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WO1992007551A1 - Procede de production d'une emulsion grasse - Google Patents

Procede de production d'une emulsion grasse Download PDF

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Publication number
WO1992007551A1
WO1992007551A1 PCT/JP1991/001510 JP9101510W WO9207551A1 WO 1992007551 A1 WO1992007551 A1 WO 1992007551A1 JP 9101510 W JP9101510 W JP 9101510W WO 9207551 A1 WO9207551 A1 WO 9207551A1
Authority
WO
WIPO (PCT)
Prior art keywords
emulsion
sodium chloride
present
fat
particle size
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1991/001510
Other languages
English (en)
Japanese (ja)
Inventor
Junzo Seki
Hirofumi Yamamoto
Shuji Yamane
Yutaka Takahashi
Kouichi Ushimaru
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Shinyaku Co Ltd
Original Assignee
Nippon Shinyaku 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 Nippon Shinyaku Co Ltd filed Critical Nippon Shinyaku Co Ltd
Publication of WO1992007551A1 publication Critical patent/WO1992007551A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to an improved technique for producing a fat-and-oil emulsion having an average particle size of 10 nm to 100 nm.
  • the fat-resistant emulsion having an average particle size of 10 to 10 OOnro has an effect of improving the transferability of a drug from blood or an application site to a diseased tissue, and has excellent characteristics.
  • a fat emulsion having such an average particle size has the property of avoiding uptake (RBS) by the reticuloendothelial system.
  • RBS uptake
  • a fat emulsion having a diameter of lOOmn or more it can maintain a high concentration in the blood, and easily leak out of the blood vessel from a site where vascular permeability is enhanced.
  • blood vessels have various pore systems (pore system, small pore systems up to 9 nm in diameter and large pore systems with diameters of 25 to 70 nro).
  • the permeability is further increased.
  • more ultrafine emulsion particles than the blood vessels selectively leak through the large volume system and migrate into the diseased tissue.
  • the drug contained in the particles also moves into the lesion.
  • the drug can be easily and selectively transferred to the lesion, so that the drug concentration at the lesion can be further increased, and the effect can be increased.
  • the presence of the small pore system described above allows the permeability of particles smaller than lOnra. Prevents the transfer of such small particles from blood vessels to normal cells.
  • Average particle size is ⁇ !
  • the present inventors have already found that it is important to limit the quantitative ratio of the simple lipids and the phospholipids, which are the constituents, in order to produce a fat emulsion having a ⁇ . It contains 0.5 to 30% (w / v) of simple lipids, 0.15 to 2 times the weight of simple lipids (by weight), and an appropriate amount of water. This is achieved by:
  • lipids constituting the fat emulsion according to the present invention contain unsaturated fatty acids, they are denatured by oxidation, and May be toxic. Applying heat or applying physical pressure, such as mixing, may help to alter such lipids over a long period of time.
  • the present inventors have made various studies for the purpose of solving the above technical disadvantages, and as a result, have reached the present invention.
  • the gist of the present invention is that the average particle diameter is ⁇ ⁇ !
  • 0.01% to 0.2% (w / v) of sodium chloride in the whole fat emulsion is emulsified. It is used as an agent.
  • the time required for the emulsification step can be reduced to 1/2 to L / 3. This can reduce the total processing energy required for emulsification. This means that if the emulsification step is continued within the same time, the processing energy can be reduced as compared to before. Further, from the above, (1) the deterioration of the fat emulsion in the processing step is prevented beforehand, and (2) the present invention can prevent the abrasion of equipment for emulsification and reduce the maintenance cost. To obtain the effect of this.
  • sodium chloride I can be selectively used.
  • other clays eg, calcium chloride, magnesium chloride, sodium carbonate, etc. cannot be applied.
  • the amount of sodium chloride used in the present invention is suitably 0.01% to 0.2% (w / v) of the total amount of fat to be emulsified.
  • the specific effects of the present invention can be obtained only in the range of 0.0% to 0.2%. Preferably, it is 0.01 to 0.1%.
  • sodium chloride can be added in any step of emulsion production. It is possible to mix it with lipids before emulsification, or it may be dissolved in ice before emulsification. Alternatively, it may be added during the emulsification step.
  • sodium chloride is added before the end of the emulsification step. There is a need. Before the end of the emulsification step, it can be added to simple lipids or to phospholipids.
  • Examples of the lipid used in the present invention include simple lipids derived from natural plant minerals, derived lipids, complex lipids, and mixtures thereof.
  • any of pure lipid, conductive lipid, or complex lipid derived from egg yolk, soybean, cotton, or the like, or any of pure synthetically produced simple lipid, conductive lipid, or complex lipid may be used.
  • Examples of the simple lipid include those which can be usually used such as refined soybean oil, cottonseed oil, rapeseed oil, sesame oil and the like.
  • phospholipids examples include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and the like. These hydrogenated products can also be used.
  • a particularly preferred representative example is egg yolk purified lecithin.
  • the drug to which the present invention can be applied is not particularly limited as long as it is pharmaceutically acceptable. Even insoluble or poorly soluble drugs can be used. In the present invention, the drug easily forms an emulsion.
  • Drugs to which the emulsion of the present invention can be applied include, for example, anti-inflammatory drugs, analgesics, anti-allergic drugs, antibiotics, chemotherapeutic drugs, anti-cancer drugs, Anti-viral agent, Anti-atherosclerotic agent, Anti-lipemic agent, Anti- * ⁇ agent, Immunomodulator, Pectin, Radical remover, Bronchodilator, Hypnotic, Tranquilizer, Local anesthetic, Fat-soluble vitamins, new medicines and the like can be mentioned.
  • Examples of these include, for example, ancitabine, fluorouracil, mitomycin (:, mitomycin C, furnesylate, mitomycin C, funnesyl acid amide, nonyloxycarbonylmytomycin (:, Mystomycin C derivatives such as cholesteryl oxyglysilmytomysin C, etc., limofur, phtofuryl palmitate, 5—fluorosilyl myristate, ryolimycin, daunomycin.
  • mitomycin :, mitomycin C, furnesylate, mitomycin C, funnesyl acid amide
  • nonyloxycarbonylmytomycin :, Mystomycin C derivatives such as cholesteryl oxyglysilmytomysin C, etc., limofur, phtofuryl palmitate, 5—fluorosilyl myristate, ryolimycin, daunomycin.
  • Anti-cancer drugs such as cytarabine derivatives such as aclarubicin hydrochloride, macra j revisin, vinblastine, pinklistin, cytarabine B-fatty acid ester, mittan, estramustine, and dichloroflavan Viruses, steroids, e.g.
  • Antiallergic agents such as tranilast, ketotifen, and zelastine can also be used.
  • antibiotics and chemotherapeutic agents include tetracycline base, erythromycin, midecamysin, ammho ⁇ -lysine Bs, minocycline, miconazole and the like.
  • PGE! And PGA! Are examples of brostaglandin agents. PGA 1 alkyl ester, PGE i alkyl ester, PGE j derivative, PGI 2 derivative, PGD derivative and the like can be used.
  • Agents can also be mentioned.
  • local anesthetics such as lidocaine, penzocaine, dantrolene, cocaine, tetraccaine, virokine, mebira-kin, and derivatives thereof can also be mentioned. .
  • Hepatopathy ameliorating agents such as mallotilate, glycyrrhetinic acid, acetyltillyl retinoic acid ethyl ester, glycyrrhetinic acid methyl ester, and anti-inflammatory agents, such as farnesol, geraniol, gefarnet, tepreno , Brown towels, and softcon.
  • Central nervous system drugs such as penobarbital, methaqualone, passed, diazepam, medazeham, frazeham *, clotiazepam, etizolam, mecridin, buclidin, ajifu Methine, methamphetamine, imimiramin, chlorimiramin, imitriptyline, mianserin, trimetadione, phensuximid, tetrabe Enzamide, penzunamide, camphor, dimorpholine, striki, chlorepromazine, 'promethazine, brochlorazine, mequitazine, triflupromazine, levomepromazine, ziff JL Nido And their derivatives.
  • bronchodilators examples include vestophilin and other theophylline derivatives, methyl efdrine and the like.
  • Anti-cholinergic agents such as benztrobin, physostigmine, at-mouth bottle, scopolamine, etc.
  • parasympathetic ⁇ -blockers such as oxyphencycline, virenzebine, etmidrin, etc.
  • Calcium blockers for example, diltiazem, diphezibine, perapamil, etc.
  • opener for example, dipenzamine, phenoxybenzamine, etc.
  • antitussives for example, nosibi bin, dextromethorphan , Pentoxibelin, pembu ⁇ -perin, etc., therapeutic agents for prostate hypertrophy, eg, gastron, oxenden, etc. , Spartin, pavulin, etc., antihyperlipidemic drugs such as crofibrate, simfibrate, blobcol, etc. It can be also mentioned.
  • vaccines such as polyamino acids, vitamins, dilazeb hydrochloride, ubitecarenone, flavoxate, cyclosporin II, influenza, dibenzthion, diphenirabiline, phenova Renewal, metadion, tofisobam, limonene, etc.
  • Fat-soluble vitamins include vitamin ⁇ and its derivatives ⁇ , vitamin E and its derivatives, vitamin K and its derivatives, vitamin D and their derivatives, and the like. .
  • guaiazulene and essential oily crude drugs such as, for example, oil of quinnin, oil of primrose, time oil, turpentine oil, eucalyptus oil, palm oil, poppy oil, camellia oil and the like can be mentioned.
  • New drugs include, for example, compounds labeled with radioisotopes, and radiopharmaceuticals, iodized poppy oil fatty acids, which are X-ray contrast agents. Steal and the like can be mentioned.
  • the drug to which the present invention can be applied is not particularly limited, as described above. However, when judging from the characteristics of the emulsion properties derived from the particle size of the emulsion, inflammation, blood, vascular Or drugs that are involved in the immune system are generally desirable.
  • the drug concentration in the fat emulsion of the present invention can be appropriately reduced according to the biological activity of the drug.
  • concentrations of the emulsion constituents and the drug in the preparation using the present invention can be appropriately determined as desired. is there
  • the shape and particle size of the fat emulsion of the present invention can be easily confirmed by communication with an electron microscope, a light scattering type particle size analyzer, a membrane filter, or the like.
  • Optional components of the fat emulsion of the present invention include additives and auxiliary substances used in general injections.
  • additives and auxiliary substances used in general injections For example, antioxidants, preservatives, stabilizers, tonicity agents, buffers and the like can be mentioned.
  • the required and optimal amounts of these additives, trapping substances, etc. can be varied according to the purpose.
  • the fat emulsion of the present invention can be sterilized (eg, sterilized by filtration or high-pressure steam) as necessary, and enclosed in an amble together with nitrogen gas. It can be freeze-dried if necessary.
  • the lyophilized material can be reconstituted by adding an appropriate solution.
  • the emulsion of the present invention can be provided as it is, but if necessary, it is easy to remove sodium chloride added as an emulsifying aid by a general de-wetting operation.
  • the fat emulsion of the present invention is generally administered intravenously, As in the case of conventional products, it can also be administered as an injection intraarterially, intramuscularly, intracavitary, subcutaneously, or the like.
  • the emulsion of the present invention can also be formulated and used as eye drops, drops *, inhalants, orally administered drugs, bladder injections, external preparations or suppositories.
  • additives such as pharmaceutically acceptable bases and excipients can be cited as optional components.
  • Test example 1 The present invention will be described in more detail with reference to Test Examples and Examples of the present invention under £ 1. Test example 1
  • a control sample was prepared by roughly dispersing a 5% aqueous solution of dalcose containing no sodium chloride and then dispersing the solution. Each of them was emulsified under the same conditions using an ultrasonic homogenizer (Branson model 185) under ice cooling, and the temporary particle size was measured. The results are shown in Table 1.
  • Amphotericin B (3 mg), purified soybean oil (0.5 g) and purified egg yolk lecithin (0.4 g) ⁇ dimyristylphosphatidylglycerol (0.1 g) mixed with a mouth-form / methanol (1/1, v / v) mixture 100 m After mixing and dissolving in £, the solvent is completely removed under reduced pressure using a rotary evaporator. to this
  • the mixture was emulsified with an ultrasonic homogenizer (Branson model 185) for 30 minutes under ice-cooling to obtain an emulsion having 10 to 10 nm of emulsion particles. This was freeze-dried according to a conventional method.
  • chomhotericin B 5 g of refined soybean oil and 5 g of refined egg yolk lecithin are homogenized in a mortar, and 10 g of maltose is added to the mixture.
  • 10 mg of sodium chloride was added as an emulsifying aid, and after dissolution, water for injection was added, and the volume was adjusted to 100 mL.
  • the emulsion was emulsified with a microfluidizer under permanent cooling. An emulsion with a diameter of 10 to 100 nm was obtained. This was freeze-dried according to a conventional method.
  • the condition of the dried cake was very good, and no defects such as chipping, cracking, and convergence were observed.
  • water for injection was added and redissolved, the dissolution was completed very quickly, and the emulsion particles were completely restored with no change in the particle size of the emulsion particles after the dissolution.
  • the mixture was treated with an ultrasonic homogenizer (Branson model 185) for 60 minutes.
  • the emulsion was emulsified to obtain an emulsion having a particle diameter of 10 to 100 nm. This was freeze-dried according to a conventional method.
  • Amphotericin B 3 nig 0.5 g of refined soybean oil, 0.4 g of refined egg yolk lecithin, and 0.1 g of dimyristyl phosphatidylglycerol were added to form mouth Z methanol (1/1). , y / v )
  • the solvent is completely removed under reduced pressure using a rotary evaporator.
  • To this is added 8 mL of a 0.1% sodium chloride ice solution, and the mixture is stirred with a homogenizer to obtain a coarse emulsion.
  • the emulsion was emulsified with an ultrasonic homogenizer (Branson model 185) for 60 minutes to obtain an emulsion having an emulsion particle size S of 10 to 10 OOnra. After 1 g of maltose was added to this and dissolved, water was added to adjust the volume to 10 ⁇ £. This was freeze-dried according to a conventional method. The condition of the dried cake was extremely good, and no chipping, cracking, shrinkage, etc. were observed. When water for injection was added and redissolved, the dissolution was completed very quickly, and the emulsion particles after the dissolution were completely restored without any change in the particle diameter.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Medicinal Preparation (AREA)

Abstract

Procédé de production d'une émulsion grasse dont les particules ont un diamètre moyen compris entre 10 et 100 nm, caractérisé par le raccourcissement du temps d'émulsification en ajoutant du chlorure de sodium comme agent favorisant l'émulsification en une quantité comprise entre 0,01 et 0,2 % (pds/v) calculée sur l'émulsion totale au cours d'une étape arbitraire du procédé de production. Ce procédé sert également à réduire la décomposition des composants de l'émulsion suite au raccourcissement du temps d'émulsification.
PCT/JP1991/001510 1990-11-06 1991-11-05 Procede de production d'une emulsion grasse Ceased WO1992007551A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP30163990 1990-11-06
JP2/301639 1990-11-06
JP30164090 1990-11-06
JP2/301640 1990-11-06
JP31205890 1990-11-16
JP2/312058 1990-11-16

Publications (1)

Publication Number Publication Date
WO1992007551A1 true WO1992007551A1 (fr) 1992-05-14

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/001510 Ceased WO1992007551A1 (fr) 1990-11-06 1991-11-05 Procede de production d'une emulsion grasse

Country Status (1)

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WO (1) WO1992007551A1 (fr)

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
US7884037B2 (en) 2006-12-15 2011-02-08 Kimberly-Clark Worldwide, Inc. Wet wipe having a stratified wetting composition therein and process for preparing same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6229513A (ja) * 1985-07-29 1987-02-07 アボツト　ラボラトリ−ズ 凍結乾燥したエマルジヨン組成物およびその方法
JPS6323811A (ja) * 1986-07-11 1988-02-01 ベ−リングヴエルケ・アクチエンゲゼルシヤフト 医薬製剤およびその製法
JPH01249716A (ja) * 1988-03-29 1989-10-05 Taisho Pharmaceut Co Ltd 微粒子脂肪乳剤
JPH02203A (ja) * 1987-10-28 1990-01-05 Nippon Shinyaku Co Ltd 薬物担体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6229513A (ja) * 1985-07-29 1987-02-07 アボツト　ラボラトリ−ズ 凍結乾燥したエマルジヨン組成物およびその方法
JPS6323811A (ja) * 1986-07-11 1988-02-01 ベ−リングヴエルケ・アクチエンゲゼルシヤフト 医薬製剤およびその製法
JPH02203A (ja) * 1987-10-28 1990-01-05 Nippon Shinyaku Co Ltd 薬物担体
JPH01249716A (ja) * 1988-03-29 1989-10-05 Taisho Pharmaceut Co Ltd 微粒子脂肪乳剤

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
US7884037B2 (en) 2006-12-15 2011-02-08 Kimberly-Clark Worldwide, Inc. Wet wipe having a stratified wetting composition therein and process for preparing same

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