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WO2005065676A1 - Emulsion grasse contenant paclitaxel ou docetaxel - Google Patents

Emulsion grasse contenant paclitaxel ou docetaxel Download PDF

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Publication number
WO2005065676A1
WO2005065676A1 PCT/JP2005/000059 JP2005000059W WO2005065676A1 WO 2005065676 A1 WO2005065676 A1 WO 2005065676A1 JP 2005000059 W JP2005000059 W JP 2005000059W WO 2005065676 A1 WO2005065676 A1 WO 2005065676A1
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WO
WIPO (PCT)
Prior art keywords
fat emulsion
fatty acid
stabilizer
acid
carbon atoms
Prior art date
Application number
PCT/JP2005/000059
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English (en)
Japanese (ja)
Inventor
Koichi Takeda
Kenji Matsuda
Toshimitsu Terao
Tadaaki Inoue
Original Assignee
Otsuka Pharmaceutical Factory, Inc.
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Filing date
Publication date
Application filed by Otsuka Pharmaceutical Factory, Inc. filed Critical Otsuka Pharmaceutical Factory, Inc.
Publication of WO2005065676A1 publication Critical patent/WO2005065676A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a stable fat emulsion containing paclitaxel or docetaxel in a dissolved or dispersed state and having an acidic pH, a method for preparing the same (a method for stabilizing a fat emulsion in an acidic region), and a method for preparing the fat emulsion. For stabilizers.
  • Active ingredients administered intravenously, orally, or enterally as injections or the like each have a stable pH range.
  • Paclitaxel and docetaxel known as antineoplastic agents, are unstable in alkaline or neutral fluids.Potency is less than 7, especially around 6 or less. Since it is stable in the region, it is formulated in the acidic region (see Patent Document 1).
  • the resulting formulation has less emulsifying stability than the formulation having the above-mentioned acidic pH, but has a serious disadvantage that the activity of the active ingredient itself rapidly decreases. is there.
  • Patent Document 2 discloses a method for obtaining a stable fat emulsion by using these surfactants as a stabilizing agent and mixing a fat emulsion and an injection in the presence of the surfactant. (See Patent Document 2).
  • polysorbate 80 as described above is not yet permitted in Japan as a food additive, and its use is problematic in terms of safety.
  • Polyoxyethylene hydrogenated castor oils 50 and 60 are also known to cause side effects such as the appearance of anaphylactic shock and have a safety problem (Patent Document 3, especially page 1, 22-). 30 Line).
  • Non-patent Document 1 Non-patent Document 1
  • Patent Document 1 US Patent No. 6,071,952
  • Patent Document 2 Japanese Patent Application Laid-Open No. 08-127529
  • Patent Document 3 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.
  • An object of the present invention is to provide a new stabilizer which can be used for solubilizing or dispersing paclitaxel or docetaxel, and a technique for solubilizing or dispersing the above-mentioned drug using the same to obtain a stable fat emulsion. It is in.
  • the present inventors have conducted intensive studies and found that paclitaxel or docetaxel fat A new stabilizer effective for solubilization or dispersion in an emulsion has been found.
  • the present inventors have established a technique for solubilizing or dispersing paclitaxel or docetaxel in an acidic fat emulsion by using the stabilizing agent, and intensively containing paclitaxel or docetaxel in a acidic region.
  • a fat emulsion was found.
  • the present invention has been completed as a result of further research based on these findings.
  • the present invention provides a fat emulsion, a stabilizer for the fat emulsion, use of the stabilizer and a method for stabilizing a fat emulsion described in the following section 1-19.
  • Item 1 A stable fatty emulsion containing at least one active ingredient selected from the group consisting of norritaxel and docetaxel, an oily ingredient, an emulsifier, and a stabilizer, and having an acidic pH.
  • the stabilizer is
  • a phosphatidylethanolamine modified with a polyalkylene glycol 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 stabilizer (a) is present in the fat emulsion at a concentration of 0.01-lw / v%, the stabilizer (b) is present at a concentration of 0.01_lw / v%, and the stabilizer (c) is present at a concentration of 0.05-5w / v%.
  • a fat emulsion characterized in that:
  • the active ingredient is present at a concentration of 0.01-0.5 w / v%
  • the oily component is present at a concentration of 2-20 w / v%
  • Item 3 The fat emulsion according to Item 2, wherein the acidic pH is less than 7, or 4 or more.
  • 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 10 to 22 carbon atoms.
  • Item 14. The lipid emulsion according to any one of Items 13 to 13, which is at least one type of phospholipid selected from the group consisting of phosphatidylinositol and phosphatidylserine.
  • Item 5 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 type of phospholipid selected from the group consisting of phosphatidylinositol and phosphatidylserine.
  • 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 phosphatidylinositol, distearoyl phosphatidyl phosphatidyl phosphatidyl phosphatidyl
  • Item 7 The fat emulsion according to any one of Items 13 to 13, wherein the stabilized IJ is distearoylphosphatidylglycerol.
  • Item 8 The fat emulsion according to any one of Items 417, wherein the stabilizer is present in the fat emulsion at a concentration of 0.03_lw / v%.
  • the stabilizer is a phosphatidylethanolamine modified with a polyalkylene glycol, and the fatty acid esterified to the glycerol moiety is a linear or branched saturated fatty acid having 10 to 22 carbon atoms.
  • Item 13 The fat emulsion according to any one of Items 13 to 13, which is at least one kind of a phospholipid derivative which is an unsaturated fatty acid.
  • the stabilizer is modified with a polyalkylene glycol having an average molecular weight of 1,000 to 5,000.
  • Phosphatidylethanolamine wherein the fatty acid esterified to the glycerol moiety is at least one type of phospholipid derivative in which the fatty acid is a linear or branched saturated or unsaturated fatty acid having 14 to 18 carbon atoms.
  • Item 14 The fat emulsion according to any one of Items 1-3.
  • the phospholipid selected from the group consisting of distearoyl phosphatidylethanolamine polyethylene glycol 5000, distearoyl phosphatidyl ethanolamine polyethylene glycol 3000, and distearoyl phosphatidyl ethanolamine polyethylene glycol 2000, wherein the stabilized lj is lj Item 14.
  • the fat emulsion according to any one of Items 13 to 13, which is at least one derivative.
  • Item 12 The fat emulsion according to any one of Items 9-11, wherein the stabilizer is present in the fat emulsion at a concentration of 0.1_lw / v%.
  • Item 13 The item according to any one of items 13 to 13, 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 22 carbon atoms.
  • Item 14 The item 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 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 any one of Items 1 to 3, which is a seed.
  • Item 16 The fat emulsion according to any one of Items 13 to 15, wherein the stabilizer is present in the fat emulsion at a concentration of 0.05-2 w / v%.
  • Item 17 Use of the following stabilizer (a)-(d) for the production of a fat emulsion according to any of items 1 to 11:
  • Item 18 A stabilizer for a stable fat emulsion, containing at least one active ingredient selected from the group consisting of norritaxel and docetaxel in a dissolved or dispersed state and having an acidic pH, ,
  • a phosphatidylethanolamine modified with a polyalkylene glycol 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.
  • Item 19 A method for stabilizing a fat emulsion having at least one active ingredient selected from the group consisting of paclitaxel and docetaxel in a dissolved or dispersed state and having an acidic pH, wherein the fat emulsion further comprises Add the following stabilizers (a)-(d), and add 0.01-lw / v% of stabilizer (a) and 0.01-lw / v% of stabilizer (b) in the resulting fat emulsion. , Stabilizer (c)
  • A Fatty acid power esterified to glycerol moiety S, phosphatidino reglycerol, phosphatidine, which is 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 an acid, phosphatidylinositol and phosphatidylserine, (b) a phosphatidylethanolamine modified with a polyalkylene glycol, 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. At least one lipid derivative,
  • the present invention also provides a fat emulsion described in the following Items 20 to 21.
  • 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 0.01 to 1 ⁇ m.
  • Item 21 The fat emulsion according to any one of items 11 to 16 and 20, wherein the fat emulsion retains 90% or more of the activity of the active ingredient contained after autoclaving.
  • the fat emulsion of the present invention a stable fat emulsion containing paclitaxel or Z and docetaxel and having an acidic pH (hereinafter, may be referred to as “the fat emulsion of the present invention”) will be described in detail.
  • the fat emulsion of the present invention contains at least one selected from the group consisting of paclitaxel and docetaxel as an active ingredient. These are known as anti-neoplastic compounds.
  • the blending ratio in the fat emulsion of the present invention is described in “
  • the fat emulsion of the present invention contains an oil component, an emulsifier, and a stabilizer, in addition to the active components.
  • the oil component used is usually a vegetable oil.
  • 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.
  • the oil component may be a medium-chain triglyceride.
  • Specific examples include various commercially available products such as "COCONARD” (COCONARD TM, Kao Corporation), ⁇ TM (Nissin Oil Co., Ltd.), "Miglyol” (Myglyol TM, SASOL), "Panasate” (Panasate TM, Nippon Yushi Co., Ltd.).
  • the oil component is not limited to the above-described vegetable oil and medium-chain triglyceride, and may be, for example, one kind of animal oil, mineral oil, synthetic oil, essential oil, etc., or a mixture of two or more kinds. There may be. Further, these animal oils and the like may be used in combination with the vegetable oil and / or the medium-chain triglyceride.
  • emulsifiers include natural phospholipids such as egg yolk lecithin, egg yolk phosphatidylcholine, soy lecithin, soy phosphatidylcholine, hydrogenated yolk lecithin obtained by hydrogenating them, hydrogenated egg yolk phosphatidylcholine, hydrogenated soy lecithin, water Soybean phosphatidylcholine and the like can be mentioned.
  • the emulsifier may be chemically synthesized phosphatidylcholine and phosphatidylethanolamine.
  • the chemically synthesized phosphatidylcholine includes dipalmitoyl phosphatidylcholine, dimyristyl phosphatidylcholine, distearoyl phosphatidylcholine, dioleoyl phosphatidylcholine, and the like.
  • the chemically synthesized phosphatidylethanolamine includes dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, and dioleoylphosphatidylethanolamine.
  • emulsifiers can be used alone or as a mixture of two or more.
  • preferred emulsifiers are egg yolk lecithin, egg yolk phosphatidinorecolin, soy lecithin and soy phosphatidylcholine.
  • the stabilizer is selected from the group consisting of the following (a) to (d).
  • A Fatty acid power S esterified to the glycerol moiety S, a linear or branched saturated or unsaturated fatty acid having 10 to 22 carbon atoms, preferably a linear fatty acid having 18 carbon atoms
  • a phosphatidylethanolamine modified with a polyalkylene glycol where the fatty acid esterified 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 saturated or unsaturated fatty acid having carbon atoms. At least one phospholipid derivative that is a fatty acid,
  • the “glycerol moiety” refers to the structures of phosphatidylglycerol, phosphatidic acid, phosphatidylinositol and phosphatidylserine, and phosphatidinoleethanolamine (the constituent fatty acid is palmitic acid). In each of the following formulas, it refers to the illustrated portion.
  • Glycerol moiety 5 Fatty acid constituting phospholipid (&) (ie, fatty acid esterifying glycerol moiety of phospholipid ⁇ ), fatty acid constituting phospholipid derivative (b) (ie, phospholipid derivative ( b Dali ) Specific examples of the fatty acid obtained by esterifying the serol moiety and the fatty acid (C) include naturally occurring linear or branched saturated or unsaturated fatty acids.
  • fatty acids include, for example, linear acids such as acetic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, oleic acid, linolenic acid, linolenic acid, arachidonic acid and eicosapentaenoic acid.
  • linear acids such as acetic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, oleic acid, linolenic acid, linolenic acid, arachidonic acid and eicosapentaenoic acid.
  • Fatty acids and branched chain fatty acids such as isomyristic acid, isopalmitic acid, isostearic acid, and isoarachidonic acid.
  • 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 phosphatidino Le glycerol, diarachidoyl phosphatidyl glycerol, dibehenyl phosphatidic acid, distearoyl phosphatidylinositol, distearoyl phosphatidic acid, distearoyl phosphatidyl serine, diisomyristoyl phosphatidyl glycerol, diiso stearoyl phosphatidyl acid, diso arathiyl, diiso arachidyl, etc. Is included.
  • distearoyl phosphatidyl glycerol distearoyl phosphatidyl acid, distearoyl phosphatidylinositol and distearoyl phosphatidyl serine are preferred, and distearoyl phosphatidyl glycerol and distearoyl phosphatidic acid are more preferred. .
  • 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).
  • R 1 and R 2 are linear or branched saturated or unsaturated fatty acids having 10 to 22 carbon atoms, preferably linear or branched chains having a carbon number of 14 to 18) Saturated or unsaturated This shows the residue obtained by removing the carboxy group from the fatty acid (constituent fatty acid).
  • R 3 and R 4 represent a hydrogen atom or a methyl group.
  • -X- is the group -CO (CH) CO-, -CO (CH) CO-
  • n represents an integer of 20 to 120.
  • 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.
  • phospholipid derivative (b) in the present invention include, for example, distearoyl phosphatidylethanolamine polyethylene glycol 5000 (SUNBRIGHT
  • DSPE-050C distearoyl phosphatidylethanolamine polyethylene glycol 3000 (MPEG 3000PE, Avanti), distearoyl phosphatidyl ethanolamine polyethylene glycol 2000 (SUNBRIGHT DSPE_020CN, NOF Corporation), etc.
  • 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.
  • each of the above-listed compounds can be used singly, And two or more types can be used together.
  • the compounds belonging to the respective groups of the phospholipid (a), the phospholipid derivative (b), and the fatty acid (c) are appropriately selected and used together. It is possible.
  • the phospholipid (a) is incorporated in the fat emulsion of the present invention at a final concentration of 0.01-lw / v% (when two or more phospholipids are used in combination, The total amount is the same, hereinafter the same), more preferably within the range of 0.03_lw / v%. Utilization within this range can provide a fat emulsion having excellent emulsion stability as expected of the present invention.
  • w / v% representing the blending amount (concentration) of the stabilizer and each of the other components in the fat emulsion of the present invention is represented by the weight of each component / the volume of the fat emulsion lOOmL. means.
  • the blending amount of the phospholipid derivative (b) in 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 It is appropriate to select from the range of 0.1-lw / v%. Utilization within this range provides a fat emulsion having excellent emulsion stability in the present invention.
  • 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 0.05-2w / v% range Force It is appropriate to be selected. Utilization in this range can provide a fat emulsion having excellent emulsion stability as expected in the present invention.
  • the components used in combination 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. Generally, the total amount of each component used in combination is within the range of 0.01-lw / v% at the final concentration in the fat emulsion of the present invention, more preferably
  • the use of the above-mentioned specific stabilizer has excellent emulsification stability, high safety, and hardly decreases the activity of the active ingredients paclitaxel and docetaxel. It has been found for the first time that a fat emulsion can be obtained.
  • the present invention provides a lipid emulsion containing the phospholipid (a), the phospholipid derivative (b) or the fatty acid (c), which is solubilized or dispersed in paclitaxel or docetaxel and is stable in an acidic region.
  • a stabilizer is solubilized or dispersed in paclitaxel or docetaxel and is stable in an acidic region.
  • the present invention further comprises adding a predetermined amount of the stabilizer containing the phospholipid (a), the phospholipid derivative (b) or the fatty acid (c) to paclitaxel or docetaxel, an oil component and an emulsifier,
  • the present invention also provides a method for stabilizing a fat emulsion in which paclitaxel or docetaxel is solubilized or dispersed in an acidic region, comprising emulsifying the obtained mixture.
  • the fat emulsion of the present invention can be further compounded with various additives, if desired.
  • additives are included in this type of emulsion which can be administered by injection.
  • Antioxidants, antibacterial agents, pH adjusters, tonicity agents, and the like which 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.
  • 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.
  • glycerin As the tonicity agent, glycerin; sugars such as glucose, fructose and maltose; sugar alcohols such as sorbitol and xylitol can be used.
  • 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 obtained emulsion.
  • the amounts of these additives are obvious to those skilled in the art, and are not particularly different from those conventionally known.
  • the fat emulsion of the present invention can further be added with a cyclodextrin compound, if necessary.
  • the use of the cyclodextrin compound may make it possible to stably solubilize or disperse the drug to be solubilized or dispersed at a higher concentration.
  • the cyclodextrin compounds include cyclodextrins, 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.
  • the blending amount of the cyclodextrin compound in the fat emulsion of the present invention can be appropriately selected from the range of about 0.01 to 50 w / v%, preferably about 0.02 to 40 w / v%.
  • the amount of the cyclodextrin conjugate is preferably selected so as to be in an equimolar amount to about 3000 times the molar amount of the emulsifier constituting the fat emulsion.
  • the method for preparing the fat emulsion of the present invention is not particularly limited as long as an emulsion can be obtained, and can be a general method.
  • a typical method is to mix paclitaxel or docetaxel, an oil component, an emulsifier, a stabilizing agent, and, if necessary, an oil-soluble additive component.
  • a method of adding water for injection to the compound, coarsely emulsifying the mixture, and then finely emulsifying (perfectly emulsifying) using an appropriate high-pressure emulsifier or the like can be employed.
  • the mixing ratio of paclitaxel or docetaxel, the oil component and the emulsifier in the fat emulsion of the present invention is determined by the concentration of the obtained emulsion (final fat emulsion product), that is, weight% (final concentration, w / v%), the amount of paclitaxel or docetaxel is 0.01 to 0.5 w / v%, the oil component is 2 to 20 w / v%, and the emulsifier is 0.4 to 10 w / v%.
  • a particularly preferred blending ratio is selected from the amounts that give paclitaxel or docetaxel in a final concentration of 0.02-0.3 w / v%, an oil component of 3_10 w / v%, and an emulsifier of 0.5_7 w / v%.
  • the mixing ratio of the stabilizer in the fat emulsion of the present invention is as described in (2) above.
  • the coarse emulsification and the fine emulsification employed in the above method for example, using a homomixer such as TK homomixer manufactured by Tokushu Kika Kogyo Co., Ltd., usually for 5000 minutes or more for 5 minutes or more at Z minutes
  • 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 carried out by passing about 2 to 50 times, preferably about 5 to 20 times under a pressure condition of about 200 kg m 2 or more.
  • each emulsification operation is carried out by employing a slight heating operation (for example, 80 ° C. or less, preferably about 40-70 ° C.) which can be performed at room temperature.
  • the fat emulsion of the present invention obtained by force is not particularly required, but depending on the type of each component to be used, a suitable pH adjuster is further added to adjust the pH.
  • a suitable pH adjuster is further added to adjust the pH.
  • the pH can be adjusted by adding an appropriate acid or alkali as a pH adjuster.
  • the preferred pH range to be adjusted is about 5.0 or more, less than 7.0, and more preferably about 5.0-6.5.
  • the adjustment of the pH can be performed at any time before and after the milking operation for preparing the fat emulsion.
  • 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.
  • Preferred sterilization operations include, for example, autoclaving using autoclave (eg,
  • the fat emulsion of the present invention has excellent emulsification stability based on the inclusion of a specific stabilizer.
  • the stabilizer itself is excellent in safety, and therefore, the present invention fat emulsion also has a feature of high safety.
  • the excellent emulsification stability of the fat emulsion of the present invention is that the emulsified state is not substantially changed in an acidic pH region, usually 5.0 or more and less than 7.0.
  • the fat emulsion of the present invention has excellent temperature stability. That is, even when the fat emulsion of the present invention is subjected to a heat sterilization operation such as high-pressure steam sterilization, the emulsion stability is maintained without being impaired by the operation.
  • the fat emulsion of the present invention is characterized in that the average particle size of the emulsified particles is as fine as about 0.3 zm or less, and the particle size does not substantially change before and after sterilization. Furthermore, the above-mentioned emulsion stability is maintained even after long-term storage (for example, 3 months at 40 ° C). That is, the fat emulsion of the present invention is characterized in that the emulsified particles are negatively charged, and the emulsion does not break down, separate into two layers, precipitate or the like due to long-term storage.
  • the fatty emulsion of the present invention not only maintains excellent emulsification stability for a long period of time, but also maintains the activity of paclitaxel or docetaxel contained as an active ingredient by the above-mentioned heat sterilization operation and subsequent long-term storage. It also has the characteristic that it hardly decreases.
  • Emulsifier 0.4-10 w / v% 0.5-7 w / v%
  • the fat emulsion of the present invention is excellent in emulsification stability and activity retention of active ingredients, and further has the same viscosity and osmotic pressure as those of commercially available nutritional fat emulsions. Can be easily prepared. The adjustment of the viscosity and the osmotic pressure has an advantage that the burden on the patient can be reduced when the obtained fat emulsion is administered to the patient.
  • the fat emulsion of the present invention is administered intravenously or intravenously, for example, as an antineoplastic drug in the same manner as a conventional fat emulsion.
  • the fat emulsion itself is stable and can be used safely without risk of separation into two layers, enlargement of fat particles, and precipitation of sediment.
  • the fat emulsion product of the present invention is prepared by previously blending an active ingredient with a stabilizer having excellent safety in one agent, the mixing operation at the time of use is not required unlike a two-pack type product. Yes, there is no concern about medical accidents due to poor mixing during use, and there is an advantage that handling is very simple.
  • a fat emulsion of the present invention comprising the components shown in Table 2 below (total amount of 100 mL) was prepared as follows.
  • Soybean oil (refined soybean oil; Nisshin Oil Co., Ltd.)
  • DSPE-PEG disearoyl phosphatidylethanolamine-polyethylene glycol 2000, rsUNBRIGHT DSPE-020CNJ, manufactured by NOF Corporation
  • DSPG Disistearoyl phosphatidyl glycerol, NOF Corporation
  • the active ingredient paclitaxel or docetaxel
  • soybean oil were mixed. Then, after adding any of DSPE-PEG, DSPG and oleic acid, and egg yolk lecithin, the mixture was further added. A solution prepared by dissolving glycerin in water for injection to a final concentration of 2.21 w / v% is added to the obtained mixture, and the mixture is mixed with a polytron homogenizer.
  • the obtained coarse emulsified liquid was subjected to an emulsification temperature of 40 to 80 ° C using a high-pressure homogenizer (APV) under a nitrogen stream until the average particle diameter became 0.3 ⁇ or less.
  • the emulsion was finely emulsified at an emulsification pressure of 550 kg m 2 .
  • a 10 mL glass vial was filled in 10 mL portions and sealed to obtain a fat emulsion sample.
  • a sample adjusted to the alkaline region (pH 8) was prepared for reference.
  • Comparative fat emulsion samples (pH 5, 5.5, 6, and 8) containing paclitaxel were prepared in the same manner as in Example 1 except that DSPE-PEG was not added.
  • Comparative fat emulsion samples (pH 5, 5.5, 6 and 8) containing docetaxel were prepared in the same manner as in Example 4 except that DSPG was not added.
  • Table 4-9 shows the results of determining the particle size of the emulsified particles before and after sterilization of each sample.
  • Table 4 shows the results for the samples described in Example 1
  • Table 5 shows the results for the samples described in Example 2
  • Table 6 shows the results for the samples described in Example 3
  • Table 7 shows the results for the samples described in Example 3.
  • Table 8 shows the result of the sample described in Comparative Example 1
  • Table 9 shows the result of the sample described in Comparative Example 2.
  • Table 10 shows the results of determining the residual ratio (%) of the active components after sterilization of the samples obtained in Examples 1 and 2.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un émulsion grasse stable contenant paclitaxel or docetaxcel à l'état d'une dispersion ou une solution présentant un pH acide, un stabilisant pour application dans l'émulsion grasse et un procédé pour stabiliser un émulsion graisse contenant paclitaxel ou docetaxcel à l'état d'une dispersion ou une solution présentant un pH acide. L'émulsion graisse comporte au moins un ingrédient actif sélectionné parmi paclitaxel et docetaxcel, un ingrédient huileuse, un émulsifiant et un stabilisateur, par exemple, le phosphatidylglycérol, sélectionné parmi les phospholipides, dérivés de phospholipides, et acides gras.
PCT/JP2005/000059 2004-01-09 2005-01-06 Emulsion grasse contenant paclitaxel ou docetaxel WO2005065676A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004-004025 2004-01-09
JP2004004025 2004-01-09

Publications (1)

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WO2005065676A1 true WO2005065676A1 (fr) 2005-07-21

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PCT/JP2005/000059 WO2005065676A1 (fr) 2004-01-09 2005-01-06 Emulsion grasse contenant paclitaxel ou docetaxel

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TW (1) TW200526269A (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2387991A1 (fr) 2006-02-01 2011-11-23 Adventrx Pharmaceuticals, Inc. Compositions pharmaceutiques stabilisées à succinate de vitamine E, procédés de préparation et utilisation associée
US8470873B2 (en) 2006-02-01 2013-06-25 Mast Therapeutics, Inc. Vitamin E succinate stabilized pharmaceutical compositions, methods for the preparation and the use thereof
US8557861B2 (en) 2004-09-28 2013-10-15 Mast Therapeutics, Inc. Low oil emulsion compositions for delivering taxoids and other insoluble drugs

Citations (5)

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Publication number Priority date Publication date Assignee Title
US5478860A (en) * 1993-06-04 1995-12-26 Inex Pharmaceuticals Corp. Stable microemulsions for hydrophobic compound delivery
JPH08508046A (ja) * 1993-11-12 1996-08-27 ザ・リサーチ・ファウンデーション・オヴ・ステイト・ユニヴァーシティ・オヴ・ニューヨーク タキソール製剤
JPH09278672A (ja) * 1996-04-12 1997-10-28 Green Cross Corp:The 薬物含有脂肪乳剤
JPH10502921A (ja) * 1994-07-19 1998-03-17 ヘマジェン／ピーエフシー タキシン類（タキソール）を含んでいる安定な水中油エマルジョンおよびその製造方法
WO2000040236A1 (fr) * 1999-01-04 2000-07-13 Hans Dietl Emulsion sterile et stable contenant des taxanes et son procede de production

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478860A (en) * 1993-06-04 1995-12-26 Inex Pharmaceuticals Corp. Stable microemulsions for hydrophobic compound delivery
JPH08508046A (ja) * 1993-11-12 1996-08-27 ザ・リサーチ・ファウンデーション・オヴ・ステイト・ユニヴァーシティ・オヴ・ニューヨーク タキソール製剤
JPH10502921A (ja) * 1994-07-19 1998-03-17 ヘマジェン／ピーエフシー タキシン類（タキソール）を含んでいる安定な水中油エマルジョンおよびその製造方法
JPH09278672A (ja) * 1996-04-12 1997-10-28 Green Cross Corp:The 薬物含有脂肪乳剤
WO2000040236A1 (fr) * 1999-01-04 2000-07-13 Hans Dietl Emulsion sterile et stable contenant des taxanes et son procede de production

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Title
IWASAWA ET AL: "Kaimen Handbook", 27 September 2001, NTS, pages: 992 - 997, XP002997666 *
SINGLA A.K. ET AL: "Paclitaxel and its formulations", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 235, 20 March 2002 (2002-03-20), pages 179 - 192, XP002298069 *
WHEELER J.J. ET AL: "Polyethylene Glycol Modified Phospholipids Stabilize Emulsions Prepard from Triacylglycerol", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 83, no. 11, November 1994 (1994-11-01), pages 1558 - 1564, XP001016109 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8557861B2 (en) 2004-09-28 2013-10-15 Mast Therapeutics, Inc. Low oil emulsion compositions for delivering taxoids and other insoluble drugs
EP2387991A1 (fr) 2006-02-01 2011-11-23 Adventrx Pharmaceuticals, Inc. Compositions pharmaceutiques stabilisées à succinate de vitamine E, procédés de préparation et utilisation associée
US8470873B2 (en) 2006-02-01 2013-06-25 Mast Therapeutics, Inc. Vitamin E succinate stabilized pharmaceutical compositions, methods for the preparation and the use thereof

Also Published As

Publication number Publication date
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