WO2000059470A1 - Emulsion et son procede de production - Google Patents

Emulsion et son procede de production Download PDF

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Publication number
WO2000059470A1
WO2000059470A1 PCT/JP2000/001879 JP0001879W WO0059470A1 WO 2000059470 A1 WO2000059470 A1 WO 2000059470A1 JP 0001879 W JP0001879 W JP 0001879W WO 0059470 A1 WO0059470 A1 WO 0059470A1
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WO
WIPO (PCT)
Prior art keywords
oil
emulsion
nonionic surfactant
added
medicinal
Prior art date
Application number
PCT/JP2000/001879
Other languages
English (en)
Japanese (ja)
Inventor
Katsuhiro Inada
Masazumi Yamaguchi
Original Assignee
Senju 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 Senju Pharmaceutical Co., Ltd. filed Critical Senju Pharmaceutical Co., Ltd.
Publication of WO2000059470A1 publication Critical patent/WO2000059470A1/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

Definitions

  • the present invention relates to a stable oil-in-water emulsion in which a pharmaceutically active ingredient having low solubility in both water and oil is contained dissolved in an oil phase, and a method for producing the same.
  • an oil-in-water emulsion containing a water-insoluble and oil-soluble drug has been produced by first dissolving the drug in a base oil and then adding it to an aqueous phase containing a surfactant. This has been done by stirring.
  • the oil-in-water emulsion can contain only a limited amount in the form of an oil-in-water emulsion. The required drug content may not be achieved. For this reason, drugs with a solubility higher than that of oil have been added to oils, and some of the drugs have been dissolved or suspended in the oil to form the oil phase.
  • An object of the present invention is to provide an oil-in-water emulsion capable of dissolving a large amount of drug exceeding its original solubility in oil and maintaining stability, and a method for producing the same. Disclosure of the invention
  • the present invention relates to an oil-in-water emulsion, wherein the oil phase component of the emulsion is dissolved in the oil at a concentration exceeding (a) an oil as a base and (b) a solubility in the oil.
  • a medicinal ingredient and (c) a nonionic surfactant, wherein the emulsion has a transmittance of 10% or less at a wavelength of 500 nm as measured at a layer width of 1 cm.
  • an oil, a nonionic surfactant and a medicinal ingredient as bases are mixed to form a uniform solution, which is added to an aqueous phase as an oil phase component of an emulsion and stirred, and the layer width is 1 cm.
  • Characterized in that the emulsion is emulsified so that the transmittance of the emulsion at a wavelength of 520 nm as measured by the above method is 10% or less.
  • a manufacturing method is provided.
  • the present invention provides the above method, wherein the base oil and the nonionic surfactant are uniformly mixed, and a pharmaceutically active ingredient soluble in the oil is added thereto and mixed to form a uniform solution. This is added to the aqueous phase as an oil phase component of the emulsion and stirred, and the emulsion is emulsified so that the transmittance of the emulsion at a wavelength of 520 nm measured at a layer width of 1 cm is 10% or less.
  • the present invention also provides a method for producing an oil-in-water emulsion containing a medicinal component dissolved in an oil phase.
  • an oil-in-water emulsion According to the method for producing an oil-in-water emulsion according to the present invention, even a medicinal ingredient having insufficient solubility in the base oil can be contained in a form dissolved in oil droplets at a high concentration, so that the medicinal ingredient in the emulsion is contained. The amount can be improved. Furthermore, an emulsion in which the medicinal component is dissolved in the oil droplets is obtained, so that the chemical stability of the medicinal component and the physical stability of the emulsion are high. Furthermore, as the oil droplets become finer, the whole emulsion generally becomes more transparent and the transmittance increases. However, the total area of the interface between the oil phase and the aqueous phase sharply increases, and the water molecules and the medicinal properties increase.
  • the chemical stability of the medicinal ingredient is likely to be impaired due to the increased contact of the ingredients.
  • excessive emulsification is prevented by emulsifying in accordance with the standard that “the transmittance of the emulsion at a wavelength of 520 nm when measured at a layer width of 1 cm is 10% or less”.
  • the total area of the interface between the phase and the aqueous phase does not become too large, and also in this respect, the chemical stability of the medicinal component is maintained.
  • the amount of the nonionic surfactant to be added is 0.1 to 5 parts by weight, preferably 0.1 to 2 parts by weight, per 1 part by weight of the base oil. Preferably, it is 0.2 to 1 part by weight. If the amount is less than 0.1 part by weight, the solubility of the drug in the oil phase cannot be sufficiently increased, and if the amount is more than 5 parts by weight, foaming of the emulsion becomes remarkable and handling in the manufacturing process becomes difficult, and Is also likely to be uneven.
  • the ratio of the oil to the whole emulsion is usually preferably 1 to 20 WZV%.
  • the drug content tends to be insufficient, and above this range, it becomes difficult to produce a physically stable emulsion.
  • the ratio of the oil to the whole emulsion is 1 to 10 W / V%, and still more preferably, 2 to 8 W / V%. A more stable emulsion can be easily produced.
  • particularly preferred base oils are castor oil, soybean oil, medium-chain fatty acid triglycerides, cottonseed oil, oleic acid, liquid paraffin, silicon oil, peanut oil, arable oil, and Sesame oil.
  • nonionic surfactant polysorbate, polyoxyethylene hydrogenated castor oil, sorbitan sesquitate, tyloxapol, and sucrose fatty acid ester are particularly preferable.
  • Suitable for the emulsion of the present invention and the method for producing the same are drugs whose conventional method for producing an emulsion has insufficient solubility in oil.
  • Particularly preferred examples include indomethacin, hydrocortisone, and full-length rome.
  • concentrations of these drugs in the emulsion of the present invention may vary depending on the strength of action of the drugs, the purpose of use, and the like, but may be, for example, 0.004 to 5 WZV%.
  • the emulsion of the present invention is produced, for example, as follows. That is, an oil such as castor oil, a nonionic surfactant such as polysorbate, and a medicinal component are added and agitated, and the medicinal component is dissolved to form a uniform liquid containing the medicinal component to form an oil phase component. At this time, if necessary, the surfactant and the medicinal ingredient are mixed in advance to dissolve the medicinal ingredient in the nonionic surfactant, and then added to the oil or to the mixture of the oil and the nonionic surfactant. You may.
  • polyhydric alcohols such as propylene glycol and glycerin are May be supplementarily added to the nonionic surfactant.
  • the oil phase component thus prepared is added to the separately prepared water phase component with stirring, and the mixture is stirred with a homomixer (for example, TK ROBO MICS, Tokushu Kika Kogyo Co., Ltd.) to perform coarse emulsification.
  • a homomixer for example, TK ROBO MICS, Tokushu Kika Kogyo Co., Ltd.
  • These procedures may be performed, for example, at 70 ° C. by appropriately heating using a water bath or the like.
  • a high-pressure emulsifier at about 40 ° C (eg, microfluidizer M-110EH (icrofizidizer M-110EH): manufactured by icrof curdics Corporation).
  • the mixture is emulsified by processing, and sterilized by filtration using a filter with a pore size of 0.45 m to obtain the final emulsion.
  • the transmittance at a wavelength of 520 nm when the finally obtained emulsion is measured with a layer width of 1 cm is 10% or less, more preferably 5% or less, still more preferably 2% or less, and particularly preferably.
  • the degree of emulsification by the high-pressure emulsifier is adjusted so as to be substantially opaque.
  • a nonionic surfactant such as polysorbate 80 is added to oil such as castor oil and stirred to obtain a uniform liquid.
  • a medicinal component such as indomethacin is added thereto, and the mixture is stirred in a water bath at about 70 ° C. to completely dissolve the drug, and the resulting oil phase is separately prepared.
  • the oil phase is separately prepared and heated to about 70 ° C.
  • a homomixer eg, TK ROBO MICS, Tokushu Kika Kogyo
  • a high-pressure emulsifier eg, Microfluidizer M-110EH
  • the product is emulsified by treating with a filter manufactured by Luidics Corporation) and sterilized by filtration using a filter with a pore size of 0.45 m to obtain the final emulsion.
  • the transmittance of the finally obtained emulsion measured at a layer width of ⁇ cm at a wavelength of 520 nm is 10% or less, more preferably 5% or less, still more preferably 2% or less, and particularly preferably.
  • the degree of emulsification by the high-pressure emulsifier is adjusted so as to be substantially opaque.
  • a surfactant in the production method of the present invention, unlike the conventional production method of an oil-in-water emulsion, it is not necessary to add a surfactant to the aqueous phase.
  • the aqueous phase also contains other ingredients commonly used in emulsions, such as buffers such as borate, acetate, and phosphate, tonicity agents such as sodium chloride, preservatives such as sorbic acid, EDT It is possible to appropriately add a stabilizer such as A it can.
  • glycerin, sorbitol, mannitol, and the like may be contained in the aqueous phase for adjusting the osmotic pressure, etc., so that the stability of the preparation is not impaired.
  • the oil phase heated to about 70 ° C was added dropwise to the aqueous solution at about 70 ° C over about 5 minutes while stirring.
  • the mixture was stirred at a homomixer (8000 rpm) while maintaining the mixture at about 70 ° C. to carry out coarse emulsification.
  • a homomixer 88000 rpm
  • the mixture is emulsified with a microfluidizer -110EH (pressure 1500 kgfm 2 , number of passes: 20 passes) at a liquid temperature of 40 ° C, and subjected to two-stage filtration with a 0.45 m pore size filter (HVLP).
  • HVLP 0.45 m pore size filter
  • Tiloxapol 50 g was added to castor oil (50 g), and the mixture was stirred to make a uniform liquid. Then, indomethacin (4 g) was added, and the mixture was stirred in a water bath at 70 ° C. to completely dissolve the drug. Separately, 85 OmL of sterilized purified water heated to 70 ° C was prepared, and the oil phase was added dropwise thereto with stirring. Subsequently, the mixture was coarsely emulsified by stirring with a homomixer (8000 rpm) while maintaining the mixture at about 70 ° C.
  • the mixture was sterilized by two-stage filtration ( ⁇ V L ⁇ ⁇ ) to obtain a final emulsion, which was aseptically filled in a container.
  • the resulting emulsion contained 0.4 W / V% of indocyanine with respect to the whole emulsion, and had a transmittance of 0.03% at a wavelength of 52 nm measured at a layer width of 1 cm. Yes, it was opaque.
  • Indomethacin was added to 50 g of castor oil and stirred in a water bath at 70 ° C to completely dissolve the drug.
  • a solution prepared by adding 50 g of tyloxapol to 85 mL of sterilized purified water while heating to 70 ° C the castor oil containing indomethacin was added, and thereafter the same procedure as in Example 2 was carried out.
  • the maximum possible content of indomethacin in the resulting emulsion was only about 0.08 WZ V%.
  • Hydrocortisone was added to 50 g of Migliol 812 and stirred in a water bath at 70 ° C. to completely dissolve the drug.
  • This hydrocortisone-containing Miglyol 812 was added to a solution prepared by adding 50 g of polysorbate 80 to 850 mL of sterilized purified water while heating to 70 ° C, and thereafter, the same procedure as in Example 3 was performed.
  • the maximum possible content of hydrocortisone in the emulsion obtained in the procedure was only about 0.004 WZV%.
  • This coarse emulsion was subjected to 10 passes with a microfluidizer M-110EH (pressure: 1500 kg / cm 2 ) to obtain a finely divided product.
  • the resulting emulsion contained 0.4 WZV% of indomethacin relative to the whole emulsion, and had a transmittance of 0.03% at a wavelength of 520 nm measured at a layer width of 1 cm. It was opaque.
  • indomethacin 0.5 g was added to 50 g of castor oil, and the mixture was stirred at 70 ° C. and dissolved to form an oil phase.
  • 50 g of tyloxapol was added to 85 OmL of sterile purified water, and the mixture was stirred and dissolved to form an aqueous phase.
  • This aqueous phase heated to about 70 ° C is homomixed (TK ROBOMICS: Tokushu Kagaku Kogyo Co., Ltd.) While stirring at 8000 rpm, add the above oil phase heated to about 70 ° C, and keep at 70 ° C for 30 minutes at 8000 rpm The mixture was stirred to obtain a crude emulsion, and sterilized purified water at about 70 ° C was added to make the whole amount 1 unit. The coarse emulsion was subjected to 10 passes with a microfluidizer M-110EH (pressure: 1500 kg / cm 2 ) to obtain a finely divided product.
  • M-110EH pressure: 1500 kg / cm 2
  • the resulting emulsion contains only 0.05 WZV% of indomethacin, which is close to the maximum obtained by this method, based on the whole emulsion.
  • the transmittance at a wavelength of 520 nm was 0.76%.
  • This coarse emulsion was subjected to 10 passes with a microfluidizer M-110EH (pressure: 1500 kgZcm 2 ) to obtain a finely divided product.
  • the resulting emulsion contains 0.05 W / V% of hydrocortisone based on the whole emulsion and has a transmittance of 0.1% at a wavelength of 520 nm measured at a layer width of 1 cm. there were.
  • Miglyol 812 To 50 g of Miglyol 812 was added 0.02 g of hydrocortisone, and the mixture was stirred at 70 ° C. and dissolved to form an oil phase.
  • 50 g of polysorbate 80 was added to 85 O mL of sterile purified water, and the mixture was stirred and dissolved to form an aqueous phase.
  • the aqueous phase heated to about 70 ° C was stirred with a homomixer (T. R0B0MICS: Tokushu Kagaku Kogyo KK) at 8000 rpm, and the oil phase heated to about 70 ° C was added.
  • the residual ratio of the active drug was measured by HPLC.
  • the measurement conditions are as follows. (Indomethacin)
  • the particle size of the emulsion was measured using a 5 mL emulsion sample, using purified water as the dispersion medium during the measurement, and using a laser-diffraction particle size distribution analyzer SALD-2000 (Shimadzu Corporation).
  • Table 4 shows the results of stability studies on Examples 4 and 5 and the corresponding Comparative Examples 3 and 4.
  • Example 4 and corresponding Comparative Example 3 are compared with Example 5 and corresponding Comparative Example 4, respectively, there is no substantial difference in the residual ratio of the active substance and the average particle size.
  • the emulsion according to the present method contains a much higher concentration of the active ingredient than a stable emulsion containing a concentration of the drug that can be naturally dissolved in oil according to the conventional method.
  • the conventional method did not reduce the stability of harm caused by the transfer of drug particles to the aqueous phase, etc., and enabled the inclusion of high-concentration drugs without adversely affecting the stability.
  • the method of the present invention provides a drug that has been conventionally required but has not been able to achieve a sufficient concentration, and does not cause a problem in stability, and has a significantly increased concentration and, therefore, usefulness. enable.
  • emulsions suitable for production by the method of the present invention are shown below. These exemplified emulsions can be produced by preparing an oil phase and an aqueous phase separately, mixing and emulsifying according to the above-mentioned Examples of the present invention.
  • castor oil and tyloxapol are mixed to form a uniform liquid, and a full-length rometron is added thereto, mixed and dissolved to form an oil phase.
  • an oil phase and an aqueous phase composed of concentrated glycerin and sterile purified water an emulsion is obtained according to the above-described example.
  • soybean oil and polyxylene-ethylene hydrogenated castor oil are mixed to form a uniform liquid, to which prednisolone is added, mixed and dissolved to form an oil phase.
  • an oil phase and an aqueous phase composed of concentrated glycerin, sodium dihydrogen phosphate and sterile purified water, an emulsion is obtained according to the above-described example.
  • liquid paraffin and tyloxapol are mixed to form a uniform liquid, and dexamethasone is added thereto, mixed and dissolved to form an oil phase.
  • an oil phase composed of concentrated glycerin, sodium edetate and sterilized purified water, an emulsion is obtained according to the above-mentioned Example.
  • Total volume (pH 2.5) 100 mL 100 mL
  • a solution prepared by uniformly mixing the remaining amounts of castor oil and polysorbate, and uniformly mixed to obtain a solution.
  • the carboxyvinyl polymer and sucrose fatty acid ester (S-770) (sucrose stearate, monoester ratio: 40%: manufactured by Mitsubishi Chemical Corporation) are added to the mixture, and the mixture is mixed uniformly to form an oil phase. .
  • a microemulsion is prepared from this oil phase and an aqueous phase composed of concentrated glycerin, phosphoric acid and sterilized purified water according to the above-described procedure.
  • a drug having insufficient solubility in the base oil can be stably contained in a state of being dissolved in a high concentration in the oil phase of the oil-in-water emulsion. Therefore, even a poorly soluble drug can be provided as an oil-in-water emulsion containing a high concentration, and the usefulness of such a drug can be improved.

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

Abstract

L'invention concerne une émuslion aqueuse qui se caractérise en ce que les composants de la phase huileuse contiennent (a) une huile servant de base, (b) un composant médicamenteux dissous dans l'huile, selon une concentration dépassant sa solubilité dans l'huile, et (c) un tensio-actif non-ionique, le facteur de transmission à 520 nm de l'émulsion, mesuré à une épaisseur d'un cm, est de 10 % ou moins.
PCT/JP2000/001879 1999-04-05 2000-03-27 Emulsion et son procede de production WO2000059470A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/98200 1999-04-05
JP9820099 1999-04-05

Publications (1)

Publication Number Publication Date
WO2000059470A1 true WO2000059470A1 (fr) 2000-10-12

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002193790A (ja) * 2000-12-27 2002-07-10 Lion Corp 水難溶性薬剤含有水中油型エマルジョン及びその製造方法
JP2007504124A (ja) * 2003-08-29 2007-03-01 ノバガリ、ファルマ、エスアー 難水溶性薬剤の投与のための自己ナノ乳化油性製剤
JP2008255111A (ja) * 2007-03-13 2008-10-23 Santen Pharmaceut Co Ltd ピレノキシンを含有する懸濁型水性液剤

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0257454A1 (fr) * 1986-08-18 1988-03-02 Morishita Pharmaceutical Co. Ltd. Emulsion grasse du type huile-dans-eau de 1-[2-(2,4-dichlorophényl)-3-méthyl-1-pentényl]-1H-imidazole
JPS63255228A (ja) * 1987-04-14 1988-10-21 Otsuka Pharmaceut Factory Inc ステロイドクリ−ム製剤
JPH04210903A (ja) * 1990-01-10 1992-08-03 F Hoffmann La Roche Ag 局所用薬剤組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0257454A1 (fr) * 1986-08-18 1988-03-02 Morishita Pharmaceutical Co. Ltd. Emulsion grasse du type huile-dans-eau de 1-[2-(2,4-dichlorophényl)-3-méthyl-1-pentényl]-1H-imidazole
JPS63255228A (ja) * 1987-04-14 1988-10-21 Otsuka Pharmaceut Factory Inc ステロイドクリ−ム製剤
JPH04210903A (ja) * 1990-01-10 1992-08-03 F Hoffmann La Roche Ag 局所用薬剤組成物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002193790A (ja) * 2000-12-27 2002-07-10 Lion Corp 水難溶性薬剤含有水中油型エマルジョン及びその製造方法
JP2007504124A (ja) * 2003-08-29 2007-03-01 ノバガリ、ファルマ、エスアー 難水溶性薬剤の投与のための自己ナノ乳化油性製剤
JP2008255111A (ja) * 2007-03-13 2008-10-23 Santen Pharmaceut Co Ltd ピレノキシンを含有する懸濁型水性液剤

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