WO2005065677A1 - Fat emulsion for dissolving or dispersing paclitaxel or docetaxel - Google Patents

Abstract

A fat emulsion for use in solubilizing or dispersing at least one active ingredient selected from the group consisting of paclitaxel and docetaxel, the fat emulsion comprising an oily ingredient, an emulsifying agent, and a stabilizer, e.g., phosphatidylglycerol, selected among specific phospholipids, phospholipid derivatives, and fatty acids. Also provided is a method of obtaining a fat emulsion which contains the active ingredient in a dissolved or dispersed state and is prevented from suffering precipitation of crystals of the active ingredient, the method comprising using that fat emulsion to obtain this emulsion.

Description

 Specification

 No ,. Fatty emulsion for dissolving or dispersing taritaxel or docetaxel

 Technical field

 The present invention relates to a fat emulsion for dissolving or dispersing at least one active ingredient selected from paclitaxel and docetaxel as well as group power.

 Background art

 [0002] Conventionally, in stabilizing a preparation prepared by mixing an injection such as an anticancer agent and a fat emulsion, polyoxyethylene hydrogenated castor oils 50 and 60, polysorbate 80 and the like are used as stabilizers. There is known a method of utilizing (see Patent Document 1).

 [0003] The use of polysorbate 80 as a food additive is not yet approved in Japan, and its use is problematic in terms of safety. Polyoxyethylene hydrogenated castor oils 50 and 60 are also known to contribute to side effects such as the appearance of anaphylactic shock, and have a problem in safety (Patent Document 2, especially page 1, 22-). See line 30).

 [0004] Further, it is generally known that nonionic surfactants containing these are accompanied by problems such as precipitation of crystals when preparing fat emulsions by using them (Non-Patent Document 1). reference).

 [0005] As described above, conventionally, at least one active ingredient in which a group power including notaritaxel and docetaxel power is also selected can be soluble or dispersed without a problem of crystal precipitation, and safety such as side effects can be improved. However, there is no problem in terms of solubilization or dispersing agent, and solubilization or dispersing technology using such a solubilizing or dispersing agent has not yet been developed.

 Patent Document 1: JP 08-127529 A

 Patent Document 2: US Patent No. 5,616,330

 Non-patent document l: Adam, J.D "et al, (1993)," Journal of the National Cancer Institute Monographs ", No. 15, p. 141-147.

Disclosure of the invention Problems the invention is trying to solve

 [0006] An object of the present invention is to provide a new solubilizing agent or dispersing agent which can be used for solubilizing or dispersing notaritaxel or docetaxel, and to dissolve or disperse the above drug using the same. It is to provide a technology to make it more sophisticated.

 Means for solving the problem

 [0007] The inventors of the present invention have conducted intensive studies, and as a result, have found that the stabilization effective for dissolving or dispersing at least one active ingredient selected from the group consisting of notaritaxel and docetaxel in a fat emulsion is also obtained. And a solubilizing or dispersing agent containing the stabilizing agent (a fat emulsion for solubilizing or dispersing the active ingredient) and using the same to solubilize or disperse the active ingredient. Technology has been established. The present invention has been completed as a result of further research based on these findings. The present invention relates to a fat emulsion according to the following item 1-15, a method for producing a fat emulsion containing the active ingredient according to item 16, and a method for producing a fat emulsion containing the active ingredient according to item 17, Use, a container according to item 18, and a method for preventing crystal precipitation of the active ingredient according to item 19.

 Item 1. Paclitaxel and docetaxel power A fat emulsion for dissolving or dispersing at least one selected active ingredient, wherein the fat emulsion is composed of an oil component, an emulsifier and a stabilizing agent. An agent, wherein the stabilizer comprises:

 (a) Fatty acid force esterified to the glycerol moiety: a phosphatidylglycerol, phosphatidic acid, phosphatidylinositol and phosphatidylserine, a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms. At least one phospholipid selected from the group consisting of

 (b) a phosphatidylethanolamine modified with a polyalkylene glycol, which is esterified to a glycerol moiety, wherein the fatty acid is a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms. At least one phospholipid derivative,

 (c) a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms.

 (d) A mixture of at least two of the above (a), (b) and (c)

And Concentration of stabilizer (a) 0.01-lw / v%, stabilizer (b) 0.01-lw / v%, stabilizer (c) force S0.05-5w / v% in fat emulsion A fat emulsion characterized by being present in the following.

[0009] Item 2. In fat emulsion

 (1) oily components are present at a concentration of 2-20 w / v%,

 (2) The fat emulsion according to item 1, wherein the emulsifier is present at a concentration of 0.4 to 10 w / v%.

 Item 3. The phosphatidyl dalycerol, phosphatidic acid wherein the fatty acid esterified to the glycerol moiety of the stabilizer is a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms Item 3. The fat emulsion according to Item 1 or 2, which is at least one selected from the group consisting of phosphatidylinositol and phosphatidylserine.

 Item 4. The phosphatidyl dalycerol, phosphatidic acid wherein the fatty acid esterified to the glycerol moiety of the stabilizer is a linear or branched saturated or unsaturated fatty acid having 12 to 18 carbon atoms Item 14. The lipid emulsion according to any one of Items 13 to 13, which is at least one selected from the group consisting of phosphatidylinositol and phosphatidylserine.

 Item 5. The stabilizer is distearoyl phosphatidyl glycerol, dipalmitoyl phosphatidyl glycerol, dimyristoyl phosphatidyl glycerol, dioleoyl phosphatidyl glycerol, distearoyl phosphatidic acid, dipalmitoyl phosphatidin. Acid, dimyristoyl phosphatidic acid, dioleoyl phosphatidic acid, distearoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol, dimyristoyl phosphatidylinositol, dioleoyl phosphatidylinositol, distearoyl phosphatidyl phosphatidyl phosphatidyl phosphatidyl phosphatidylinositol At least one of the phospholipids selected from the group consisting of glycerin and dioleoylphosphatidylserine Item 14. The fat emulsion according to any one of Items 1-3, which is also one kind.

 [0013] Item 6. The fat emulsion according to any one of Items 13 to 13, which is distearoyl phosphatidyl glycerol.

Item 7. The fat emulsion according to any one of Items 3 to 6, wherein the stabilizer is present in the fat emulsion at a concentration of 0.03-lw / v%. Item 8. The stabilizer is a phosphatidylethanolamine modified with a polyalkylene glycol, and the fatty acid obtained by esterification to the glycerol portion has a linear or branched chain having 10 to 22 carbon atoms. Item 14. The fat emulsion according to any one of Items 13 to 13, which is at least one kind of a phospholipid derivative that is a saturated or unsaturated fatty acid.

 Item 9. The stabilizer is a phosphatidylethanolamine modified with a polyalkylene glycol having an average molecular weight of 1,000 to 5,000, which is esterified to a glycerol moiety to form a fatty acid having 14 to 18 carbon atoms. Item 14. The fat emulsion according to any one of Items 13 to 13, which is at least one kind of a phospholipid derivative that is a linear or branched saturated or unsaturated fatty acid.

 Item 10. A phospholipid derivative selected from the group consisting of distearoyl phosphatidyl ethanolamine polyethylene glycol 5000, distearoyl phosphatidyl ethanolamine polyethylene glycol 3000, and distearoyl phosphatidyl ethanolamine polyethylene glycol 2000. Item 4. The fat emulsion according to any one of Items 1 to 3, which is at least one of the following.

 Item 11. The fat emulsion according to any one of Items 8 to 10, which is present in the fat emulsion at a concentration of 0.1-lw / v%.

 Item 12. The stabilizer according to any one of Items 1 to 3, wherein the stabilizer is at least one member selected from the group consisting of a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms. The fat emulsion as described.

 Item 13. The stabilizer according to any one of Items 1 to 3, wherein the stabilizer is at least one member selected from the group consisting of a linear or branched saturated or unsaturated fatty acid having 10 to 20 carbon atoms. The fat emulsion as described.

 Item 14. The stabilizing agent is at least one fatty acid selected from the group consisting of oleic acid, isomyristic acid, isopalmitic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, and arachidic acid. Item 4. The fat emulsion according to any one of Items 1 to 3, which is a seed.

 Item 15. The fat emulsion according to any one of Items 12 to 14, which is present in the fat emulsion at a concentration of 0.05-2 w / v%.

Item 16. At least one active ingredient selected from the group consisting of paclitaxel and docetaxel is mixed with the fat emulsion according to any one of Items 1 to 15 to dissolve or dissolve the active ingredient. A method for producing a fat emulsion contained in a dispersed state.

 Item 17. The fat according to any one of Items 1 to 15 for the production of a fat emulsion containing at least one active ingredient selected from the group consisting of paclitaxel and docetaxel in a dissolved or dispersed state. Use of emulsion.

 Item 18. A container for a fat emulsion containing at least one active ingredient selected from the group consisting of paclitaxel and docetaxel in a dissolved or dispersed state, wherein the container is partitioned by a partition means capable of communicating. One of which contains the fat emulsion according to any one of Items 1 to 15, and the other has at least one of paclitaxel and docetaxel. An active ingredient is contained therein.

 Item 19. A method for preventing crystal precipitation of an active ingredient in a fat emulsion containing at least one active ingredient selected from the group consisting of paclitaxel and docetaxel, comprising the steps of: A method characterized by mixing with the fat emulsion according to any one of the above.

 Hereinafter, the fat emulsion of the present invention for preparing a stable fat emulsion containing paclitaxel and Z or docetaxel as active ingredients will be described in detail.

[0028] The fat emulsion of the present invention is a fat emulsion for dissolving or dispersing paclitaxel and docetaxel, and contains the following oily components, an emulsifier, and a stabilizer as essential components.

 [0029]

 (1) ¾ 5 ^ ぉ and emulsification

 The oil component used for preparing the fat emulsion of the present invention is usually a vegetable oil. Specific examples of the vegetable oil include soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, olive oil, castor oil and the like.

[0030] The oil component may be a medium-chain triglyceride. Specific examples include various commercially available products such as “COCONARD” (COCONARD ™, Kao Corporation), “ODO ™” (Nissin Oil Co., Ltd.), “Miglyol” (Myglyol ™, SASOL), “Panasate” (Panasate) ™, Nippon Oil & Fats Co., Ltd.). These vegetable oils and medium-chain triglycerides use one species alone They may be used from the same group (vegetable oil or medium-chain triglyceride) or two or more kinds from different groups may be appropriately mixed and used.

 [0031] Furthermore, the oil component is not limited to the above-described vegetable oil and medium-chain triglyceride, and may be, for example, an animal oil, a mineral oil, a synthetic oil, an essential oil, or a mixture of two or more. There may be. Further, these animal oils and the like may be used in combination with the vegetable oil and Z or medium-chain triglyceride.

 Typical examples of the emulsifier include natural phospholipids such as egg yolk lecithin, yolk phosphatidylcholine, soy lecithin, soy phosphatidylcholine, hydrogenated yolk lecithin obtained by hydrogenating them, hydrogenated yolk phosphatidylcholine, hydrogenated soy lecithin, water Soybean phosphatidylcholine and the like can be mentioned. Further, the emulsifier may be chemically synthesized phosphatidylcholine and phosphatidylethanolamine.

 [0033] The chemically synthesized phosphatidylcholine includes dipalmitoyl phosphatidylcholine, dimyristyl phosphatidylcholine, distearoyl phosphatidylcholine, dioleoyl phosphatidylcholine, and the like. The chemically synthesized phosphatidylethanolamine includes dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, and the like.

 [0034] These emulsifiers can be used alone or as a mixture of two or more. Among these, preferred emulsifiers are egg yolk lecithin, egg yolk phosphatidylcholine, soy lecithin and soy phosphatidylcholine.

 The mixing ratio of the oil component and the emulsifier in the fat emulsion of the present invention will be described in detail in the section “(4) Fat emulsion of the present invention” below.

 [0036]

 (2) Agent

 In the fat emulsion of the present invention, the stabilizer is selected from the group consisting of:

(A) Fatty acid strength by esterification to the glycerol moiety is a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms, preferably a linear or branched fatty acid having 12 to 18 carbon atoms. Phosphatidylglycerol, phosphatidyl, which is a linear or branched saturated or unsaturated fatty acid At least one phospholipid selected from the group consisting of atidic acid, phosphatidylinositol and phosphatidylserine,

 (b) a phosphatidylethanolamine modified with a polyalkylene glycol, which is esterified to a glycerol moiety to obtain a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms, Preferably at least one kind of a phospholipid derivative which is a linear or branched saturated or unsaturated fatty acid having 14 to 18 carbon atoms,

 (c) a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms, preferably a linear or branched saturated or unsaturated fatty acid having 10 to 20 carbon atoms; Power at least one selected,

 (d) A mixture of at least two of the above (a), (b) and (c).

In (a) and (b) above, the term "glycerol moiety" refers to the structure of phosphatidylglycerol, phosphatidic acid, phosphatidylinositol and phosphatidylserine, and phosphatidylethanolamine (the constituent fatty acid is palmitic acid). In each of the following formulas, the portion shown in the figure is referred to.

[0039] [Formula 1]

 Phosphatidylethanolamine

 Glycerol part

[0040] Fatty acids constituting the phospholipid (a) (ie, the glycerol portion of the phospholipid (a) is esterified). Examples of the fatty acid constituting the phospholipid derivative (b) (i.e., the fatty acid obtained by esterifying the dalicerol portion of the phospholipid derivative (b)) and the fatty acid (C) include naturally occurring fatty acids. There may be mentioned straight-chain or branched-chain saturated or unsaturated fatty acids which are present. These fatty acids include, for example, linear fatty acids such as ricopric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid and eicosapentaenoic acid. And branched fatty acids such as isomyristic acid, isopalmitic acid, isostearic acid, and isoarachidonic acid.

 [0041] More specifically, the phospholipid (a) containing the above fatty acid as a constituent fatty acid component includes dicaprol phosphatidyl glycerol, dilauroyl phosphatidic acid, dimyristoyl phosphatidyl inosino, dipalmitoyl phosphatidyl serine, distearoyl phosphatidyl glycerol, Diarachidoylphosphatidylglycerol, dibehenylphosphatidic acid, distearoylphosphatidylinositol, distearoylphosphatidic acid, distearoylphosphatidylserine, diisomyristoylphosphatidylglycerol, diisostearoylphosphatidylic acid, diisoarachiditolphosphatidylic acid, etc. .

 [0042] Among these, distearoyl phosphatidylglycerol, distearoylphosphatidic acid, distearoylphosphatidylinositol and distearoylphosphatidylserine are preferable, and distearoylphosphatidylglycerol and distearoylphosphatidic acid are more preferable.

The phospholipid derivative (b) containing the above fatty acid as a constituent fatty acid component more specifically includes a phosphatidylethanolamine modified with a polyalkylene glycol represented by the following general formula (I). [0044] [Formula 2]

C ^ O-CO-R ¹

R ⁴ OH CH-OCO-R ² _(|)

_{^{R 3 0- (CH 2 CHO)}} n -X-NH-CH 2 CH 2 -0- P- 0-CH 2

 O

(Wherein R ¹ and R ² are linear or branched saturated or unsaturated fatty acids having 10 to 22 carbon atoms, preferably linear or branched fatty acids having 14 to 18 carbon atoms) R ³ and R ⁴ represent a hydrogen atom or a methyl group, and -X- represents a group -CO (CH). CO-,-CO (CH) CO- or

 2 2 2 3

 Indicates -CO-. n represents an integer of 20 to 120. )

 As shown in the above formula (I), the polyalkylene glycol that modifies phosphatidylethanolamine in the phospholipid derivative (b) is more specifically a substituent (substituted on a nitrogen atom) at the amino group of phosphatidylethanolamine. As a group) through an X group. The polyalkylene glycol is polyethylene glycol or polypropylene glycol.

 In the present invention, preferred examples of the phospholipid derivative (b) include, for example, distearoyl phosphatidylethanolamine polyethylene glycol 5000 (SUNBRIGHT

 DSPE-050C, NOF Corporation), Distearoylphosphatidylethanolamine polyethylene glycol 3000 (MPEG 3000PE, Avanti), Distearoylphosphatidylethanolanol polyethylene glycol 2000 (SUNBRIGHT DSPE-020CN, NOF Corporation) Examples can be given. The numerical value in the name of each compound indicates the average molecular weight of polyethylene glycol. The average molecular weight of the polyalkylene glycol, such as polyethylene glycol, is preferably in the range of about 1000-5000.

As the phospholipid (a), the phospholipid derivative (b) and the fatty acid (c) as the stabilizing agent, each of the compounds exemplified above can be used alone, and each of the compounds in each group can be used. And two or more types can be used together. In the present invention, the compounds belonging to the respective groups of the phospholipid (a), the phospholipid derivative (b) and the fatty acid (c) may be appropriately selected and used in combination. It is possible. [0048] The amount of the phospholipid (a) to be incorporated into the fat emulsion of the present invention is more preferably 0.01-lw / v% (the total amount thereof when two or more phospholipids are used in combination, the same applies hereinafter), and more preferably. Should be within the concentration range of 0.03-lw / v%. Utilization in this range can provide a fat emulsion having excellent emulsion stability as expected in the present invention.

 [0049] In the present specification, "w / v%" representing the blending amount (concentration) of the stabilizer and other components in the fat emulsion of the present invention means each component weight g / volume of fat emulsion lOOmL. I do.

 [0050] The amount of the phospholipid derivative (b) incorporated into the fat emulsion of the present invention is 0.01-lw / v% (when two or more phospholipid derivatives are used in combination, the total amount thereof is the same hereinafter), More preferably, a concentration range power of 0.1-lw / v% is suitably selected. Utilization within this range provides a fat emulsion having excellent emulsion stability as expected of the present invention.

 [0051] The amount of the fatty acid (c) to be incorporated into the fat emulsion of the present invention is 0.05-5 w / v% (when two or more fatty acids are used in combination, the total amount thereof, the same applies hereinafter), more preferably It is appropriate to select from the concentration range of 0.05-2w / v%. Utilization in this range can provide a fat emulsion having excellent emulsion stability as expected in the present invention.

 [0052] When two or more of the phospholipid (a), the phospholipid derivative (b) and the fatty acid (c) are used in combination, the respective components to be used are appropriately selected from the ranges described above. Although it is advantageous to use them together, a synergistic effect can be expected by using these together, so that each of the components used together can be near the lower limit within the above range. Further, in some cases, the amount may be lower than the lower limit. In general, the total amount of the components used together should be selected from the range of a concentration of 0.01-lw / v% in the fat emulsion of the present invention, more preferably from the range of a concentration of 0.01-0.7w / v%. Can be. The desired effect of the present invention is also exhibited by this combination.

 [0053] The present invention has been found for the first time that the use of the above-mentioned specific stabilizing agent enables to obtain a fat emulsion having excellent emulsion stability and high safety.

 [0054]

 (3) Other additives

Various additives can be further added to the fat emulsion of the present invention, if necessary but not particularly required. Such additives are included in this type of emulsion which can be administered by injection. Examples thereof include antioxidants, antibacterial agents, pH adjusters, and tonicity agents that are known to be compatible. Specific examples of the antioxidant include sodium metabisulfite (which also acts as an antibacterial agent), sodium sulfite, sodium bisulfite, potassium metabisulfite, and potassium sulfite. Examples of antibacterial agents include sodium caprylate, methyl benzoate, sodium metabisulfite (which also acts as an antioxidant), sodium edetate, and the like. Sodium hydroxide, hydrochloric acid and the like can be used as the pH adjuster. As the tonicity agent, glycerin; saccharides such as butdu sugar, fructose and maltose; sugar alcohols such as sorbitol and xylitol can be used. Among these, those which are oil-soluble can be used by being previously mixed with the oily components constituting the emulsion. The water-soluble additive can be added to and mixed with the water for injection or the aqueous phase of the resulting emulsion. The amounts of these additives are obvious to those skilled in the art, and are not particularly different from those conventionally known.

 [0055] The fat emulsion of the present invention may further contain a cyclodextrin conjugate as needed. According to the use of the cyclodextrin conjugate, the drug to be dissolved or dispersed may be stably soluble or dispersed at a higher concentration.

 [0056] Cyclodextrin conjugates include cyclodextrin, derivatives thereof, and pharmacologically acceptable salts thereof. Derivatives of cyclodextrin include alkyl derivatives of cyclodextrin, hydroxyalkyl derivatives, sulfoalkyl ether derivatives, sugar bond derivatives and the like. The pharmacologically acceptable salts of cyclodextrin and its derivatives include sodium salts, potassium salts, magnesium salts and the like.

 [0057] The amount of the cyclodextrin conjugate in the fat emulsion of the present invention is about 0.01-50 w / v%, preferably the range of the concentration is about 0.02-40 w / v%. .

[0058] Preparation of the fat emulsion of the present invention is not particularly limited as long as an emulsion is obtained, and can be according to a general method. A typical method is to mix an oil component, an emulsifier, a stabilizer and, if necessary, an oil-soluble additive component, add water for injection to this mixture, coarsely emulsify, and then use an appropriate high-pressure emulsifier, etc. Then, a method of fine emulsification (main emulsification) can be employed. [0059] The mixing ratio of the oil component and the emulsifier in the fat emulsion of the present invention is such that the oil component is

It is appropriate to select the range power at which each concentration of 2-20 w / v% and emulsifier is 0.4-10 w / v%. A particularly preferable mixing ratio can be selected from a range in which the oil component has a concentration of 3-10 w / v% and the emulsifier has a concentration of 0.5-7 w / v%. The mixing ratio of the stabilizer is as described in the above (2). Table 1 below shows the mixing ratios of these components and particularly preferable mixing ratios.

 [Table 1]

[0061] As a specific means of the coarse emulsification and the fine emulsification adopted in the above method, for example, using a homomixer such as TK homomixer manufactured by Tokushu Kika Kogyo Co., Ltd. The required coarse emulsification means and the fine emulsification means using a high-pressure homogenizer or an ultrasonic homogenizer can be exemplified. The fine emulsification using a high-pressure homogenizer can be generally performed by passing about 2 to 50 times, preferably about 5 to 20 times under a pressure condition of about 200 kg / cm ² or more. In addition, each emulsification operation may be carried out by employing a slight heating operation (for example, 80 ° C. or less, preferably about 40-80 ° C.) which may be carried out at normal temperature.

 [0062] The fat emulsion of the present invention obtained by force is not particularly required, but may be further added with a suitable pH adjuster (acid or alkali) depending on the type of each component to be used to obtain a pH suitable for human administration. After adjustment, the product is filled in an appropriate container, for example, a vial, a syringe, a plastic bag, an ampule, etc., according to a conventional method, and then sterilized by a usual filtration operation, sterilization operation or the like to obtain a final product.

[0063] The pH can be adjusted by adding an appropriate acid or alkali as a pH adjuster. Preferred pH ranges to be adjusted include 5.0-9.0, more preferably 6.0-8.0. Can. The pH can be adjusted at any time before and after the emulsification operation for preparing the fat emulsion of the present invention.

 [0064] The filtration operation can be performed using a normal membrane filter. The sterilization operation can be performed by, for example, high-pressure steam sterilization, hot water immersion sterilization, shower sterilization, or the like. More preferably, the sterilization operation includes, for example, a high-pressure steam sterilization operation (eg, 121 ° C., 12 minutes) using an autoclave.

 [0065] As described above, the fat emulsion of the present invention is excellent in emulsification stability, and in addition, its viscosity and osmotic pressure can be adjusted to those similar to those of a commercially available nutritional fat emulsion. The thus prepared fat emulsion of the present invention is administered to a patient after dissolving or dispersing at least one active ingredient selected from the group consisting of paclitaxel and docetaxelca into the patient. This can reduce the burden on the patient.

 [0066]

 (5) Solubilization of activities or>

 The fat emulsion of the present invention can easily dissolve or disperse therein at least one active ingredient selected from the group consisting of paclitaxel and docetaxel. The drug-containing fat emulsion obtained by force is prevented from adverse effects such as crystal precipitation. The fat emulsion can be in a fine and uniform emulsion form, usually having an average particle size of about 0.3 m or less.

 The present invention provides a method for dissolving or dispersing at least one active ingredient selected from the group consisting of paclitaxel and docetaxelca in the fat emulsion using the fat emulsion of the present invention as described above ( Fat emulsion production method).

 According to this method, it is possible to obtain a desired fat emulsion without recognizing precipitation. Therefore, this method utilizes the fat emulsion of the present invention to dissolve or disperse at least one active ingredient selected from the group consisting of paclitaxel and docetaxel carpa in the fat emulsion. At this time, it can be regarded as a method for preventing the crystal precipitation.

This method can be carried out simply by mixing at least one active ingredient selected from the group consisting of paclitaxel and docetaxel with the fat emulsion of the present invention. The above mixture In general, it can be carried out using a mechanical stirring operation. At that time, no emulsification operation is required again. When preparing the fat emulsion of the present invention and at least one active ingredient selected from the group consisting of paclitaxel and docetaxel, in a form suitable for mixing at the time of use as described below, for example, an injection kit preparation such as a double bag type The mixing can be carried out, for example, by opening the partition of the double bag and slightly shaking the bag.

 [0070] The mixing ratio of the fat emulsion of the present invention and the paclitaxel and docetaxel power is selected from the group consisting of paclitaxel and docetaxel power in the final fat emulsion product obtained after mixing. Generally, the at least one active ingredient is selected from a range that provides a concentration of about 0.01-0.5 w / v%, preferably about 0.02-0.3 w / v%. At least one active ingredient selected from the group consisting of notaritaxel and docetaxel is also dissolved in various forms available, for example, powdered forms (including powders in the form of hydrates), and appropriate dissolution solutions. Any of a liquid form may be used. Usually, it is preferably used in the form of a solution dissolved in polyethylene glycol (PEG), ethanol, or the like.

 [0071] The drug-containing fat emulsion thus obtained is intravenously administered or infused, for example, as an antineoplastic drug in the same manner as a conventional fat emulsion of this kind. During the administration, the fat emulsion is stable and can be used safely without the risk of separating into two layers, enlargement of fat particles and precipitation of sediment.

 [0072]

 (6) The present invention H emulsion was used.开

 The fat emulsion of the present invention can be prepared into various forms in which at least one active ingredient selected from the group consisting of paclitaxel and docetaxel can be mixed at the time of use, for example, a kit form for injection. Specific examples of the kit preparation form include a double bag type, a two-chamber syringe type, and an integrated type (double-ended needle, connecting needle). The preparation into a compact kit preparation for injection can be carried out quickly and accurately, and the prepared preparation can suppress the risk of bacterial contamination and needle stick accidents during compounding in practical use. In addition, it is possible to prevent the particles from increasing even in the current administration using a three-way stopcock.

[0073] Particularly preferred examples of the kit formulation include the fat emulsion of the present invention, paclitaxel and And a product (kit product) in which at least one active ingredient selected from the group consisting of docetaxel and group power and a solvent solution thereof are contained in a specific container. More specifically, the kit milk product according to the present invention is contained in a container having at least two compartments (multiple compartments) partitioned by partitioning means (partition walls) which can be opened and communicated during use. In another room, at least one active ingredient selected from the group consisting of paclitaxel and docetaxel power or a solvent solution thereof is housed.

 [0074] The container used for this product is preferably a flexible container, and a specific example of the container is a double bag known in the field of infusion such as hemodialysis fluid. And the like.

 The double bag (plastic bag-like material) can be formed of various flexible plastics commonly used in medical containers and the like. It is preferable that the plastic has gas nolia property. Specific examples of plastics having gasnolia properties include, for example, resins such as polyethylene terephthalate, polyethylene naphthalate, ethylene'butyl alcohol copolymer, polyvinylidene chloride, polyacrylonitrile, polybutyl alcohol, polyamide, and polyester. Can be mentioned. The container used in the present invention has a force constituted by these various resin films or sheets, a force constituted by a sheet or film obtained by depositing silica, alumina or the like on these films or sheets, and a force constituted by these films or sheets. The laminate force is suitably composed.

 Further, specific examples of means for forming a multiple chamber in the container include, for example, (1) a method of forming a partition by easy peeling (easy peeling) (JP-A-2-4671; No. -5138), (2) a method of forming a partition by sandwiching the chambers with clips (see Japanese Patent Application Laid-Open No. 63-309263), and (3) various communication means that can be opened in the partition. (See Japanese Patent Publication No. 63-20550). Of these, the container described in (1) is particularly suitable for mass production, and the communication operation is easy, so that it is preferable. That is, the partition walls in the container can be easily formed by, for example, fusing a part of the inner surface of the plastic bag-shaped container using a heat seal bar or the like. Further, the seal portion is weak and can be easily opened by pressing.

[0077] The product of the present invention contains the fat emulsion of the present invention in one room of a double bag as described above, One chamber contains at least one active ingredient selected from the group consisting of paclitaxel and docetaxel or a solvent solution thereof. These medicines can be accommodated through, for example, a chemical liquid filling or taking-out port member provided at the upper and lower ends of the container. The resulting product can then be sterilized by high-pressure steam sterilization using an autoclave according to a conventional method. When the product is used, the partition is opened and the chambers are communicated with each other to mix the two preparations contained in each room to prepare a desired mixed fat emulsion. The mixed fat emulsion is used as an antineoplastic agent, which is an original use of at least one active ingredient selected from the group having paclitaxel and docetaxel strength.

Intravenous administration or drip administration can be performed from the above-mentioned drug solution extracting member. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, examples will be given to explain the present invention in more detail. Example 1-3

 (1) Fat emulsions of the present invention (total of 100 mL) having the respective component strengths shown in Table 2 below were prepared as follows.

[0079] [Table 2]

[0080] The following components were used as the components in the table.

[0081] Paclitaxel (Wako Pure Chemical Industries, Ltd.)

Soybean oil (refined soybean oil; Nisshin Oil Co., Ltd.) Egg yolk lecithin (purified yolk lecithin; Kewpie)

 DSPE-PEG (distearoyl phosphatidylethanolamine-polyethylene glyco

 2000

 2000, "SUNBRIGHT DSPE-020CN", NOF Corporation)

 DSPG (Distearoyl phosphatidyl glycerol, NOF Corporation)

 That is, the oily components (soy oil and egg yolk lecithin) were mixed with each component described in Table 2, and

V, mix the mixture with DSPE-PEG, DSPG and oleic acid! /

 2000

 After the addition, a solution prepared by dissolving glycerin in water for injection so that the final concentration becomes 2.21 w / v% is further added thereto, and the mixture is heated under a nitrogen stream using a polytron homogenizer (KINEMATICA) under a nitrogen flow of 25,000. The coarse emulsification took 10 minutes with rotation Z minutes.

[0082] Next, the obtained coarse emulsion was subjected to an emulsification temperature of 40-80 ° C and a nitrogen pressure under a nitrogen stream using a high-pressure homogenizer (APV) until the average particle diameter became μm or less. It was emulsified at 550 kg / cm ² .

 [0083] After adjusting the pH of the obtained emulsion to a predetermined value (pH 5-9) using hydrochloric acid or sodium hydroxide, 10 mL glass vials are filled in 10 mL each, sealed, and then subjected to high pressure steam. After sterilization (121 ° C., 12 minutes), a fat emulsion sample of the present invention was obtained.

 [0084]

 II

 In Example 1, the deviations of DSPE-PEG, DSPG and oleic acid were not added. / ヽ

 2000

 Except for the above, comparative fat emulsion samples comprising the components shown in Table 2 were prepared in the same manner.

 [0085]

 Row 1

 To each sample prepared in the above Examples and Comparative Examples, a 12.5% solution of paclitaxel in polyethylene glycol (PEG400 Nippon Oil & Fats Co.) was added so that the final concentration of paclitaxel was 0.10 w / v%, and then left at room temperature. Then, the presence or absence of the precipitation of crystals was observed over time. The presence or absence of crystal precipitation was visually observed.

 [0086] The results are shown in Table 3.

[0087] [Table 3] Fat emulsion sample storage days (days)

 0 1 2 4 7 Example 1 A A A A A A Example 2 A A A A A A Example 3 A A A A A Comparative example 1 A B B B B

A: No crystal B: Crystal precipitation

[0088] The results shown in Table 3 indicate the following.

 That is, when the fat emulsion of the present invention (Example G3) was used, no precipitation of crystals was observed even after 7 days of storage, and the emulsion state was stably maintained. In contrast, when the comparative fat emulsion shown in Comparative Example 1 was used, precipitation of crystals was already observed one day after storage.

 As described above, according to the present invention, it is possible to obtain a stable fat emulsion containing paclitaxel and at least one active ingredient having a group power of docetaxel, and paclitaxel or the like can be obtained as the fat emulsion. If solubilized or dispersed, the resulting fat emulsion can be safely administered to the human body.

Claims

Claims [1] A fat emulsion for solubilizing or dispersing at least one active ingredient having a group strength of notary taxel and docetaxel, wherein the fat emulsion comprises an oil component, an emulsifier and A stabilizing agent, wherein the stabilizing agent is (a) a linear or branched saturated or unsaturated fatty acid having 10-22 carbon atoms, which is a fatty acid which is esterified to the glycerol moiety; (B) at least one phospholipid selected from the group consisting of phosphatidylglycerol, phosphatidic acid, phosphatidylinositol and phosphatidylserine, (b) phosphatidylethanolamine modified with a polyalkylene glycol, which is esterified to the glycerol portion. Fatty acids are linear or branched saturated or unsaturated fatty acids having 10 to 22 carbon atoms. (C) at least one selected from the group consisting of linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms, or (d) the above (a), ( a mixture of at least two of b) and (c), wherein the stabilizer (a) is 0.01-lw / v% and the stabilizer (b) is 0.01-lw / v%, stabilized in the fat emulsion Formulation (c) A fat emulsion characterized by being present at a concentration of S0.05-5 w / v%. [2] In fat emulsion  (1) oily components are present at a concentration of 2-20 w / v%,  (2) The fat emulsion according to claim 1, wherein the emulsifier is present at a concentration of 0.4 to 10 w / v%.  [3] phosphatidyl glycerol, phosphatidic acid, phosphatidylinositol and the like, wherein the fatty acid esterified to the glycerol moiety is a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms. The fat emulsion according to claim 1, which is at least one selected from phospholipids selected from the group consisting of phosphatidylserine. [4] The phosphatidyl glycerol, phosphatidic acid, phosphatidylinositol and phosphatidyl glycerol wherein the fatty acid esterified to the glycerol moiety is a linear or branched saturated or unsaturated fatty acid having 12 to 18 carbon atoms. The fat emulsion according to claim 1, which is at least one selected from phospholipids selected from the group consisting of phosphatidylserine. [5] The stabilizing agent is distearoyl phosphatidyl glycerol, dipalmitoyl phosphatidyl glycerol, dimyristoyl phosphatidyl glycerol, dioleoyl phosphatidyl glycerol, distearoyl phosphatidic acid, dipalmitoyl phosphatidic acid, dimyristoyl phosphatidic acid , Dioleoyl phosphatidic acid, distearoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol, dimyristoyl phosphatidylinositol, dioleoyl phosphatidylinositol, distearoyl phosphatidyl serine, dipalmitoyl phosphatidyl serine, dimyrtoyl phosphatidyl serine At least one of the phospholipids selected from the group consisting of phospholipids and dioleoylphosphatidylserine. Fat emulsion according to claim 1 is.  [6] The fat emulsion according to claim 1, wherein the stabilizer is distearoyl phosphatidyl glycerol.  [7] The fat emulsion according to claim 3, wherein the stabilizer is present in the fat emulsion at a concentration of 0.03-lw / v%. [8] The stabilizing agent is a phosphatidylethanolamine modified with a polyalkylene glycol, which is esterified to a glycerol moiety, so that a fatty acid having 10 to 22 carbon atoms is linear or branched. 2. The fat emulsion according to claim 1, which is at least one phospholipid derivative which is a saturated or unsaturated fatty acid.  [9] The stabilizing agent is a phosphatidylethanolamine modified with a polyalkylene glycol having an average molecular weight of 1,000 to 5,000, which is esterified to a glycerol portion, and the fatty acid is a straight-chain having 14 to 18 carbon atoms. 2. The fat emulsion according to claim 1, which is at least one phospholipid derivative which is a linear or branched saturated or unsaturated fatty acid.  [10] The stabilizer is at least a phospholipid derivative selected from the group consisting of distearoylphosphatidylethanolamine polyethylene glycol 5000, distearoylphosphatidylethanolamine polyethylene glycol 3000, and distearoylphosphatidylethanolamine polyethylene glycol 2000. 2. The fat emulsion according to claim 1, which is one kind.  [11] The fat emulsion according to claim 8, wherein the stabilizer is present in the fat emulsion at a concentration of 0.1-lw / v%. [12] The stabilizer is a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms. The fat emulsion according to claim 1, wherein the fat emulsion is at least one member selected from the group consisting of: [13] The fat emulsion according to claim 1, wherein the stabilizer is at least one member selected from the group consisting of linear or branched saturated or unsaturated fatty acids having 10 to 20 carbon atoms. [14] The stabilizer is at least one fatty acid selected from the group consisting of oleic acid, isomyristic acid, isopalmitic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid. Item 4. The fat emulsion according to Item 1. [15] The fat emulsion according to claim 12, wherein the stabilizer is present in the fat emulsion at a concentration of 0.05-2 w / v%.  [16] A fat emulsion containing the active ingredient in a dissolved or dispersed state, comprising mixing at least one active ingredient selected from the group consisting of notaritaxel and docetaxel strength with the fat emulsion according to claim 1. Production method. [17] Use of the fat emulsion according to claim 1, for producing a fat emulsion containing at least one active ingredient selected from the group consisting of notaritaxel and docetaxel in a dissolved or dispersed state.  [18] A container for a fat emulsion containing at least one active ingredient selected from the group consisting of notaritaxel and docetaxel and dissolved or dispersed therein, the container being partitioned by communicable partition means. It has a multi-compartment, one of which contains the fat emulsion of claim 1, and the other contains at least one active ingredient selected from the group consisting of paclitaxel and docetaxel. Container.  [19] A method for preventing crystal precipitation of an active ingredient in a fat emulsion containing at least one active ingredient selected from the group consisting of notaritaxel and docetaxel, wherein the active ingredient is described in claim 1 A method comprising mixing with a fat emulsion.