WO1992004886A1 - Emulsion grasse pour injection intraveineuse - Google Patents

Emulsion grasse pour injection intraveineuse Download PDF

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Publication number
WO1992004886A1
WO1992004886A1 PCT/JP1991/001283 JP9101283W WO9204886A1 WO 1992004886 A1 WO1992004886 A1 WO 1992004886A1 JP 9101283 W JP9101283 W JP 9101283W WO 9204886 A1 WO9204886 A1 WO 9204886A1
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WO
WIPO (PCT)
Prior art keywords
fat emulsion
glycol
fat
emulsion
particle size
Prior art date
Application number
PCT/JP1991/001283
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English (en)
Japanese (ja)
Inventor
Hiroshi Tanimura
Yoshio Maniwa
Katsunari Takifuji
Original Assignee
Meito Sangyo Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Meito Sangyo Co., Ltd. filed Critical Meito Sangyo Co., Ltd.
Publication of WO1992004886A1 publication Critical patent/WO1992004886A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to a lipid emulsion for intravenous injection which is metabolized immediately after administration, has a low possibility of causing emboli in the retinal system such as lung, liver, spleen, etc., has a small particle size, and is excellent in stability. Things.
  • Fat emulsions are used parenterally as a source of energy or essential fatty acids to provide nutrition to patients.
  • Oils and fats are emulsified with an emulsifier and provided in the form of fine particles.
  • Intralipid a commercially available intravenous fat emulsion (trade name sold by Otsuka Pharmaceutical Co., Ltd.)) developed by Wret liquid in 1960. Since then, fat emulsion has been based on soybean oil or safflower oil. Emulsions with lecithin or egg yolk lecithin dominate and have not changed much in the last 20 years. Currently, MCT fat emulsions and fat emulsions using chemically synthesized structured lipids are being studied.
  • the particle diameter of the fat particles is irregular, ranging from 0.2 to 1.2 m, and sometimes large, exceeding 5 x m.
  • microemboli may be caused in tissues of the retina such as lung, spleen, and liver Kupffer cell (Kupffer cell).
  • liver failure the metabolism in the liver is slow, and in the case of cirrhosis, the incorporation of exogenous fat emulsion particles is reduced due to the decrease and narrowing of hepatic endothelial cell pores through which fat particles pass. Because of the hindrance, only the endogenous fat could be used.
  • conventional fat emulsions have a relatively low metabolic rate, which increases the triglyceride concentration in liver tissue, which limits the administration to patients with liver disease.
  • conventional fat emulsions have poor stability at high temperatures or during long-term storage, and have the problem of flocculation and creaming.
  • phosphatidylated polyvalent alcohol a compound in which the hydroxyl group of a specific polyvalent alcohol is substituted with a phosphatidyl group (hereinafter referred to as phosphatidylated polyvalent alcohol). ) was used as the main emulsifier to find that an excellent fat emulsion satisfying the above requirements was obtained, and completed the present invention.
  • the present invention provides, as a main emulsifier, at least one selected from the group consisting of phosphatidylglycerol, phosphatidylpolyglycerol, phosphatidylethylene glycol, diphosphatidylethylene glycol, phosphatidylpolyethylene glycol, and diphosphatidylpolyethylene glycol.
  • Another object of the present invention is to provide a fat emulsion for intravenous injection characterized in that it contains.
  • FIG. 1 shows changes in serum neutral fat concentration after intravenous administration of a fat emulsion.
  • FIG. 2 shows the change in neutral fat concentration in liver tissue after intravenous administration of a fat emulsion.
  • phosphatidyl glycerol and phosphatidyl polyglycerol used in the present invention are represented by the following general formula (1)
  • phosphatidylethylene glycol and phosphatidyl polyethylene glycol are represented by the following general formula (2)
  • diphosphatidylethylene glycol and diphosphatidyl Polyethylene glycol has a structure represented by the following general formula (3).
  • R ′, R 2 , R 3 and R 4 may be the same or different, and each represents a saturated or unsaturated acyl group having 6 to 32 carbon atoms, preferably 12 to 18 carbon atoms, and m represents 1 to A number of 10 and n is an integer of 1 -150.
  • the phosphatidylglycerol used in the present invention is widely distributed in nature and is particularly present in a large amount in plants and bacteria, and can be synthesized and prepared therefrom by an extraction operation.
  • Chemistry Experiment Lecture 3 Lipid Chemistry pp. 294-295 (Tokyo Kagaku Dojin) 1974, etc.] and reacting phospholipase D with lecithin contained in soybean, egg yolk, etc. as raw material in the presence of glycerol Can be easily prepared. Further, these phospholipids after the transfer can be purified by solvent fractionation, high performance liquid chromatography, etc., if necessary.
  • the phosphatidylpolyglycerol, phosphatidylethylene glycol, phosphatidylpolyethylene glycol, diphosphatidylethylene blendol and diphosphatidylpolyethylene glycol used in the present invention are also contained in, for example, soybeans, egg yolks, etc. according to known methods.
  • the polyglycerin used herein include those having a degree of condensation of 2 to 10, and polyethylene glycol.
  • the glycol include diethylene glycol, triethylene glycol, and various polyethylene glycols having an average molecular weight of 200 to 6,000.
  • emulsifiers can be used alone or in combination of two or more.
  • the use amount thereof is not particularly limited, but is preferably about 0.1 to 5% by weight based on the fat emulsion.
  • the emulsifier for the fat emulsion of the present invention basically, only the above-mentioned phosphatidylated polyvalent alcohol is used, but other emulsifiers may be blended within a range of less than 40% by weight.
  • the resulting phosphatidylated polyvalent alcohol may contain lecithin as a raw material, but the remaining amount is less than 40% by weight. It is particularly desirable that the content be less than 20% by weight.
  • the concentration of the phosphatidylated polyvalent alcohol is a value quantified according to the description of the standard method for analysis of fats and oils (edited by Japan Oil Chemists' Society).
  • the lipid used in the present invention may be any liquid at room temperature, and is not particularly limited. Among them, soybean oil, sesame oil, rapeseed oil, cottonseed oil, safflower oil, and olive oil Oil, structured lipid, etc. are preferred.
  • the amount of the lipid used is not particularly limited, but is preferably about 5 to 25% by weight based on the fat emulsion.
  • the intravenous fat emulsion of the present invention is produced, for example, as follows. That is, first, coarse emulsification is carried out by a liquid crystal dispersion method using an oil droplet dispersion phase in a liquid crystal, using the phosphatidylated polyvalent alcohol [(1), (2) or (3) as an emulsifier. It is carried out by fine emulsification by the method. To carry out the coarse emulsification, first, the above-mentioned phosphatidylated polyvalent alcohol (1), (2) or (3) is mixed with glycerin and water in an amount of about twice each, and a surfactant is added. Allow a phase to form.
  • a lamellar liquid crystal phase is formed by adding a small amount of a lipid such as soybean oil to the surfactant phase while stirring the same amount or twice as much as the surfactant phase. Add 3 to 10 times the amount of water to this liquid crystal phase while stirring little by little, and use Ultra Homo Mixer on lOOOOrpm 1
  • an oil-in-water emulsion is obtained by coarse emulsification at 5000 rpm or more for 10 minutes or more.
  • an oil-in-water emulsion having a small particle diameter can be obtained by emulsification using a high-pressure homogenizer or an ultrasonic homogenizer.
  • the conditions for milking are not particularly limited, but in the case of ultrasonic emulsification, emulsification at 100 W or more, preferably 200 W or more, preferably for 10 minutes or more is preferable.
  • these refining means in the case of mass production, it is preferable to use a high-pressure homogenizer.
  • the resulting emulsion can be adjusted to pH with aqueous rukari solution. After adjusting to ⁇ 8, filtration is continued several times with a membrane filter with a pore size of 1 to 5 ⁇ , and finally, once with a membrane filter with a pore size of 0.4 to 0.5 / im.
  • a fat emulsion having a particle size of 0.3 / m or less and having a relatively uniform particle size can be obtained. This is dispensed under a nitrogen atmosphere, and then sterilized using an autoclave, thereby obtaining a fat emulsion that can be injected intravenously into a living body without largely changing the particle size before and after sterilization.
  • Example 1 Phosphatidylglycerol derived from soybean lecithin as an emulsifier (prepared by allowing phospholipase D to act on soybean lecithin in the presence of glycerol: “Standard fat and oil test analysis method” (edited by Japan Oil Chemists' Society) [5.3.3 Composition of phospholipids] 1.2 g was used and mixed with 2.5 g of 98.5% glycerin and 2.5 g of distilled water.
  • Example 1 phosphatidylglycerol was replaced by 1.2 g of phosphatidylglycerol, and phosphatidylpolyethylene glycol 400 derived from soybean lecithin (prepared by allowing phospholipase D to act on soybean lecithin in the presence of polyethyleneglycol 400: the same as in Example 1) A fat emulsion having a small particle size and excellent storage stability was obtained in the same manner as in Example 1 by using 1.2 g of the compound (purity according to analytical method: 83 mol%).
  • a corresponding fat emulsion was obtained in the same manner as in Example 1, except that 1.2 g of purified egg yolk lecithin was used instead of 1.2 g of phosphatidylglycerol in Example 1.
  • Test example 1 high temperature stability test
  • Tables 1 and 2 show changes in pH and average particle size of each fat emulsion before and after the autoclave sterilization treatment (121, 20 minutes) in the final stage of the production process in Examples 1 and 2 and Comparative Example 1.
  • the pH was measured with a digital PH meter 225 (manufactured by Iwaki Glass Co., Ltd.), and the average particle size was measured using a Coulter Counter (manufactured by Coulter Electronics, Coulter Model N4).
  • the fat emulsions obtained in Examples 1 and 2 and Comparative Example 1 and a commercially available intravenous fat emulsion Intralipid (manufactured by Otsuka Pharmaceutical Co., Ltd.) was tested for changes in PH and average particle size during long-term storage at 4: and 37 :. Measurements were made immediately after production and at 10, 30 and 60 days after storage.
  • Example 1 The average particle size, maximum particle size, particle size distribution, zeta potential and viscosity of the fat emulsions obtained in Example 1 and Comparative Example 1 were also measured. The results are shown in Table 2. Table 3 shows the results of the long-term storage stability test. The maximum particle size and particle size distribution were determined by scanning electron microscopy using a fat emulsion particle fixation method (Miki, Tanimura, H .; J. Clin. Electron Microscopy, 12: 855-856 (1979)), and computer It was calculated by image processing.
  • the average particle size of the fat emulsion of the present invention was 190 ⁇ 2.5 ⁇ , which was significantly smaller than that of the fat emulsion using lecithin as an emulsifier, 2 to 2 ⁇ 10 nm ( P 0.01). .
  • particles having a particle size of 0.5 jum or less were 94.1 ⁇ 2.5% in the fat emulsion of the present invention and 91.0 ⁇ 1.5% in the emulsion of Comparative Example 1, which was a problem.
  • the ratio of particles of 1 im or more was also small.
  • the zeta potential of the fat emulsion of the present invention showed a low value, and the viscosity showed a somewhat high value.
  • the fat emulsion of the present invention showed little change in particle size even after long-term storage.
  • fat emulsions using lecithin as an emulsifier coalesce most of the particles into giant particles of about lO ⁇ in, and some of them were destroyed and the surface became coarse.
  • the fat emulsion of the present invention did not show any giant particles or a destructive image considered to be fused.
  • the fat emulsion obtained in the same manner as in Example 1 and Comparative Example 1 was administered to a rat via a bolus vein, and the pharmacokinetics and metabolic rate of the fat emulsion were examined.
  • FIG. 1 shows changes in serum neutral fat concentration after administration of the fat emulsion.
  • the serum neutral fat increased sharply to 391 ⁇ 53 mg / ⁇ in the fat emulsion of Comparative Example 1, whereas it increased only slightly to 146 ⁇ 12 mgZo3 ⁇ 4 in the fat emulsion of the present invention. (P ⁇ 0.01).
  • Fig. 2 shows the change in neutral fat concentration in liver tissue.
  • triglyceride in liver tissue showed a small increase in triglyceride from 5 minutes to 120 minutes after administration, and little accumulation of triglyceride in liver tissue.
  • Table 4 the distribution rate of the administered 3 H-labeled emulsifier to the main tissues was higher in the liver of the fat emulsion of the present invention than in the fat emulsion of Comparative Example 1 5 minutes after administration, as shown in Table 4. .
  • Comparative Example 1 138 zCi / kg (2.5 ml / kg as fat emulsion)
  • the fat particles of the present invention were actively taken up by hepatocytes, and most of the fat particles were metabolized 60 minutes after administration.
  • the metabolic rate in the liver was faster than in the fat emulsion of Example 1.
  • the fat emulsion of the present invention is rapidly taken up by the liver after administration, so that it is rapidly eliminated from the blood, and is well metabolized in liver tissue.
  • the intravenous fat emulsion of the present invention has a small particle size, the change in the particle size of the fat particles is small even under high temperature or long-term storage, and the pH of PH which is an indicator of peroxide production is small.
  • the degree of reduction is very stable, equivalent to or lower than that of a conventional fat emulsion containing egg yolk lecithin as an emulsifier.
  • the intravenous fat emulsion of the present invention (1) is less likely to cause emboli such as the reticular system due to its fine particle size, and (2) accumulates in the liver because of its rapid metabolism in blood and liver. It can be administered to patients with liver dysfunction without using it.
  • the decomposition product is glycerin, which has advantages such as being used as an energy source.

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Abstract

Emulsion grasse pour injection intraveineuse contenant comme émulsifiant principal au moins un composé choisi dans le groupe constitué de phosphatidylglycérol, phosphatidylpolyglycérol, phosphatidyléthylèneglycol, phosphatidylpolyéthylèneglycol et disphosphatidylpolyéthylèneglycol. Le diamètre de la particule grasse est petit et subit peu de changement, même à température élevée ou après stockage. Cette émulsion se métabolise si rapidement qu'il n'existe qu'un faible risque de microembolie provoquée dans le poumon, la rate, les tissus réticulendothéliaux, etc., et elle présente un degré de sécurité si élevé qu'elle peut être administrée au patient souffrant d'hépatopatie.
PCT/JP1991/001283 1990-09-26 1991-09-26 Emulsion grasse pour injection intraveineuse WO1992004886A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/256733 1990-09-26
JP25673390 1990-09-26

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WO1992004886A1 true WO1992004886A1 (fr) 1992-04-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5851510A (en) * 1994-05-16 1998-12-22 The Board Of Regents Of The University Of Michigan Hepatocyte-selective oil-in-water emulsion
US8334321B2 (en) 2006-09-05 2012-12-18 Q.P. Corporation Prostaglandin fat emulsion, method for producing the same, method for stabilizing the same, and emulsifying agent

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283912A (en) * 1976-01-01 1977-07-13 Ajinomoto Co Inc Fat emulsion for intravenous injection
JPS5283911A (en) * 1976-01-01 1977-07-13 Ajinomoto Co Inc Fat emulsion for intravenous injection
JPS60501557A (ja) * 1983-06-17 1985-09-19 フアーマ―ロジツク・インコーポレイテツド 水不溶性薬剤を含む微小滴
JPS61289026A (ja) * 1985-06-18 1986-12-19 Nippon Oil & Fats Co Ltd 静脈注射用脂肪乳剤
JPS6416716A (en) * 1987-07-13 1989-01-20 Asahi Chemical Ind Production of emulsion pharmaceutical containing sparingly soluble drug sealed therein

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283912A (en) * 1976-01-01 1977-07-13 Ajinomoto Co Inc Fat emulsion for intravenous injection
JPS5283911A (en) * 1976-01-01 1977-07-13 Ajinomoto Co Inc Fat emulsion for intravenous injection
JPS60501557A (ja) * 1983-06-17 1985-09-19 フアーマ―ロジツク・インコーポレイテツド 水不溶性薬剤を含む微小滴
JPS61289026A (ja) * 1985-06-18 1986-12-19 Nippon Oil & Fats Co Ltd 静脈注射用脂肪乳剤
JPS6416716A (en) * 1987-07-13 1989-01-20 Asahi Chemical Ind Production of emulsion pharmaceutical containing sparingly soluble drug sealed therein

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5851510A (en) * 1994-05-16 1998-12-22 The Board Of Regents Of The University Of Michigan Hepatocyte-selective oil-in-water emulsion
US5985941A (en) * 1994-05-16 1999-11-16 University Of Michigan Method of making hepatocyte-selective oil-in-water emulsion
US6126946A (en) * 1994-05-16 2000-10-03 University Of Michigan, The Board Of Regents Hepatocyte-selective oil-in-water emulsion
US8334321B2 (en) 2006-09-05 2012-12-18 Q.P. Corporation Prostaglandin fat emulsion, method for producing the same, method for stabilizing the same, and emulsifying agent

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