Drug – bio-affecting and body treating compositions – Dispersion or emulsion
Reexamination Certificate
1999-10-15
2001-10-16
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Dispersion or emulsion
C514S513000, C514S738000, C514S763000, C514S267000, C514S938000, C514S937000, C424S400000, C424S401000
Reexamination Certificate
active
06303662
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a microemulsion containing a highly polar and fat-soluble drug, and more particularly relates to a microemulsion which has a minute particle size and has an enhanced stability of the drugs in aqueous solutions.
BACKGROUND ART
In order to produce a liquid preparation of fat-soluble drugs in the past, there were adopted methods for preparing an aqueous solution by dissolving these drugs in a solubilizing agent such as alcohols or surface active agents. In particular, it is ordinary to use polyoxyethylene hydrogenated castor oils or polyoxyethylene glycol fatty acid esters as a surface active agent in the methods for dissolving the fat-soluble drugs. However, the amount of the fat-soluble drug which can be dissolved by these methods is insufficient, and the internal liquid preparation obtained thereby is uncomfortable in taste.
On the other hand, in order to contain a fat-soluble drug in an aqueous liquid preparation, there is widely used a method wherein the fat-soluble drug is dissolved in an oil and stirred together with an emulsifying agent to give an emulsion, thereby an aqueous phase and an oily phase are completely isolated from each other.
It is known that the stability of emulsions ordinarily increases with decreasing the particle size of emulsions. Japanese Patent Publication Nos. 88-61050-B and 94-57316-B disclose techniques for the preparations of emulsions with minute particles (microemulsion). However, these techniques have a drawback which, when a highly polar and fat-soluble drug is applied thereto, the particle size of the emulsion is increased, and the emulsion becomes unstable by heating, acids and ionic substances.
In addition, Japanese Patent Publication No. 95-23303-B discloses a microemulsion preparation containing a slightly water-soluble drug, however, the microemulsion described in the patent needs vigorous stirring at the time of production thereof, and it is impossible to apply a highly polar and fat-soluble drug thereto.
DISCLOSURE OF THE INVENTION
As a result of extensive researches, the present inventors have found that a highly polar and fat-soluble drug is combined with a mixture of a highly polar oil and a lowly polar oil as an oil for dissolution, a specific amount ratio of a polyglycerol mono-fatty acid ester as an emulsifying agent to the oil and a specific amount of a water-soluble polyhydric alcohol with stirring to give a gel, which is then diluted with water, thereby there is obtained an O/W emulsion having minute particles, thus the present invention has been accomplished.
That is, the present invention is directed to a microemulsion which contains (A) a highly polar and fat-soluble drug, a highly polar oil and a lowly polar oil, (B) a polyglycerol mono-fatty acid ester and (C) a water-soluble polyhydric alcohol, wherein the amount of (B) is 0.3 to 3 parts by weight based on one part by weight of (A) and the amount of (C) is 0.1 to 3 parts by weight based on one part by weight of the total amount of (A) and (B).
The highly polar oil used in the present invention refers to an oily substance which has the value of the inorganic character in the range of 115 to 500, and which has the number of carbon atoms in the range of 9 to 19. Preferred examples of the highly polar oil to satisfy such conditions are triethyl citrate, triacetin, piperonyl butoxide, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dioctyl phthalate and the like.
The amount of the highly polar oil is 1 to 50 parts by weight based on one part by weight of the highly polar and fat-soluble drug, preferably 1 to 20 parts by weight. In case of less than one part by weight, the highly polar and fat-soluble drug may be poorly dissolvable, while, in case of more than 50 parts by weight, the emulsion with minute particles may not easily obtainable.
In the present invention, it is necessary to contain the lowly polar oil for emulsification. The lowly polar oil to be used herein is an oily substance which has the value of the inorganic character of 200 or less, and has the number of carbon atoms of 20 or more. Preferred examples of the lowly polar oil are liquid paraffin, squalane, squalene, tocopherol, tocopherol acetate, tocopherol nicotinate, avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, wheat germ oil, sasanqua oil, castor oil, safflower oil, cotton seed oil, soybean oil, peanut oil and medium chain fatty acid triglycerides such as tricaprilin. The amount of the lowly polar oil is 1 to 200 parts by weight based on one part of the highly polar and fat-soluble drug, preferably 10 to 50 parts by weight. In case of less than one part by weight, it may be difficult to emulsify, while, in case of more than 200 parts by weight, the highly polar and fat-soluble drug may be poorly dissolvable.
The value of the inorganic character in the present invention means the value which is calculated according to the method of Fujita indicated in Journal of Japanese Chemistry, vol. 11, 10, 719-725 (1957).
In the present invention, it is necessary to use the polyglycerol mono-fatty acid ester as an emulsifying agent because the emulsion having minute particles can not be obtained by using other emulsifying agents.
Preferred polyglycerol mono-fatty acid esters are those in which the glycerol polymerization grade is 5 or more, the number of carbon atoms of the fatty acid is in the range of 10 to 22 and the HLB is 12 or more. Among these polyglycerol mono-fatty acid esters, especially preferable ones are decaglycerol monostearate, decaglycerol monooleate, decaglycerol monopalmitate, decaglycerol monomyristate, decaglycerol monolaurate, hexaglycerol monomyristate or hexaglycerol monolaurate.
The amount of polyglycerol mono-fatty acid ester is in the range of 0.3 to 3 parts by weight based on one part by weight of the total amount of the oil phase (the highly polar and fat-soluble drug, the highly polar oil and the lowly polar oil), preferably 0.4 to 2 parts by weight. In case of less than 0.3 part by weight, the particle size may be increased, while, in case of more than 3 parts by weight, the internal preparation obtained thereby may cause bad taste.
In the present invention, it is essential to contain a water-soluble polyhydric alcohol for preparing the microemulsion.
Examples of the water-soluble polyhydric alcohol to be used in the present invention are ethylene glycol, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, dipropylene glycol, polypropylene glycol, glycerol, diglycerol, polyglycerol, polyethylene glycol, erythritol, xylytol, sorbitol, maltitol, lactitol, mannitol, trehalose, sugar alcohol derived from digestion product of starch and the like. Among these water-soluble polyhydric alcohols, especially preferred ones are glycerol, diglycerol, polyglycerol and sorbitol. These water-soluble polyhydric alcohols are usually used in the form of a hydrous product. In this case, the weight ratio of the water-soluble polyhydric alcohol and water is preferably in the range of 95:5 to 50:50, and especially 90:10 to 55:45.
The amount of the water-soluble polyhydric alcohol to be used in the present invention is from 0.1 to 3 parts by weight based on one part by weight of the total amount of the oil phase and the polyglycerol mono-fatty acid ester, preferably 0.2 to 2 parts by weight.
In the present invention, the combination ratio of the oil phase, the polyglycerol mono-fatty acid ester and the water-soluble polyhydric alcohol is important, when the combination ratio is out of the range of the present invention, the microemulsion can not be obtained though the same components are used.
The highly polar and fat-soluble drug in the present invention refers to drugs having the value which is obtained by dividing the value of the inorganic character of the compound by the number of the carbon atoms contained in the compound molecule is 11 or more. The polarity of the drug can not be defined by only the value of the inorganic character, but gives generality b
Hasegawa Kazuo
Nagahama Tohru
Jones Dameron L.
Lurosso & Loud
Taisho Pharmaceutical Co. Ltd.
Wells Lauren Q.
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