WO2002043697A1 - Emulsion composite e/h/e - Google Patents

Emulsion composite e/h/e Download PDF

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Publication number
WO2002043697A1
WO2002043697A1 PCT/JP2001/010421 JP0110421W WO0243697A1 WO 2002043697 A1 WO2002043697 A1 WO 2002043697A1 JP 0110421 W JP0110421 W JP 0110421W WO 0243697 A1 WO0243697 A1 WO 0243697A1
Authority
WO
WIPO (PCT)
Prior art keywords
composite emulsion
emulsion
type composite
wzo
aqueous phase
Prior art date
Application number
PCT/JP2001/010421
Other languages
English (en)
Japanese (ja)
Inventor
Tohru Nagahama
Tomoaki Yoshino
Original Assignee
Taisho Pharmaceutical 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 Taisho Pharmaceutical Co.,Ltd. filed Critical Taisho Pharmaceutical Co.,Ltd.
Priority to JP2002545670A priority Critical patent/JPWO2002043697A1/ja
Priority to AU2002218497A priority patent/AU2002218497A1/en
Publication of WO2002043697A1 publication Critical patent/WO2002043697A1/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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/113—Multiple emulsions, e.g. oil-in-water-in-oil

Definitions

  • the present invention relates to a W / OZW composite emulsion.
  • Conventional technology
  • Liquid preparations are very easy to use for consumers.
  • liquids for internal use are widely used in pharmaceuticals and functional foods because they can be easily taken by elderly people and children with poor swallowing ability.
  • liquid medicines for internal use have a drawback in that when a drug having an unpleasant taste such as bitterness is to be blended, the flavor of the drug is directly felt, and the flavor is significantly reduced.
  • it is difficult to mix highly reactive drugs into liquids because drugs easily interact with each other in an aqueous solution.
  • Emulsions have been reported in recent years and are being applied to pharmaceuticals, etc., because water-soluble drugs and fat-soluble drugs can be mixed simultaneously. However, it was difficult to prevent drug interaction with general o / w emulsions.
  • the w / o zw type composite emulsion makes it possible to mix even water-soluble drugs that are usually difficult to formulate in terms of stability, flavor, etc. by encapsulating them in the internal aqueous phase.
  • the advantage is that the drug can be separated and blended into the phases, so that it is difficult to combine them at the same time.
  • wz o / w type composite emulsions are generally inferior in stability.Thus, wh o / w type composite emulsions are used for creams with high viscosity, etc. Low viscosity of less than 15 O mPas Have not been reported for the new formulation.
  • the value of the W / OZW composite emulsion increases as the amount of drug that can be encapsulated per particle increases.
  • the drug encapsulation rate generally decreases as the amount of drug encapsulated per particle increases.
  • the evaluation of the encapsulation rate of the drug in the emulsion was performed by calculating the encapsulation rate (%) of the drug encapsulated in the inner aqueous phase of the wzozw-type composite emulsion by the average particle size of the wzozw-type composite emulsion.
  • Japanese Patent Application Laid-Open No. 4-100536 discloses a technology for producing a WZO / W type emulsion using polyglycerin condensed ricinoleic acid ester, which is one type of lipophilic emulsifier. It has been disclosed. However, with these technologies, the particle size of the obtained emulsion is large, and it is still not enough for practical use from the viewpoint of the dispersion stability of the emulsion.
  • JP-A-3-127952, JP-A-10-158152, JP-A-10-20 3962, JP-A-11-188256, JP-A-11-240840, etc. include W / O / W type or SZOZW type.
  • wzo / w-type composite emulsions that have been miniaturized have sufficient stability and can maintain a high encapsulation rate of drugs to be encapsulated in the inner aqueous phase of WZO / W-type composite emulsions.
  • Intensive studies were conducted with the aim of obtaining a mold composite emulsion.
  • a water, oily component, and lipophilic emulsifier are mixed at a specific mixing ratio different from the conventional product to produce a WZO emulsion, and the W / 0 emulsion is dispersed in the aqueous phase by a hydrophilic emulsifier.
  • the w / zzw-type composite emulsion obtained has a very small particle size, sufficient stability, and a high encapsulation rate of the drug encapsulated in the internal aqueous phase.
  • the present invention was found to be maintained, and the present invention was completed.
  • a wzo-type emulsion having a mass ratio of water, an oil component, and a lipophilic emulsifier in a range surrounded by a thick line in FIG. 1 is dispersed in an aqueous phase containing a hydrophilic emulsifier. It is a w / ozw type composite emulsion.
  • the present invention uses a wzo-type emulsion prepared by mixing water, an oily component, and a lipophilic emulsifier in a specific ratio, and disperses it in an external aqueous phase with a hydrophilic emulsifier to ensure dispersion stability in the liquid formulation.
  • a very small WZOZW-type composite emulsion with an average particle size of 200 nm or less, which is an easy range, can be manufactured, and the encapsulation rate of the drug encapsulated in the internal aqueous phase can be maintained high.
  • the volume of the internal aqueous phase can be increased,
  • the amount of drug that can be encapsulated per WZOZW-type composite emulsion particle can be greatly improved.
  • a polyglycerin fatty acid ester having an HLB value of 10 or less is preferable.
  • the degree of polymerization of the polyglycerin moiety is preferably from 4 to 12.
  • the fatty acid moiety of the polyglycerin fatty acid ester is preferably an unsaturated fatty acid, more preferably an unsaturated fatty acid having 16 to 22 carbon atoms, and even more preferably a hydroxy unsaturated fatty acid.
  • Specific examples include oleic acid, linoleic acid, linolenic acid, ricinoleic acid, and erucic acid, and ricinoleic acid is particularly preferred.
  • particularly preferred polyglycerin condensed ricinoleate include tetraglycerin condensed ricinoleate, hexaglycerin condensed ricinoleate, pentaglycerin condensed ricinoleate, decaglycerin condensed ricinoleate, and the like. It is also possible to use a mixture.
  • the oily components used in the present invention include liquid paraffin, squalane, squalene, tocopherol, tocopherol acetate, tocopherol nicotinate, apogado oil, camellia oil, evening oil, macadamia nut oil, corn oil, mink oil, olive oil, Common oily components such as rapeseed oil, egg yolk oil, sesame oil, wheat germ oil, southern power oil, castor oil, safflower oil, cottonseed oil, soybean oil, peanut oil, and tricaprylin can be used, but are preferred. Examples include tocopherol acetate. In addition, a fat-soluble drug can be added to the oily component.
  • hydrophilic emulsifier used in the present invention examples include polyglycerin fatty acid esters having an HLB value of 8 or more.
  • polyglycerin fatty acid esters include decaglycerin monostearate, decaglycerin monooleate, decaglycerin monopalmitate, decaglycerin monomyristate, decaglycerin monolaurate, and decaglycerin monolinoleate.
  • the amount of the hydrophilic emulsifier is preferably 0.001 to 2% by mass of the external aqueous phase. If the concentration of the hydrophilic emulsifier is too high, the encapsulation rate of the drug encapsulated in the internal aqueous phase will decrease, and if the amount is too small, it will be difficult to obtain a uniform and fine WZO ZW type composite emulsion.
  • the inner aqueous phase of the composite emulsion of the present invention contains a drug having an unpleasant flavor,
  • the effect of the present invention is particularly exerted when a drug or the like that easily interacts with other components is blended, but improvement in stability can be expected even with a general water-soluble drug.
  • the amount of the water-soluble drug that can be added to the inner aqueous phase in the present invention varies depending on the solubility. If adjusted, the effects of the present invention can be obtained.
  • a commercial product can be improved by blending a drug which does not impair the effect of the present invention, other components, a flavoring agent, a pH regulator, a preservative, etc., into the external aqueous phase, if necessary. .
  • the wzozw type composite emulsion of the present invention can be produced as follows. First, the oily component and the oil phase such as a lipophilic emulsifier are put into a container, and this is set in a stirrer such as a vacuum emulsifier, and is heated and dissolved at about 50 to 90 ° C while stirring to make it uniform. Next, a predetermined amount of the aqueous phase containing the substance to be enclosed in the internal aqueous phase and any additives is gradually added, and the mixture is stirred and emulsified while keeping the liquid temperature constant at about 50 to 90 ° C. The mixture is stirred for a certain period of time while cooling to 20 to 40 ° C to prepare a WZO emulsion.
  • a stirrer such as a vacuum emulsifier
  • the emulsion is manufactured so as to have an average aqueous phase particle diameter of about 10 to 500 nm. Further, this W / O emulsion is added to an external aqueous phase containing a predetermined amount of a hydrophilic emulsifier and optional additives by a conventional method, for example, a high-pressure homogenizer method, a high-speed stirring method, an ultrasonic emulsification method, a film emulsification method.
  • a WZOZW-type composite emulsion can be produced by dispersing by such a method. When preparing this WZOZW type composite emulsion, heat can be applied as necessary.
  • the average particle diameter of the WZO emulsion was 178.1 nm as measured by a dynamic light scattering particle size distribution analyzer (NICOMP Model 370, manufactured by HIAC / R0YC0).
  • the encapsulation rate of the substance to be included in the WZOZW type composite emulsion was calculated by the following formula. .
  • Encapsulation rate (%) (Wi-WoXA) / WiX 100
  • Wi Amount of substances to be included in WZOZW type composite emulsion
  • the amount of the substance to be included in the w / o / w type composite emulsion is subjected to a pretreatment operation such as wet ashing, and the amount of the substance to be included in the external aqueous phase is determined by centrifuging the wz ⁇ zw type composite emulsion. After the separation of the W / OZW type composite emulsion particles from the external aqueous phase by separation, the measurement was performed by the atomic absorption method. As a result, the encapsulation rate of the substance to be included (measured with iron as the substance to be included) was 99.88%. Examples 2 to 12 and Comparative Examples 1 to 10
  • Example 1 Using the respective compositions shown in Tables 1 to 4, it was prepared in the same manner as in the production method of Example 1. Further, the method for measuring the average particle size of the WZO emulsion was also performed in the same manner as in Example 1.
  • FAC iron ammonium citrate
  • PGCR polyglycerin condensed ricinoleate (CRS-75)
  • DGMM decaglycerin monomyristate (Nikko Chemicals, Decaglyn 1-M ).
  • Example 2 It was prepared in the same manner as in the production method described in Example 1. Further, the method for measuring the average particle size of the WZOZW type composite emulsion was also performed in the same manner as in Example 1.
  • Example 1 The encapsulation rate of the substance to be encapsulated (measured with iron as the substance to be encapsulated) in the WZOZW-type composite emulsion was measured in the same manner as in Example 1.
  • Example 2 Example 3
  • Example 4 Actual lung I 5
  • Example 6 The encapsulation rate of the substance to be encapsulated (measured with iron as the substance to be encapsulated) in the WZOZW-type composite emulsion was measured in the same manner as in Example 1.
  • Example 2 Example 3
  • Example 4 Actual lung I 5 Example 6
  • Composition PGCR (g) 10.00 20.0 mouth 30.0D 18.00 24.00 1 B.67 Tokoff acetate:! : Roll) 70.00 60.00 50.00 70.00 70.00 50.00
  • Comparative Example 8 Comparative Example 9 Comparative Example 10 Purified water (g) 70.62 64.42 45.00
  • composition PGCR (g) 6.54 13.42 50.00 Tocopheryl acetate (g) 15.00 15.00 0.00
  • Example 5 Using the compositions shown in Table 5, it was prepared in the same manner as in the production method of Example 1. The method for measuring the average particle size of the W / W emulsion was also in accordance with Example 1.
  • Example 6 Using the compositions shown in Table 6, it was prepared by the production method of Example 1. The method for measuring the particle size of the W / O emulsion was also in accordance with Example 1.
  • Example 7 Using the compositions shown in Table 7, it was prepared by the production method of Example 1. The method for measuring the particle size of the W / O emulsion was also in accordance with Example 1.
  • the encapsulation rate of the substance to be encapsulated (measured with iron as the substance to be encapsulated) in the WZOZW-type composite emulsion was measured in accordance with Example 1. Table 7
  • Example 8 Using the compositions shown in Table 8, it was prepared by the production method of Example 1. The method for measuring the particle size of the W / O emulsion was also in accordance with Example 1.
  • Example 2 It was prepared by the production method described in Example 1. The method for measuring the average particle size of the W / O / W composite emulsion was also in accordance with Example 1.
  • Example 9 Using the compositions shown in Table 9, it was prepared by the production method of Example 1. The method for measuring the particle size of the WZO emulsion was also in accordance with Example 1.
  • the composition of the wz ⁇ emulsion used is within the range of the present invention, a very fine w / o / w composite emulsion having a good drug encapsulation rate could be obtained.
  • the encapsulation rate (%) of the drug dissolved and encapsulated in the inner aqueous phase of the W / OZW-type composite emulsion is determined by the average particle diameter (nm) of the type-composite emulsion. divided by the common logarithm of) (Table 1 in B / L og 1Q C) was satisfied that this is 27 or more (examples 24 to 30). Examples 31 to 33 and Comparative Examples 11 to 13
  • Example 10 Using the compositions shown in Table 10, it was prepared by the production method of Example 1. The method for measuring the particle size of the WZ ⁇ emulsion was also in accordance with Example 1.
  • the WZO emulsion obtained above was mixed with 180 g of an aqueous solution containing decaglycerin monomyristate (Nikko Chemicals, Decaglyn 1-M) and sugar shown in Table 10 while stirring with a magnetics mixer or homogenizer. After adding 20 g, a WZOZW-type composite emulsion having a relatively large particle size was obtained, and then passed through a porous membrane to obtain a fine WZOZW-type composite emulsion having a particle size of about 1300 to 1900 nm. I got Lushon. The method for measuring the average particle diameter of the WZO / W-type composite emulsion was also in accordance with Example 1.
  • Example 1 It was prepared by the production method of Example 1 using each composition shown in Table 11. The method for measuring the particle size of the W / ⁇ emulsion was also in accordance with Example 1.
  • the WZ ⁇ type obtained above was stirred into a 190 g aqueous solution containing decaglycerin monomyristate (Nikko Chemicals, Decaglyn 1-M) and sugar shown in Table 11 with a magnetic stirrer or homogenizer. 10 g of the emulsion was added to obtain a W / ⁇ / W composite emulsion having a relatively large particle diameter, and then passed through a porous membrane to form a fine WZO ZW composite emulsion having a particle size of about 500 nm. Obtained.
  • the method for measuring the average particle size of the WZO / W type composite emulsion was also in accordance with Example 1.
  • the wzo-type emulsion having the composition within the scope of the present invention when the wzo-type emulsion having the composition within the scope of the present invention is dispersed in the external aqueous phase, when the concentration of the hydrophilic emulsifier in the external aqueous phase is low, the drug encapsulation rate is good and very fine. WZOZW type composite emulsion was obtained. In addition, even if a very fine w / o / w composite emulsion is obtained, the encapsulation rate (%) of the drug dissolved and encapsulated in the inner aqueous phase of the w / ozw composite emulsion can be determined by the WZO / W composite emulsion.
  • Table 12 shows the results of iron taste
  • Table 13 shows the results of astringent taste.
  • the metallic taste It was proved that the reduction could be achieved.
  • a drug having an unpleasant taste, an unstable drug, and the like can be stably compounded even in a liquid preparation having a low viscosity.
  • FIG. 1 is a diagram showing a composition range showing the effect of the present invention, in which the bottom surface shows the lipophilic emulsifier, the left slope shows the amount of water, and the right slope shows the amount of the oil component.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une émulsion composite E/H/E, qui comprend une phase aqueuse renfermant un agent émulsifiant hydrophile et une émulsion E/H dispersée à l'intérieur. Cette émulsion contient de l'eau, un constituant huileux et un agent émulsifiant oléophile dans un rapport moléculaire situé dans la plage indiquée sur la fig. 1 et encadrée par les lignes épaisses. Cette émulsion présentant une stabilité suffisante, une grande quantité d'un médicament peut être maintenue encapsulée dans la phase aqueuse interne de ladite émulsion. Il est ainsi possible d'incorporer un médicament ayant un goût déplaisant, un médicament instable, etc. dans un liquide à faible viscosité, cette incorporation étant traditionnellement difficile. Cette émulsion peut donc être utilisée sous forme de préparations liquides, y compris à usage interne, sous forme d'injections, etc.
PCT/JP2001/010421 2000-11-29 2001-11-29 Emulsion composite e/h/e WO2002043697A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2002545670A JPWO2002043697A1 (ja) 2000-11-29 2001-11-29 Ｗ／ｏ／ｗ型複合エマルション
AU2002218497A AU2002218497A1 (en) 2000-11-29 2001-11-29 W/o/w composite emulsion

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JP2000-362917 2000-11-29
JP2000362917 2000-11-29

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WO2002043697A1 true WO2002043697A1 (fr) 2002-06-06

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003095925A (ja) * 2001-09-20 2003-04-03 Taisho Pharmaceut Co Ltd 複合エマルションの製造方法
JP2008107240A (ja) * 2006-10-26 2008-05-08 Taisho Pharmaceutical Co Ltd 錆味の評価方法
JP2008119568A (ja) * 2006-11-09 2008-05-29 Sakamoto Yakuhin Kogyo Co Ltd 可溶化剤
JP2012511556A (ja) * 2008-12-12 2012-05-24 ユニベルシテ ダンジュ 脂質ナノ粒子の製造方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58143831A (ja) * 1982-02-22 1983-08-26 Taihoo Kogyo Kk Ｗ／ｏ／ｗ複合エマルジヨン
JPS59169531A (ja) * 1983-03-18 1984-09-25 Meiji Milk Prod Co Ltd Ｗ／ｏ／ｗ型複合エマルジヨンの製造法
EP0120967A1 (fr) * 1982-10-01 1984-10-10 Meiji Milk Products Company Limited Procede de production de compositions alimentaires d'huile et de graisse a emulsion eau/huile/eau
EP0174377A1 (fr) * 1984-03-26 1986-03-19 Meiji Milk Products Company Limited Emulsion du type multiple eau/huile/eau pour usage cosmetique ou medical
JPH03127952A (ja) * 1989-10-11 1991-05-31 Meiji Milk Prod Co Ltd 塩類、温度によりリリースコントロールされるｗ／ｏ／ｗ型複合エマルション
JPH04100536A (ja) * 1990-08-17 1992-04-02 Meiji Milk Prod Co Ltd Ｗ／ｏ／ｗ型複合エマルション及びその製造法
JP2001151938A (ja) * 1999-11-29 2001-06-05 Lion Corp Ｗ／ｏ／ｗ型複合エマルション

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58143831A (ja) * 1982-02-22 1983-08-26 Taihoo Kogyo Kk Ｗ／ｏ／ｗ複合エマルジヨン
EP0120967A1 (fr) * 1982-10-01 1984-10-10 Meiji Milk Products Company Limited Procede de production de compositions alimentaires d'huile et de graisse a emulsion eau/huile/eau
JPS59169531A (ja) * 1983-03-18 1984-09-25 Meiji Milk Prod Co Ltd Ｗ／ｏ／ｗ型複合エマルジヨンの製造法
EP0174377A1 (fr) * 1984-03-26 1986-03-19 Meiji Milk Products Company Limited Emulsion du type multiple eau/huile/eau pour usage cosmetique ou medical
JPH03127952A (ja) * 1989-10-11 1991-05-31 Meiji Milk Prod Co Ltd 塩類、温度によりリリースコントロールされるｗ／ｏ／ｗ型複合エマルション
JPH04100536A (ja) * 1990-08-17 1992-04-02 Meiji Milk Prod Co Ltd Ｗ／ｏ／ｗ型複合エマルション及びその製造法
JP2001151938A (ja) * 1999-11-29 2001-06-05 Lion Corp Ｗ／ｏ／ｗ型複合エマルション

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003095925A (ja) * 2001-09-20 2003-04-03 Taisho Pharmaceut Co Ltd 複合エマルションの製造方法
JP2008107240A (ja) * 2006-10-26 2008-05-08 Taisho Pharmaceutical Co Ltd 錆味の評価方法
JP2008119568A (ja) * 2006-11-09 2008-05-29 Sakamoto Yakuhin Kogyo Co Ltd 可溶化剤
JP2012511556A (ja) * 2008-12-12 2012-05-24 ユニベルシテ ダンジュ 脂質ナノ粒子の製造方法

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AU2002218497A1 (en) 2002-06-11
JPWO2002043697A1 (ja) 2004-04-02

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