TW200526269A - Fat emulsion containing paclitaxel or docetaxel - Google Patents

Abstract

This invention provides a stable fat emulsion with paclitaxel or docetaxcel in a dissolved or dispersed state and has a pH in an acid region. Further, it provides a stabilizer for using in the fat emulsion. Furthermore, it also provides a method of enabling a fat emulsion containing paclitaxel or docetaxcel in a dissolved or dispersed state to be stable at a pH in an acid region. The fat emulsion comprises at least one active ingredient selected from the group including paclitaxel and docetaxel, an oily ingredient, and an emulsifying agent. Moreover, it also comprises a stabilizer, e.g., phosphatidylglycerol, selected among specific phospholipids, phospholipid derivatives, and fatty acids.

Description

200526269 IX. Description of the invention: [Technical field to which the invention belongs 3 Field of the invention The present invention relates to a stable fat emulsion containing paclitaxel or 5 paclitaxel in a dissolved or dispersed state and having an acidic pH, and a method for preparing the same. Range of stabilization methods), and stabilizers used to prepare the fat emulsion. BACKGROUND OF THE INVENTION For intravenously, orally or enterally administered active ingredients (active ingredient compounds) made into injections, each has a stable pH range. Paclitaxel and docetaxel, known as antitineoplastic agents, are not stable in alkaline or neutral solutions, but have a pH of less than 7, especially at about 6. The acidic range around or below 6 15 is stable, so it is always formulated in this acidic range (see Patent Document 1). In the past, when the active ingredient was dissolved or dispersed to prepare an injectable preparation, attempts have been made to use fat emulsions as carriers. However, related fat emulsions, especially in the acidic range, have low emulsification stability. Therefore, if the fat emulsion is used to prepare a fat emulsion having an acidic pH, the preparation will be destroyed by the emulsifier or a bilayer separation phenomenon in a short time. However, if it is prepared into a fat emulsion having a neutral or even alkaline pH, although the obtained formulation will not be as poor in emulsification stability as the formulation with the above-mentioned acidic pH, the activity of the active ingredient itself will rapidly decrease. 5 200526269 A major lack of decline. As stabilizers for fat emulsions, polyethylene oxide hardened castor oils 50 and 60, polysorbate 80 and the like are known. For example, Patent Document 2 discloses a method of mixing a fat emulsion and an injection in the presence of a basin without using these surfactants as stabilizers (see Patent Document 2). However, the use of the aforementioned polysorbate 80 as a food additive has not yet been approved in Japan, and its use is problematic in terms of safety. In addition, polyethylene oxide hardened sesame oil 50 and 60 are also known to be one of the causes of side effects such as shock anaphylaxis (anaphylaxis chock), which also has safety problems (Patent Document 3, especially (See page ^^-Deng Xing). In addition, it is known that the use of these nonionic surfactants to prepare fat emulsions is accompanied by problems such as crystal precipitation (see Non-Patent Document 1). 15 There have been proposed attempts to apply the stabilization method of the fat emulsifier described in Patent Document 2 to a method of solubilizing or dispersing paclitaxel in a fat emulsion (see Patent Document 3). However, the fat emulsion obtained by the method described in this document cannot satisfy the stability in the acidic range. That is, the fat emulsion obtained by this technology is being prepared? 11 At about 20 5 · 5-6, coarsening of emulsified particles (fat particles) may occur, and emulsification stability is significantly reduced. However, in the case of a fat emulsion prepared to be alkaline or neutral, there is a case where Pacific pacific and paclitaxel rapidly lose their activity, and it is not suitable for application in the field of actual pharmaceuticals. Such a situation makes it necessary to utilize the dissolution or dispersion of paclitaxel 6 200526269 or European paclitaxel to exert the required solubilization or dispersing effect from the past, and the safety of side effects and the loss of active ingredients Solubilizers or dispersants (stabilizers) that do not have any problems in terms of activity, etc., and techniques that use such stabilizers to solubilize or disperse pharmaceutical agents have not yet been developed. . [Patent Document 1] US Patent No. 6,071,952 [Patent Document 2] JP 08-127529 [Patent Document 3] US Patent No. 5,616,330 Specification 10 [Non-Patent Document 1] Adam, JD, et al ., (1993), "Journal of the National Cancer Institute Monographs ^, No. 15, p. 141-147 [Summary of the invention] The object of the present invention is to provide a paclitaxel or 15 paclitaxel that can be applied to A novel stabilizing agent that is soluble or dispersible, and a technology that uses the stabilizing agent to solubilize or disperse the above-mentioned agent to obtain a stable fat emulsion. Means to solve the problem The result of intensive research by the inventors, etc., A novel stabilizing agent that is quite effective for the solubilization or dispersing of Taiping 20 taxol or paclitaxel in a fat emulsion has been discovered. In addition, the inventors have established the use of this stabilizing agent to solubilize paclitaxel or paclitaxel or The technology of dispersing in acidic fat emulsion, thus inventing the product containing paclitaxel or Paclitaxel is a fat emulsion that is stable in the acidic range. The present invention 7 200526269 is based on this knowledge and is the result of further research. The present invention provides the fat emulsion described in the following item M9, which is used in the fat ceremony. Stabilizing agent, use of the stabilizing agent, and stabilizing method of the fat emulsion. 5 Item 1 A fat emulsion containing at least one active ingredient selected from the group consisting of paclitaxel and paclitaxel, An oily ingredient, an emulsifier and a stabilizer, and a stable fat emulsion having an acidic pH, characterized in that the stabilizer is (a) from a fatty acid that forms an esterification in a glycerol part to a carbon number of 10-22. Of chain-like or branched-chain saturated or unsaturated fatty acids, it consists of phosphatidylglycerol, phosphatidic acid, phosphatidylinositol, and phosphatidyl-serine ), At least one selected from the group consisting of phospholipids, (b) phospholipids, 15 ethanolamine (phophatid) modified with polyalkylene glycol ylethanolamine), and at least one of linear or branched chain saturated or unsaturated fatty acid phospholipid derivatives having a carbon number of 10 to 22 that forms a deliberate fatty acid based on glycerol, (c) from carbon number At least one selected from the group consisting of linear or branched chain saturated or unsaturated fatty acids of 10-22, or at least two of (d) more than (a), (b), and (c) Mixture, and in the fat emulsion, the stabilizer (a) is 0.01-1 w / v%, the stabilizer (b) is 0.01-1 w / v%, and the stabilizer (c) is 0.05-5 w / v A concentration of% is present. Item 2 The fat emulsion according to item 1, in the fat emulsion (1) the active ingredient is present at a concentration of 0.01-0.5 w / v%, 200526269 (2) the oily ingredient is present at a concentration of 2-20 w / v% (3) Emulsifier is present at a concentration of 0.4-10 w / v%. Item 3 The fat emulsion according to item 1 or item 2, wherein the acidic pH is less than 7 and is 4 or more. 5 Item 4 The fat emulsion according to any one of Items 1 to 3, wherein the stabilizer is saturated from a linear or branched chain having 10 to 22 carbon atoms in the fatty acid that forms an esterified fatty acid in the glycerol portion. Or at least one of the phospholipids selected from the group consisting of phospholipids, glycerol, phosphatidic acid, phosphoinositide, and phospholipids serine. 10 Item 5. The fat emulsion according to any one of items 1 to 3, wherein the stabilizer is a saturated or straight-chain or branched-chain saturated fatty acid that forms an esterified fatty acid in a glycerol moiety. Or at least one of the phospholipids selected from the group consisting of phospholipids, glycerol, phosphatidic acid, phosphoinositide, and phospholipids serine. 15 Item 6. The fat emulsion according to any one of items 1 to 3, wherein the stabilizer is selected from disearoyl phosphati-dylglycol, dipalmitylphospholipid glycerol ( dipalmitoyl phosphati-dylglycol), dimyristoyl phospha-tidylglycol, dioleoyl phosphatidyl-20 glycol, distearoyl phosphatidinic acid ), Dipalmitoyl phosphatidinic acid, dimyristoyl phosphatidinic acid, dioleoyl phosphatidinic acid, distearylphosphine Disearoyl phophatidylinositol, dipalmitoyl lipophyllum 9 200526269 dipalmitoyl phophatidylinositol, dimyristoyl phophatidylinositol, dioleoyl phophatidylinositol, dioleoyl phophatidylinositol, Disearoyl phosphtidylserine, dipalmitoyl phosphtidylserine, dipalmitoyl phosphtidylserine And at least one selected from the group consisting of dimydstoyl phosphtidylserine and dioleoyl phosphtidylserine. Item 7 The fat emulsion according to any one of Items 1 to 3, wherein the stabilizer is distearylphospholipid / glycerol. Item 8. The fat emulsion according to any one of Items 4 to 7, wherein the stabilizer is present in the fat emulsion at a concentration of 0.03-1 w / v%. Item 9: The fat emulsion according to any one of items 1 to 3, wherein the stabilizer is a phosphatidylethanolamine 15 modified with polyalkylene glycol, and a fatty acid of S form is formed in the glycerol part. It is at least one kind of linear or branched chain saturated or unsaturated fatty acid-filled lipid derivative having 10 to 22 carbon atoms. Item W The fat emulsion according to any one of items 1 to 3, wherein the stabilizer is a phospholipid ethanolamine 20 modified with polyalkylene glycol having an average molecular weight of 1,000 to 5000, and an esterification is formed in the glycerol portion. The fatty acid is at least one kind of phospholipid derivative of a linear or branched chain saturated or unsaturated fatty acid having 14 to 18 carbon atoms. Item 11 The fat emulsion according to any one of items 1 to 3, wherein the stabilizer is selected from distearylylphosphatidylethanolamine polyethylene glycol 5000 10 200526269 (distearoylphophatidylethanolamine polyethyleneglycol 5000), distearylyl At least one phospholipid derivative selected from the group consisting of phospholipids ethanolamine polyethylene glycol 3000 and distearylphospholipids ethanolamine polyethylene glycol 2000. 5 Item 2 The fat emulsion according to any one of Items 9 to 11, wherein the stabilizer is present in the fat emulsion at a concentration of 0. M w / v%. Item 13. The fat emulsion according to any one of items 1 to 3, wherein the stabilizer is selected from the group consisting of linear or branched chain saturated or unsaturated fatty acids having 10 to 22 carbon atoms. At least one. 10 Item 14. The fat emulsion according to any one of items 1 to 3, wherein the stabilizer is selected from the group consisting of linear or branched chain saturated or unsaturated fatty acids having 10 to 20 carbon atoms. At least 1 species. Item 15. The fat emulsion according to any one of items 1 to 3, wherein the stabilizer is selected from oleic acid, isomyristic 15 acid, isopalmitic acid, Selected from the group consisting of decanic acid, lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid At least one of the fatty acids. Item 16 The fat emulsion according to any one of Items 13 to 15, wherein the stabilizer in 20 is present in the fat emulsion at a concentration of 0.05-2 w / v%. Item Π Use of the following stabilizers (a) to (d) for the production of the fat emulsion according to any one of items 1 to 16: (a) From the fatty acid that forms an esterification in the glycerol part to a carbon number of 10 Of linear or branched chain saturated or unsaturated fatty acids of -22, at least the phospholipids selected from the group consisting of squid lipoglycerin, 11 200526269 phosphatidic acid, phospholipid inositol and phospholipid serine 1 type, (b) ethanolamine modified with scaly fat modified with polyethylene terephthalate, which is a straight or branched carbon number of 10-22 carbon atoms, which is acetic acid fatty acid that is partially acetated in saccharine = 5 saturated Or at least one phospholipid derivative of an unsaturated fatty acid, (c) at least one selected from the group consisting of linear or branched chain saturated or unsaturated fatty acids having 10 to 22 carbon atoms, or ( d) A mixture of at least two of the above (a), (b) and (c). Item 1S-Stabilizing agent, a stabilizing agent for stable fat emulsions containing at least one active ingredient selected from the group consisting of paclitaxel or paclitaxel in a dissolved or dispersed state and having an acidic pH And (a) from the linear or branched chain saturated or unsaturated fatty acids of which the esterified fatty acid formed in the glycerol portion is a carbon number, consisting of phospholipids, glycerol, 15 phosphatidic acid, phosphatidylinositol, and phospholipids At least one phospholipid selected from the group consisting of sericin, (b) linalcoholamine modified with a polycridine, and a fatty acid having an acetic acid formed in the glycerol portion, having a carbon number of 10-22. At least one of the phospholipid derivatives of straight-chain or branched-chain saturated or unsaturated fatty acids, 20 (C) is composed of linear or branched-chain saturated or unsaturated fatty acids having a carbon number of 10-22. At least one of the selected ethnic groups, or a mixture of at least two of (d) above (a), (b), and (c). Item 19 A method for stabilizing a stable fat emulsion having an acidic pH in a dissolved or dispersed state containing at least one active ingredient selected from the group consisting of paclitaxel or europaclitaxel, and 12200526269 The following stabilizers (a) to (d) are further added to the fat emulsion, and the stabilizer (a) is 0.01-1 w / v%, the stabilizer is o w / v%, and the stabilizer ( c) It is present at a concentration of 0.05-5 w / v% in lunar fat emulsions obtained by households: 5 (a) linear or branched from 10 to 22 carbon atoms from fatty acids that form esterification in the glycerol moiety At least one of the phospholipids selected from the group consisting of phospholipids, glycerol, stearic acid, phospholipids, inositol, and saponine serine, which is a chain of saturated or unsaturated fatty acids, (b) Alkylene glycol-modified phospholipids, ethanolamines, and at least one kind of linear or branched chain saturated or unsaturated fatty acid scale fatty acid derivatives having 10 to 22 carbon atoms which form esterified fatty acids in glycerol , (C) from the group consisting of linear or branched chain saturated or unsaturated fatty acids having 10 to 22 carbon atoms A is at least one kind or more ⑷ ⑷, a mixture of at least two of the ⑻ and ⑷. 15 In addition, the present invention provides a fat emulsion according to the following items 20 to 22. Item 20 The fat emulsion according to any one of Items 1 to 16, wherein the fat emulsion contains emulsified particles having an average particle size in the range of 0.001 to 1 μm. Item 21 The fat emulsion according to any one of Items 1 to 16 and 20, wherein the fat emulsion has an activity of more than 90% after the autoclave is sterilized by 20 points. The above has described in detail the stable fat emulsion (hereinafter sometimes referred to as the "fat emulsion of the present invention") which contains paclitaxel or / and paclitaxel and has an acidic pH. The fat emulsion of this month contains at least one active ingredient selected from the group consisting of paclitaxel and paclitaxel 13 200526269. These are known as antineoplastic compounds. The five-week formulation ratios in the fat emulsion 7 of the present invention will be described in detail in the item "(4) Preparation of fat emulsion" described later. 5 and emulsifier In addition to the above active ingredients, the fat emulsion of the present invention contains an oily component, an emulsifier and a stabilizer. The oily ingredient used is usually a vegetable oil. Specific examples of the vegetable oil include soybean oil, cottonseed oil, rapeseed oil, flax oil, corn oil, 10 peanut oil, sunflower oil, olive oil, castor oil, and the like. The oily component may be triglyceride. Specific examples thereof include various commercially available products, such as "η ΠΤ in Yibu," (c0c〇nardtm, Kao Corporation, "0D〇TM" (Nissin Oil Co., Ltd.), "Sai-l" (Mygly 〇lTM, SASOL), 〇 leaf Qiyibu (panasateTM, Japanese fats and oils company) 15 and so on. These vegetable oils and medium-chain triglycerides can also be used alone or from the same group (vegetable oil or Medium-chain triglycerides), or two or more of them can be appropriately mixed and reused. In addition, the oily ingredients are not limited to the above-mentioned vegetable oils and medium-chain triglycerides, and may be, for example, animal oils, minerals Oils, synthetic oils, essential oils, etc. can be mixed with two or more types. In addition, these animal oils can also be used in combination with the aforementioned vegetable oils and / or medium-chain triglycerides. Representatives of emulsifiers Examples include, for example, natural phospholipids lecithin, egg yolk lecithin (phophatidylcholine), soybean egg fat filling, soybean phospholipids choline, hydrogenated egg yolk lecithin, 200526269 hydrogenated egg Fat filling and choling test, tritized soybean lecithin, hydrogenated soybean filling and choline, etc. In addition, the emulsifier may also be chemically synthesized phospholipids, choline and phospholipids, ethanolamine. Dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, disearoylphosphatidylcholine, dioleylphosphatidylcholine, dioleylphospholipid bile test Dioleoyl phosphatidylcholine, etc., and the chemically synthesized phospholipids ethanolamines include dipalmitoylphosphatidyl-10 ethanolamine, dimyristoyl-phosphatidylethanolamine, distearyl Disodium phospholipids dist ethanolamine (distearoylphosphatidylethanolamine), dioleyl phospholipids diol ethanolamine (dioleoyl phosphatidylethanolamine), etc. These emulsifiers can be used singly or in combination of two or more 15. Among them, egg yolk lecithin is a suitable emulsifier , Egg yolk phospholipids, bile test, soybean egg scale fat and soybean scale醯 Bile test. The blending ratio of the oily components and emulsifiers in the fat emulsion of the present invention will be described in detail in the "(4) Preparation of fat emulsion" mentioned later. (2) Stabilizing agent 20 In the fat emulsion of the present invention, The chemical agent is selected from the group consisting of the following (a)-(d). (a) From the esterified fatty acid formed in the glycerol part, a linear or branched chain saturated or unsaturated fatty acid having 10 to 22 carbon atoms, preferably a linear or branched chain saturated with 12 to 18 carbon atoms is saturated. Or unsaturated fatty acids, at least one of the phospholipids selected from the group consisting of Dicangzhigan 15 200526269 oil, fat filling acid, phytosaccharinol, and Dipinosyl serine, (b) Polyalkylene glycol-modified phospholipid 醯 ethanolamine, and it is a linear or branched chain 5 saturated or unsaturated fatty acid with a carbon number of 10-22, which forms an esterified fatty acid in the glycerol part, preferably a number of 14- At least one of the phospholipid derivatives of linear or branched chain saturated or unsaturated fatty acids of 18, (c) from linear or branched chain saturated or unsaturated fatty acids having 10 to 22 carbon atoms, preferably At least one selected from the group consisting of linear or branched chain saturated or unsaturated fatty acids having 10 to 20 carbon atoms, or at least 10 (d) or more of (a), (b), and (c) A mixture of 2 types. In the above (a) and (b), the "glycerol part" means the structure of phospholipids, glycerol, phosphatidic acid, phospholipids, inositol, and phospholipids serine, and phospholipids ethanolamine (the constituent fatty acid is palmitic acid) In the following formulas, the parts shown in the figures. 200526269 【Chemical 1】 Phospholipid, Glycerin H? O '

〇 ch2o-c ^ 〇 CH-OC ho-h2chch2c-o- p-och2 〇 Phosphatidic acid 〇- H-O-P-OCH2 〇 oI CH-O-C ^ Phospholipids inositol OH〆

σ p—o-ch2

o CH2〇a 〇CH-OO Phospholipid serine Q- H3i4-HC-H2C-〇- P— OCH2 II o O ch2oct o CH-OC 'Phospholipid ethanolamine 〇ch2oc ^ o CH-oa h2n ~ h2ch2oo- p-o-ch2 o Glycerin partially constitutes fatty acids of phospholipid (a) (ie, fatty acids that esterify the glycerol portion of phospholipid (a)), fatty acids that constitute phospholipid derivative (b) (ie, 5 Specific examples of the glycerol partially esterified fatty acid of the phospholipid derivative (b)) and fatty acid (c) include naturally occurring linear or branched chain saturated or unsaturated lipids 17 200526269 Fatty acid as an example. The fatty acid contains, for example, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, and behenic acid), oleic acid, linoleic acid, linolenic 5 acid, arachidonic acid, eicosa-pentaenoic acid, etc. Chain fatty acids; and branched chain fatty acids such as isomyristic acid, isopalmitic acid, isostearic acid, isoarachidonic acid, and the like. Among the constitutional lipids (a) using the above fatty acids as constituent fatty acids, 10 more specifically, 'contains dicaproyl-phosphatidyl glycerol, dilauroylphosphati-dinic' aicd), dimyristoylphosphati-dylinositol, dipalmitoylphospha-tidylserine, disearoylphosphatidyl- 15 glycerol Diarachidoylphos-

phatidylglycerol), dibehenylphosphati-dinic acid, disearoylphosphatidyl-inositol, disearoylphosphatidinic aicd, distearoyl Distearoylphosphatidylserine, diisomyristoylphosphatidyl-glycerol, diisostearoylphosphatidinic aicd, diisoarachidyl phosphatidyl phospholipid Inositol (diisoarachidoyl- phosphatidylinositol) and so on. Among them, distearylphospholipids, glycerol, distearylphospholipids 18 200526269 acid, distearyl alcohol, inositol, inositol, and distearylphospholipids serine are preferred; among them, Distearyl phospholipids, glycerol and distearyl phosphatidic acid are more preferred. The phospholipid derivative 5 (b) using the above fatty acid as a constituent fatty acid component, in more detail, contains a petrolatum ethanolamine modified with a polyalkylene glycol and represented by the following general formula (I). 【Chemical 2】 ch2o-co-r1

Lo-co-R2 (In the formula, R1 and R2 represent straight or branched chain saturated 10 and or unsaturated fatty acids with 10-22 carbons, preferably straight-chain or 14-18 carbons Residues obtained by branching a chain of saturated or unsaturated fatty acids (constituting fatty acids) by removing the carboxyl moiety. R3 and R4 represent hydrogen atoms or methyl groups. · Χ_ represents groups -CO (CH2) 2CO-, -CO (CH2 ) 3CO- or -CO-. Η represents an integer of 20 to 120.) 15 As shown in the above formula ⑴, in the phospholipid derivative (b), the polyalkylene glycol modified with phospholipid ethanolamine is more specifically The amine group of phospholipids ethanolamine becomes a substituent (substituent on a nitrogen atom) through an X group bond. The polyalkylene glycol is polyethyleneglycol or polypropyleneglycol. In the present invention, a preferred specific example of the lipid derivative (b) can be exemplified.

For example, distearylphospholipid 醯 ethanolamine polyethylene glycol 3000 (MPEG 19 200526269 3000PE, Avanti Company), distearylphospholipid 醯 ethanolamine polyethylene glycol 2000 (SUNBRIGHTDSPE-020CN, Japan Oil Corporation) Wait. In addition, the numerical value in each said compound name shows the average molecular weight of polyethylene glycol. The average molecular weight of the polyalkylene glycol such as polyethylene glycol is preferably in a range between about 5 and 1,000 to 5,000. As stabilizers, phospholipids (a), phospholipid derivatives (b), and fatty vines (c) can be used individually as one of the compounds exemplified above, or γ can be used in combination from each group. the above. In the present invention, the disc lipids (a), phospholipid derivatives (b), and fatty acids (c) are compounds selected from each group as appropriate, and they may be used in combination. The amount of the phospholipid (a) to be formulated in the fat emulsion of the present invention is preferably a final concentration of 0.01-1 w / v% in the obtained fat emulsion (when two or more kinds of phospholipids are used in combination) The same is used for the total measurement; the same applies hereinafter), and the more preferable range is a concentration range of 0.00 M w / v%. By using within this range, it is possible to obtain a fat emulsion having excellent emulsifying stability desired by I5 of the present invention. In the present specification, "w / ν%" which represents the blending amount (concentration) of the stabilizer and other constituents in the fat emulsion of the present invention means 100 g of the weight of each ingredient / the volume of the fat emulsion. The formulated amount of the phospholipid derivative (b) in the fat emulsion of the present invention is 200 · 0M w / v% (when two or more kinds of phospholipids are used in combination, they are equal to each other; the same applies hereinafter), more preferably Those were selected from a concentration range of 0.M w / v%. By using within this range, a fat emulsion having excellent emulsifying stability desired by the present invention can be obtained. The blending amount of the aforementioned fatty acid (c) in the fat emulsion of the present invention is 0,20,2005,26,269 w / v% (when two or more kinds of phospholipids are used in combination, they are equal to each other; the same applies below) 'The better is from 0.05 -2 w / v% concentration range is selected. By using in this range, a fat emulsion having excellent emulsifying stability desired by the present invention can be obtained. 5 10 15 20 When two or more different types of phospholipids and phospholipid derivatives (b) and fatty acids (C) are used in combination, each component used in combination is appropriately selected and used from the aforementioned crimes. It is advantageous, but if they are used in combination, it is expected that there will be a multiplication effect, so the components used in combination can be set near the lower limit within the above range. It is also possible to set an amount lower than the lower limit depending on the circumstances. In general, in the fat emulsion of the present invention, the total amount of each component used can be made from the range of the final concentration of 0.0M w / v%, and preferably from the range of 0.001 to 7 w / v%. select. By using this in combination, the effect expected by the present invention can be achieved. It was the first to find that the use of the above-mentioned specific stabilizers can be used as a fat emulsion with excellent emulsification stability, high safety, and active ingredients, P too + annual paclitaxel and cedar. 4Difference in life or _ Lipid ⑻, 嶙 Lipid Derivatives 定 Fattening agent in the following month, which can be used to dissolve or disperse paclitaxel, W + ow or European violet In addition, this hair_neck— Kind of fat emulsion. Alcohol-soluble or dispersible lipids, such as paclitaxel or cedar, are characterized by a method for stabilizing the properties of wealth, 21,2005,26,269. Paclitaxel is further added to oily ingredients and emulsifiers, so that the obtained The mixture is emulsified. (3) Other additives There is no particular need for the fat emulsion of the present invention, but various additives can be further blended as required. Examples of the additive include antioxidants, antibacterial agents, pH adjusters, isotonic agents and the like which can be formulated into emulsions for injection administration. Specific examples of the antioxidant include sodium metabisulfite (which also functions as an antibacterial agent), sodium sulfite, sodium bisulfite, potassium metabisulfite, potassium sulfite, and the like. Antibacterial agents include, for example, sodium caprylate, methyi benzate, sodium metabisulfite (also has the role of an antioxidant), sodium ethylenediaminetetraacetate (worker's acid, and acid trihydrate) editate) and so on. Examples of the pH adjuster include sodium hydroxide and hydrochloric acid. As the isotonicity agent, sugars such as glycerin, glucose, fructose, and maltose; sugar alcohols such as sorbitol and xylitO1 can be used. Among them, 15 are oil-soluble additives, and they can be mixed with the oily components and the like constituting the emulsion before use. Water-soluble additives may be mixed in water for injection: Add emulsified water spray formulated in Ryder. The addition of 1 amount is self-explanatory for those skilled in the art, and there is no special difference from the known addition of 0 amount. It is possible to further add the cyclodextrin compound to the fat emulsion of the present invention according to need. If this cyclodextrin compound is used, it may be necessary to make the agent that should be solubilized or dispersed dissolve or dissolve at a higher concentration. Ann Cyclodextrin compounds include the pharmacology of cyclodextrin, its derivatives, and the like 22 200526269 " cfj '容 言 卞 gg — < member. The cyclodextrin derivatives include cyclodextrin-derived derivates, monobasic organisms, sulfoalkylether derivatives, sugars, and the like. In addition, cyclodextrin and its derivatives are pharmacologically tolerable to include sodium salts, unsalting salts, and sedative salts. The compounding amount of the melons and compounds in the fat emulsion of the present invention can be selected from the range of about v / 0, and preferably from about 0.002 to 40 w / v%. Relative to composition

10 In 15th, the pore-forming agent of the fat gift was about equal to the molar amount ~ 倍 times the molar amount. (4) Dispersion method and stabilization method As long as the method for preparing the monthly fat emulsion of the present invention can prepare an emulsion, there is no particular limitation, and it can be performed according to a general method. A representative method may be: mixing paclitaxel or paclitaxel, an oily ingredient, an emulsifier, a stabilizer, and an oil-soluble additive ingredient according to need; X force π is used to roughly emulsify the mixture, and then use appropriate

A method of fine emulsification (this emulsification) such as a high-pressure emulsifier. The formulation ratio of paclitaxel or paclitaxel, oily ingredients and emulsifiers in the fat emulsion is based on the concentration of the obtained emulsion (final fat emulsion product), which is the weight relative to the total capacity of the final product. % 20 (final / Chen, expressed in W / v%), it is selected from Pacific paclitaxel or European paclitaxel as 0.01 W 0.5%, oily ingredients 2-20 w / v% and emulsifier as 0.4-10_% of 4 is appropriate. In particular, the formulation is: G.02-0.3 W / V / for 最, paclitaxel, or paclitaxel. '' Is composed of 11 components of Mow / v% and an emulsifier of 0.5-7 w / v0 /. The amount. 23 200526269 The compounding ratio of the stabilizer in the fat emulsion of the present invention is as described in (2) above.

Specific examples of the coarse emulsification and fine emulsification used in the above method include, for example, a homogenizer mixer such as TK. Homogenizer 5 (homomixer) manufactured by Special Mechanization and Chemical Industry Co., Ltd., and generally Above 5000 rpm requires more than 5 minutes of coarse emulsification method, and fine emulsification method using a high-pressure homogenizer (11〇 ^ １〇 状 ^ _ zer) or an ultrasonic homogenizer. The intensive emulsification using a high-pressure homogenizer can usually be carried out under a pressure of about 200 kg / cm2 or more by about 2-50 times, preferably about 5-20 times. In addition, each emulsification operation 10 may be performed at normal temperature, and several heating operations (for example, below the wrist, preferably about 40-70 C) may be used. Although the fat emulsion of the present invention obtained in this way is not particularly required, it can also be further added according to the type of each ingredient used-after adjusting the pH, the pH is adjusted and then filled to the appropriate Containers, such as vials, 15 plastic-packed ampoules, etc., are then sterilized using ordinary filtration operations, sterilization operations, etc. to make the final product. The adjustment of p Η can be performed by adding an appropriate acid or testing as a p H adjusting agent. The adjusted pH range may be, for example, about 5.0 or more, preferably less than 7, and more preferably about 5.0 to 65. This pH adjustment can be performed at a time before the emulsification operation performed to adjust the fat emulsion. The filtering operation can be performed using a general membrane filter. The sterilization operation can be carried out, for example, by 'pressure steam sterilization, hot water immersion g, spray sterilization, and the like. Even more dedication can be done, the high-pressure steam of Xianggao's secret gas sterilizer is extinguished. c, 12 minutes) operation. 24 200526269 5

15

The "20 Emulsification" moon and sun fat extract is excellent because it contains a specific stabilizer. Of course, the stabilizer itself has excellent safety. The fat emulsion of the present invention is also characterized by high safety. In particular, the excellent emulsification stability of the fatliquor is in the acidic pH range, which is more than 5.0, and the emulsified state does not change substantially. In addition, the fat di-emulsion was also excellent in temperature stability. That is, at the time of this operation, a compound of one dose should be subjected to a heating and sterilization operation such as high-pressure steam sterilization. Fat Γ: 22 may be damaged due to this operation. In particular, the particles are very fine, with an average particle size of about 0.3 sign. In addition, the particle size does not change substantially before and after the fungus is stored for three months. Two === After a long time (for example, it has its emulsified particles at 40t. That is, the fat emulsion of the present invention ^! Excessive long-term storage It does not have the characteristics of problems such as milk breakdown, double-layer separation, and precipitation of Shen Dian. In addition, this fat emulsion is not just a material _ ㈣ 优 ㈣ emulsification stability and / or even after the above-mentioned heating sterilization operation and Subsequent long-term storage of paclitaxel or paclitaxel as an active ingredient contained in L, and the activity is still hardly reduced. The suitable blending ratio and particularly suitable blending table 1 according to the present invention utilizing these features are shown in Table 1. The composition ratio (final concentration) of each component in the fat emulsion is as follows 25 200526269 [Table 1] The appropriate composition ratio is particularly suitable The formulation ratio paclitaxel and / or paclitaxel 0.01-0.5 w / v% 0- 02-0.3 w / v% oily ingredients 2-20 w / v% 3-10 w / v% emulsifier 0.4-10 w / v% 0.5-7 w / v% (a) phospholipid 0.01-1 w / v % 0.03-1 w / v% stabilizer (b) phospholipid derivative 0.01-1 w / v% 0. 1-1 w / v% (c) Fatty acid 0.05-5 w / v% 0.05-2 w / v% The fat emulsion of the present invention is not only excellent in emulsification stability and active ingredient activity retention as described above, but also The viscosity and the osmotic pressure can be easily adjusted in the same manner as the commercially available nutritional fat 5 emulsion. The preparation of the viscosity and the osmotic pressure has the advantage of reducing the burden on the patient when the obtained fat emulsion is administered to the patient. When the fat emulsion of the present invention is used as, for example, an anti-malignant drug, it is the same as the conventional fat emulsion, and is administered intravenously or even by drip. During the administration period, the fat emulsion itself is stable and does not have Separated into two layers, the fat particles may become large, and may be safely used. The fat emulsion product of the present invention is a product in which the active ingredient and the safe female virgin agent are mixed in one agent in advance, so It does not need to be like a two-dose product, and it needs to be mixed when used. There is no doubt about medical accidents caused by poor mixing at 15 o'clock, and it has the advantages of easy handling and other advantages. Embodiment] 26 200526269 The best mode for carrying out the invention The following examples will be used to explain the present invention in more detail. Examples 1-4 The five books composed of the components shown in the following table 2 were prepared as described below. Invention of fat emulsion (1000mL in total). [Table 2]

Per 100mL Example 1 Example 2 Example 3 Example 4 Paclitaxel 0.05g 0.05g 0.05g — Paclitaxel — 0.05g Soybean Oil 4g 4g 4g 4g Egg Yolk Egg Fat 4g 4g 4g 4g DSPE-PEG2000 .5g — — — DSPG — 0.5g — 0.5g Oleic acid — 2g — Glycerol 2.21g 2.21g 2.21g 2.21g Water for injection is appropriate to the right amount. The water composition in the table uses the following products. Paclitaxel and Paclitaxel (Wako Pure Chemical Industries, Ltd.) 10 Soybean oil (refined soybean oil; Yueqing Oil Co.) egg yolk lecithin (refined egg yolk lecithin: year 21 company one company) DSPE-PEG2_ (distearyl alcohol Phospholipids, ethanolamine-polyethylene glycol 2000, "SUNBRIGHT DSPE-020CN", manufactured by Nippon Oil & Fats Co., Ltd.) DSPG (distearylphospholipids, glycerol, Nippon Oil & Fats Co., Ltd.) 27 200526269 That is, each component described in Table 2 In the process, the active ingredients (paclitaxel or paclitaxel) and soybean oil are mixed first, and then any one of DSPE-PEG ·, DSPG, and oleic acid is added to the mixture, and further added will allow the obtained The final concentration of the mixture was 5 ° C to a solution of 2.21 w / v% of glycerol dissolved in water for injection, and then a high-speed electric grinding homogenizer (p〇lytrón Hmgenizer) (manufactured by KINEMATICA) ) Under nitrogen flow and under heating, the crude emulsification is performed at 25,000 rpm for 10 minutes. Next, the obtained crude emulsion was subjected to fine emulsification using a high-pressure homogenizer (Apv Co., Ltd.) under a nitrogen gas stream at an emulsification temperature of 40-80 ° C until the average particle diameter became 0.3 µm or less. After the pH of the obtained emulsion was adjusted to a predetermined value with hydrochloric acid or sodium mouse oxide, 10 mL of the mother was filled into a 10-mL glass vial and sealed to obtain a fat emulsion sample. In addition, in this example, in addition to the sample (sample of the present invention) adjusted to the 15 acid range (PH5, 5.5, and 6), the sample adjusted to the basic range (pH 8) for reference was also prepared. Comparative Example 1 Except that no DSPE-PEG · was added, the same treatment as in Example 1 was performed to prepare comparative fat emulsion samples (ρΙί 5, 20 5.5, 6 and 8) containing paclitaxel. Comparative Example 2 A comparative fat emulsion sample (pH 5, 5.5, 6 and 8) containing paclitaxel was prepared in the same manner as in Example 4 except that DSPG was not added. The sample prescriptions for car master examples 1 and 2 are not in Table 3 below. 28 200526269 [Table 3] Ingredients per 100mL Comparative Example 1 Comparative Example 2 Paclitaxel 0.05g — Paclitaxel — 0.05g ~ — Soybean Oil 4g 4g Egg Yolk Photoreceptor 4g 4g dspe-peg 2000 — — DSPG — 1 Oleic acid-glycerin 2.21g 2.21g

The test was performed on each of the samples prepared in the foregoing Examples and Comparative Examples, and 5 of them were subjected to high-pressure steam sterilization (121 ° C, 12 minutes), and the particle size (nm) of the emulsified particles before and after the sterilization treatment was measured. And the sterilization of drug residue rate (%). The particle size was measured using a particle size measuring device (ELS-8000, Otsuka Electronics Co., Ltd.). The remaining rate of the drug is to measure the content of the active ingredient 10 in the sample before and after sterilization using a high-performance liquid chromatography (class LCM0 'Shimadzu Manufacturing Co., Ltd.'). The content of the active ingredient after the sterilization (mg / mL) is divided by the amount before the sterilization. The value of the active ingredient content (mg / mL) is expressed as a percentage (%). The particle diameters of the emulsified particles of each sample before and after sterilization are shown in Tables 4-9. Table 4 shows the results of the sample described in Example 1, Table 5 shows the results of the sample described in Example 2, and Table 6 For the results of the sample described in Example 3, 29 200526269 Table 7 shows the results of the sample described in Example 4, Table 8 shows the results of the sample described in Comparative Example 1, and Table 9 shows the results of the sample described in Comparative Example 2. result. In addition, in Table 4-7, in addition to the samples of the present invention adjusted to the acidic range of pH, that is, pH 5, 5.5, and 6, the measurement results of the samples adjusted to the basic range of pH 8 5 are also recorded for reference. . [Table 4] pH particle size (nm) before sterilization Before sterilization 5 89 95 5.5 95 96 6 98 93 8 99 95

[Table 5] pH particle size before sterilization 5 139 136 5.5 140 139 6 136 140 8 141 145 30 10 200526269 [Table 6] pH particle size (nm) before sterilization 5 147 155 5.5 154 142 6 153 150 8 157 164 Halogen-free pH particle size (nm) After sterilization before sterilization 5 139 141 5.5 141 138 6 142 147 8 138 147 Halogen-free pH particle size (nm) Before sterilization 5 97 311 5.5 98 313 6 102 285 8 102 116

[Table 7] Spring 5 [Table 8] 31 200526269 [Table 9] pH value of halofenam (nm) before sterilization after sterilization 5 131 311 5.5 129 337 6 126 303 8 119 149 As shown in Table 4-9 As a result, the following can be learned. That is, as shown in Table 4-7, the sample of the present invention prepared in Example 1-4 has no substantial change in the particle size of the emulsified particles before and after sterilization, so it can be seen that it has excellent emulsification stability. Sex. In contrast, the comparative samples obtained in Comparative Examples 1 and 2 (without using the stabilizer of the present invention) are shown in Table 8-9. Especially in the acidic range (pH 5, 5.5, and 6), the particle size will increase significantly after sterilization. , Showing that its emulsification stability is significantly reduced. 10 In addition, the residual percentages (%) of the active ingredients after sterilization of the samples obtained in Examples 1 and 2 are shown in Table 10. [Table 10] Residual percentage of active ingredients after sterilization at pH before sterilization (%) The sample prepared in Example 1 The sample prepared in Example 2 5 94 96 5.5 94 95 6 90 90 8 37 38 32 200526269 According to the table As can be seen from the results shown, the sample (acid range) of the present invention maintained an excellent active ingredient residual ratio of 90% or more regardless of the sample. In contrast, in a sample adjusted to the alkaline range (pH 8), such a high active ingredient content rate could not be maintained to the end. Based on this result, it can be seen that, according to the present invention, it is possible to obtain a fat containing paclitaxel and paclitaxel with excellent emulsification stability in the acidic range and almost no inactivation problems by using a specific stabilizer. Emulsion. Therefore, the fat emulsion of the present invention can be safely administered to the human body. tSchematic description 3 10 (None) [Description of main component symbols] (None) 33

Claims (1)

200526269 10. Scope of patent application: 1. A fat emulsion containing at least one active ingredient, oily ingredient, stylizing agent and stabilizing agent selected from the group consisting of paclitaxel and European paclitaxel, and having an acidic pH The stabilizing fat emulsion 5 is characterized in that the stabilizing agent is (a) a linear or branched chain saturated or unsaturated fatty acid having a carbon number of 10-22 from an esterified fatty acid formed in a glycerol moiety. At least one phospholipid selected from the group consisting of phospholipids, glycerol, phosphatidic acid, phospholipids, inositol, phospholipids, serine, 10 (b) phospholipids, ethanolamines modified with polyalkylene glycols, and It is at least one phospholipid derivative of a linear or branched chain saturated or unsaturated fatty acid having 10 to 22 carbon atoms which forms an esterified fatty acid in a glycerol moiety, (c) from 10 to 22 carbon atoms At least one selected from the group consisting of chain or branched chain saturated or unsaturated 15 and fatty acids, or (d) a mixture of at least two of the above (a), (b), and (c), and fat In the emulsion, the stabilizer (a) is 0.01-1 w / v%. Agent ⑻%, stabilizer agents to square ⑷ 〇5 · · 5 w / v% is present in a concentration of 0.01-1 w / v. 202. According to the fat emulsion of the first patent application scope, in the fat emulsion, (1) the active ingredient is present at a concentration of 0.001-〇_5w / v%, (2) the oily component is at 2-20w / v% concentration exists, (3) emulsifier exists at a concentration of 0-4-10w / v%. 3. The fat emulsion of item 1 in the scope of the patent application, wherein the acidic pH is less than 34 200526269 7 and more than 4. 4. For example, the tincture emulsion of the scope of the patent application, wherein the stabilizer is based on the formation of vinegarized fatty acid in the glycerol part, which is a straight-chain tincture, branched chain saturated or unsaturated fatty acid of carbon number 10-22. In other words, at least one kind of phospholipids is selected from the group consisting of phospholipids, glycerol, dilute acid, phospholipid inositol, and phospholipid serine. 10 15 20 5. The fat emulsion according to item 1 of the patent application scope, wherein the stabilizer is a linear or branched saturated or unsaturated fatty acid having a carbon number of 12 to 18 which forms an esterified fatty acid in the glycerol part. In other words, at least one kind of phospholipid is selected from the group consisting of phospholipids, glycerol, phospholipids, phospholipids, inositol, and phospholipids serine. 6. Such as the scope of patent application! Xiang Zhiyue fat emulsion, in which the stabilizer is from distearylphospholipid, glycerol, dipalmitenylphospholipid, glycerol, biscarboxylphospholipid glycerol, dioleyl_imidyl glycerol, distearyl Fermentation base = fatty acid, diglyceryl phosphatidic acid, dimyristoyl phosphatidic acid, dioleyl fatty acid, distearyl fatty acid, inositol, di palmityl inositol , Bisyl inositol, dioleyl inositol, dioleyl phosphatidyl inositol, distearylphospholipids serine, dibromophospholipids serine, dimyristoylphospholipids At least one selected from the group consisting of amino acids and dioleyl phospholipid serine. 7. The fat emulsion according to item 1 of the application, wherein the stabilizing agent is distearylphospholipid and glycerol. 8. The fat emulsion according to item 4 of the application, wherein the stabilizer is present in the fat emulsion at a concentration of G-G3qw / V%. 35 200526269 9. The fat emulsion according to item 1 of the patent application scope, wherein the stabilizing agent is a fat-filled 烧 ethanolamine 'modified with polyalkylene glycol and an esterified fatty acid having a carbon number of 10 · 22 At least one kind of linear or branched chain saturated or unsaturated fatty acid constitutive lipid derivative. 5 10. The fat emulsion according to item 1 of the scope of the patent application, wherein the stabilizer is a phospholipid ethanolamine modified with a polyalkylene glycol having an average molecular weight of 1000-5000, and an esterified fatty acid is a carbon number in the glycerol part. 14-18 At least one of the phospholipid derivatives of linear or branched chain saturated or unsaturated fatty acids. 10 11. The fat emulsion according to item 1 of the patent application range, wherein the stabilizer is selected from the group consisting of distearyl phospholipid, ethanolamine polyethylene glycol 5000, distearyl phospholipid, ethanolamine polyethylene glycol 3000, and dihard At least one kind of phospholipid derivative selected from the group consisting of fatty alcohol-based lipid fatty acid ethanolamine polyethylene glycol 2000. 15 12. The fat emulsion according to item 9 of the patent application scope, wherein the stabilizer is present in the fat emulsion at a concentration of O.Mw/v%. 13. The fat emulsion according to item 1 of the application, wherein the stabilizer is at least one selected from the group consisting of linear or branched chain saturated or unsaturated fatty acids having 10 to 22 carbon atoms. 20 14. The fat emulsion according to item 1 of the patent application range, wherein the stabilizer is at least one selected from the group consisting of linear or branched chain saturated or unsaturated fatty acids having 10 to 20 carbon atoms. 15. The fat emulsion according to item 1 of the application, wherein the stabilizer is selected from the group consisting of oleic acid, isostearic acid, isopalmitic acid, capric acid, lauric acid, nutmeg 36 200526269 acid, palmitic acid, stearin At least one fatty acid selected from the group consisting of acids and arachidic acid. 16. The fat emulsion according to item 13 of the application, wherein the stabilizer is present in the fat emulsion at a concentration of 0.05-2 w / v%. • 5 Π. —Under a kind of fat emulsion as described in any one of items 1 to 16. The use of the lian stabilizing agent ⑷ ~ a: (a) from the fatty acid that forms esterification in the glycerol part to the carbon number Phospholipid selected from the group consisting of linoleic acid ^ glycerol, phosphatidic acid, phospholipids inositol, and phospholipids serine, of linear or branched chain saturated or unsaturated fatty acids of 1-22. (B) Phospholipids ethanolamines modified with polyalkylene glycols and which are fatty acids that form esterification in the glycerol moiety are straight or branched chains with 10-22 carbon atoms, saturated or not. At least i species of phospholipid derivatives of saturated fatty acids, 15 (c) at least one species selected from the group consisting of linear or branched chain saturated or unsaturated carbons of 10-22 carbon atoms and fatty acids, or (d) A mixture of at least two of the above ⑷, ⑻, and ⑷. 18 · —A stabilizer, which is used in a dissolved or dispersed state to contain at least one active • 20 ingredient selected from the group consisting of Pacific Purple, Paclitaxel, or European Paclitaxel, and a stable fat emulsion having an acidic pH Stabilizing agent, and ⑻ from the glycerol part of the esterified fatty acid is a linear or branched chain of 10-22 carbon saturated or unsaturated fatty acids, from phospholipids to glycerol, phosphatidic acid, phospholipids Alcohol and phospholipid serine acid, at least one selected from the group 37 200526269, (b) phospholipid phosphoethanolamine modified with polyalkylene glycol, and is a fatty acid that forms an esterification in a glycerol moiety It is at least one type of phospholipid derivative of a linear or branched chain saturated or unsaturated fatty acid having 10 to 22 carbon atoms. 5 (c) Saturated from a linear or branched chain of 10 to 22 carbon atoms. Or at least one selected from the group consisting of unsaturated fatty acids, or a mixture of at least two of (d) or more of (a), (b), and ⑷. _ 19 · A stabilization method for a stable fat emulsion containing at least one active ingredient selected from the group consisting of paclitaxel or europaclitaxel in a dissolved or dispersed state and having an acidic pH of 10, which is based on the fat The following stabilizers (a) to (d) were further added to the emulsion, and the stabilizer was 0) at 0_0 M w / v%, the stabilizer was at 0.005 w / v%, and the stabilizer (c) It is present in the obtained fat emulsion at a concentration of 0.05-5 w / v%: (a) The linear or branched chain of carbon number 10-22 15 from the fatty acid which forms the esterification in the glycerol part is saturated or not Saturated fatty acid, at least one selected from the group consisting of phospholipids φ glycerol, phosphatidic acid, phospholipids inositol, and phospholipids serine, (b) modified with polyalkylene glycols Lipoethanolamine, which is at least one phospholipid derivative of a linear or branched 20-chain saturated or unsaturated fatty acid that forms an esterified fatty acid based on glycerol with a carbon number of 10-22, (c) from Family consisting of linear or branched chain saturated or unsaturated fatty acids with 10-22 carbon atoms Shu at least the selected species, or (d) above (a), (b) and (c) 2 of a mixture of two at least. 38 200526269 VII. Designated Representative Map: (1) The designated representative map in this case is: (). (None) (b) Brief description of the component symbols in this representative drawing: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: