Book ---------· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 15 Paper Scales for China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

Scope of application for patents • A concentrated emulsifier containing taxanes, which is free of hydrates and oils, contains: a, 5% to 75% of phospholipid, b 0.1% to 50% of an HLB surfactant of not less than 1〇, c, 0*1% to 50% of a mixture of propylene glycol (pr〇pyjenegiyC〇i) and polyethyleneglycol, wherein polyethylene The dilute diol has an average weight molecular weight of from 200 to 4,000, d 〇 ♦ % to 40% of a taxane or a derivative thereof, and the concentrated emulsifier can be used after being diluted with a grease or an emulsion. 2. The concentrated emulsifier according to claim 1, wherein the fat or oil which can be used after being diluted with a fat or oil can be triglycerides, propylene glycol diesters or a mixture thereof. 5 3. The concentrated emulsifier of claim 1 of the scope of the patent application, wherein the grease which can be diluted by the grease can be an approved intravenous fat product. 4. A concentrated emulsifier as claimed in claim 1, wherein the emulsion which can be diluted by the emulsion may be a commercially available intravenous lipid emulsion product, Liposyn®, Soyacal®, Travemulsion® or intralipid®. 20 5. A concentrated emulsifier according to the scope of the patent application, wherein the term is 〇1% to 5% by weight of propylene glycol. The Central Bureau of Standards of the Ministry of Economic Affairs, the Consumers' Cooperatives, printed the emulsifier of the first paragraph of the patent scope of the patent, which is 〇%% to 50% of polyethylene glycol (p〇lyethyleneg丨ycd), And its level is from 200 to 4000. 25 7. If you apply for a patent scope! A concentrated emulsifier which can be used by being diluted with a stable oil for human injection or a stable emulsion for human injection. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)