Patent Application
20110224310
The present invention relates to a ceramide dispersion and a method for producing the ceramide dispersion.
Ceramide is present in a stratum corneum of the skin and constructs a lipid barrier necessary for retaining water, and thereby it plays an important role for maintaining moisture. Ceramide in a stratum corneum is produced by degradation of cerebroside with an enzyme called cerebrosidase. It is known that a part of ceramide is changed into phytosphingosine and sphingosine with an enzyme called ceramidase, and they are important as an agent of regulating proliferation and differentiation of cells. In a human skin, seven kinds of ceramides are present, and have different functions, respectively.
However, since ceramide is a substance having high crystallizability, has low solubility in other oil solution, and precipitates a crystal at a low temperature, it was difficult to maintain stability when incorporated into cosmetics. Further, an aqueous ceramide dispersion may be dispersed using surfactants, but it is difficult to make a particle diameter of an dispersion sufficiently small, and thereby the dispersion inferior in transparency may be produced in some cases.
An emulsified composition that contains a specific group of sphingoglycolipid having moisturing effect, preventing effect on chapped skin, and emulsifying effect is disclosed as a composition containing ceramide (for example, refer to Japanese Patent Application Laid-Open (JP-A) No. 2000-51676).
A cosmetic additive combined with ceramide which contains cholesterol, fatty acid, and water-soluble polymer (for example, refer to JP-A No. H07-187987) is disclosed. As a composition for external use which is excellent in stability under rapidly changing temperature conditions and has good after-use feel, a water-in-oil type emulsified composition obtained by using sphingosines salt formed with a specific fatty acid as an emulsifying agent and adding an oil-soluble antioxidant at a specific ratio (for example, refer to JP-A No. 2006-335692) is disclosed.
As pharmaceutical preparation technique, a method for producing an additive agent for cosmetic in which a crude dispersion solution of sphingoglycolipid is micro particulated using a specified jet flow in order to sufficiently exhibit the emollient effect of sphingoglycolipid is disclosed (for example, refer to JP-A No. 11-310512).
On the other hand, a process for blending specific fatty acids and specific surfactants is disclosed as a technique for transparently solubilizing and stably blending ceramide (for example, refer to JP-A Nos. 2001-139796 and 2001-316217). However, in order for the ceramide to be made transparent and solubilized, it is necessary to increase the amount of surfactant to be added, and therefore, safety and a sense of use may be compromised. On the other hand, if a small amount of surfactant is added in order to obtain a superior sense of use, the ceramide often becomes cloudy or in a translucent milky state and cannot be made transparent and solubilized. In such a case, separation or creaming over time of the ceramide occurs, and it is difficult to secure a sufficient stability over time of the ceramide.
Thus, even by using these technique, it is, at present, not possible to obtain a ceramide dispersion in which the ceramide can be stably dispersed and which has a superior stability over time.
An object of the present invention is to provide a ceramide dispersion in which ceramide-containing particles having a very small particle diameter are stably dispersed and which has a superior stability over time.
The present invention provides ceramide dispersion and a method for producing the ceramide dispersion.
The first aspect of the present invention provides a ceramide dispersion which includes (1) ceramide-containing particles which contain a ceramide, which are dispersed in an aqueous phase as an oil-phase component and which have a volume average particle diameter from 1 nm to 100 nm, (2) a fatty acid component which is at least one of a fatty acid or a fatty acid salt, (3) a polyhydric alcohol in an amount from 5 to 20 times larger than an amount of the ceramide and (4) a polysaccharide fatty acid ester, and in which the pH is from 6 to 8.
The aspect of the present invention provides a method for producing the ceramide dispersion, the method including mixing an oil phase component containing at least the above-mentioned ceramide and an aqueous phase component at a temperature not higher than 40° C.
[Ceramide dispersion]
The ceramide dispersion of the present invention is ceramide dispersion which includes
(1) ceramide-containing particles which contain ceramide, which are dispersed in an aqueous phase as an oil-phase component and which has a volume average particle diameter from 1 nm to 100 nm,
(2) a fatty acid component which is at least either of fatty acid and fatty acid salt,
(3) a polyhydric alcohol in an amount from 5 to 20 times the above-mentioned ceramide and
(4) a polysaccharide fatty acid ester; and in which the pH is from 6 to 8.
Since the ceramide dispersion of the present invention contains the above-mentioned ceramide-containing particles, the above-mentioned fatty acid component, a prescribed amount of polyhydric alcohol and a polysaccharide fatty acid ester, and has a pH of from 6 to 8, the ceramide-containing particles are stably dispersed, and the ceramide dispersion can exhibit a good stability over time.
Even in cases in which salts such as inorganic salts, polysaccharide salts or organic acid salts are added to the dispersion, salting-out such as cloudiness, aggregation or thickening of the ceramide dispersion of the present invention can be favorably inhibited, and precipitation of ceramide over time can also be inhibited, and as a result, the dispersion stability and transparency of the ceramide dispersion can be maintained.
The term “step” used herein includes not only a discrete step, but also steps which cannot be clearly distinguished from another step, as long as the expected effect of the pertinent step can be achieved.
In addition, ranges indicated herein with “to” include the numerical values before and after “to”.
The invention will be described below.
The ceramide dispersion of the present invention is in a form of emulsion in which ceramide-containing particles which at least contain a ceramide are dispersed in an aqueous phase as an oil phase component. Here, the ceramide-containing particles as the oil phase component may be in a form of oil droplets in which the particles are completely dissolved, or in a form of partially insoluble solid as long as the diameter of the ceramide-containing particles is in a range prescribed in the present invention. Such oil droplets and solid are generally referred to herein as dispersed particles.
As the aqueous phase which constitutes a part of the ceramide dispersion of the present invention and which is a dispersion medium in which ceramide-containing particles are dispersed, an aqueous solution which contain as a main component an aqueous medium such as water may be used. Other than water, higher alcohols, or water-soluble functional components such as water-soluble antioxidants and plant extracts can be further added in an amount in which the effects of the present invention are not adversely affected.
In the following, a variety of components which are contained in the ceramide dispersion of the present invention will now be described.
(1) Ceramide-Containing Particles
The ceramide-containing particles of the present invention contain ceramide, are dispersed in an aqueous phase as an oil phase component, and have a volume average particle diameter from 1 nm to 100 nm.
The ceramide in the invention includes ceramide and derivatives thereof, which may be derived from a synthetic compound or an extracted product. The term “ceramide” as used herein includes a natural ceramide as described below, a compound having a natural ceramide as a basic skeleton, and a precursor which may be derived from these compounds, and is a collective name for a natural ceramide, a glycosylated ceramide such as a sphingoglycolipid, a synthetic ceramide, a sphingosine, a phytosphingosine, and derivatives thereof.
(Natural Ceramide)
The term “natural ceramide” as used herein means a ceramide which has the same structure as that present in the stratum corneum of human skin. A more preferred embodiment of the natural ceramide is that sphingoglycolipid is not contained and three or more hydroxyl groups are included in the molecular structure.
In the following, the natural ceramide used in the invention will be described in detail.
Examples of a fundamental structural formula of the natural ceramide which may be preferably used in the invention are shown in (1-1) to (1-10). (1-1) is known as ceramide 1, (1-2) is known as ceramide 9, (1-3) is known as ceramide 4, (1-4) is known as ceramide 2, (1-5) is known as ceramide 3, (1-6) is known as ceramide 5, (1-7) is known as ceramide 6, (1-8) is known as ceramide 7, (1-9) is known as ceramide 8, and (1-10) is known as ceramide 3B.
The above structural formula shows one example of each ceramide. Since ceramide is a natural substance, in ceramide actually derived from a human or an animal, there are various variation examples in the length of the alkyl chain, and ceramide having the above skeleton may have any structure in the alkyl chain length.
Alternatively, it is possible to use ceramide that have been modified according to purpose by, for example, introducing double bond(s) in the molecule to provide solubility for the purpose of, for example, incorporating into a formulation, or introducing hydrophobic group(s) to provide permeability.
Examples of the ceramide having a general structure, which referred to as the natural ceramide, include natural product (extract) and products obtained by microbial fermentation method. Further, synthetic substances and animal-derived substances may also be included.
A natural (D (−) isomer) optically active substance is used as such ceramide. Furthermore, a non-natural (L (+) isomer) optically active substance or a mixture of natural and unnatural type may be used, if necessary. A relative configuration of the above compounds may be natural configuration, or other non-natural configuration, or a mixture thereof.
Meanwhile, in the case of using a nanoceramide dispersion or composition for the purpose of, for example, a skin emollient, from the viewpoints of a barrier effect, it is preferable to use more of a natural optical isomer.
Such the natural ceramide are also available as a sold product, and examples include Ceramide I, Ceramide III, Ceramide IIIA ceramide IIIB, Ceramide IIIC, and Ceramide VI (all manufactured by Cosmofarm), Ceramide TIC-001 (manufactured by Takasago International Corporation), CERAMIDE II (manufactured by Quest International), DS-Ceramide VI, DS-CLA-Phytoceramide, C6-Phytoceramide, and DS-ceramide Y3S (manufactured by DOOSAN), and CERAMIDE2 (manufactured by Sedama), and the exemplified compound (1-5) is available as trade name: CERAMIDE 3, manufactured by Evonik (formerly Deggusa), and the exemplified compound (1-7) is available as trade name: CERAMIDE 6, manufactured by Evonik (formerly Deggusa).
The natural ceramide which is contained in the ceramide-containing particle may be used alone or in combination of two or more thereof. Generally, ceramide analogs have a high melting point and a high crystallinity. Therefore, the combination of two or more natural ceramide is preferable from the viewpoint of emulsion stability and handling performance.
(Glycosylated Ceramide)
The glycosylated ceramide is a ceramide compound containing saccharides in the molecule. Examples of the saccharides contained in the molecule of the ceramide compound include monosaccharides such as glucose or galactose; disaccharides such as lactose or maltose; and oligosaccharides and polysaccharides obtained by polymerizing these monosaccharides or disaccharides with a glycoside bond. Further, saccharides may be sugar derivatives in which a hydroxyl group in a sugar unit is replaced with other group. Examples of the sugar derivative include glucosamine, glucuronic acid, and N-acetyl glucosamine.
Among these, saccharides having 1 to 5 sugar units are preferable as the sugar unit in the molecule of the glycosylated ceramide from the viewpoint of dispersion stability. Specifically, glucose and lactose are preferable, and glucose is more preferable.
Specific examples of the glycosylated ceramide include the following compounds.
The glycosylated ceramide is available by synthesis or as a commercial product. For example, the exemplified compound (4-1) is available as a trade name: KOME SHINGOGLYCOLIPID manufactured by Okayasu Shoten Co., Ltd.
(Synthetic Ceramide)
The synthetic ceramide is synthesized in imitation of the structure of ceramide. As a known compound of such a synthetic ceramide, for example, the synthetic ceramide shown by the following structural formula may be used.
In the case of using the synthetic ceramide, for example, when the ceramide dispersion according to the present invention is used as a cosmetic product, from a viewpoint of an after-use feeling and a moisturizing feeling, a compound that is synthesized in imitation of the structure of the natural ceramide or the glycosylated ceramide are preferable, and a compound that is synthesized in imitation of the structure of the natural ceramide is more preferable. Synthetic ceramides are also commercially available. For example, the exemplified compound (3-2) (cetylhydroxyproline palmitamide) is available as “CeramideBio” (trade name) manufactured by Symrise Corporation.
(Sphingosine, Phytosphingosine)
For sphingosine and phytosphingosine, whether a synthetic product or a natural product, natural sphingosine or a sphingosine analog, or the combination thereof may be used.
Specific examples of the natural sphingosine include sphingosine, dihydrosphingosine, phytosphingosine, sphingadienine, dehydrosphingosine, dehydrophytosphingosine, and an N-alkylated body (e.g. N-methylated body) thereof, and an acetylated body thereof.
As these sphingosines, a natural (D (−) body) optically active body may be used, or a non-natural (L (+) body) optically active body may be used, or further, a mixture of a natural type and a non-natural type may be used. Relative configuration of the above compound may be natural configuration, may be other non-natural configuration, or may be configuration of a mixture thereof. Examples of phytosphingosine which may be preferably used in the invention include PHYTOSPHINGOSINE (INCI name; 8th Edition) and exemplified compounds described below.
Phytosphingosine may be either a natural extract or a synthetic compound. It may be produced by synthesis or may be available as a commercial product.
Commercially available examples of the natural sphingosine include D-Sphingosine (4-Sphingenine) (manufactured by SIGMA-ALDRICH), D-Sphytosphingosine (manufactured by DOOSAN), phytosphingosine (manufactured by Cosmofarm). Further, Compound (5-5) as exemplified above is available as a trade name of “PHYTOSPHINGOSINE” (manufactured by Evonik (formerly Deggusa)).
Acid
When sphingosines such as sphingosine or phytosphingosine are used in the invention, they are preferably used in combination with a compound having an acidic residue capable of forming a salt with the sphingosines. Preferable examples of the compound having acidic residue include inorganic acids or organic acids having 5 or less carbon atoms.
Examples of the inorganic acid include phosphoric acid, hydrochloric acid, nitric acid, sulfuric acid, perchloric acid, and carbonic acid, and phosphoric acid and hydrochloric acid are preferable.
Examples of the organic acid include monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, and valeric acid; dicarboxylic acids such as succinic acid, phthalic acid, fumaric acid, oxalic acid, malonic acid, and glutaric acid; oxycarboxylic acids such as glycolic acid, citric acid, lactic acid, pyruvic acid, malic acid, and tartaric acid; amino acids such as glutamic acid, and aspartic acid, and the like. As these compounds, phosphoric acid, hydrochloric acid, succinic acid, citric acid, lactic acid, glutamic acid, aspartic acid, or the combination thereof are preferable, and lactic acid, glutamic acid, aspartic acid or the combination thereof are particularly preferable.
The acid to be used together may be used by pre-mixing with sphingosines, may be added at the time of formation of the ceramide analogue containing particle, or may be added as a pH adjusting agent after the formation of the ceramide analogue containing particle.
When the acid is used together, the additive amount is preferably about 1 part by mass to 50 parts by mass relative to 100 parts by mass of sphingosines to be used.
—Ceramide Content—
In the ceramide dispersion of the present invention, it is preferred that ceramide-containing particles contain a ceramide in an amount of not less than 50% by mass with respect to the total mass of oil components contained in the oil phase, and, from the viewpoint of expecting that effective percutaneous or oral absorption of ceramide component and ceramide-induced effect be attained when the ceramide dispersion is applied to a variety of applications such as cosmetics, pharmaceuticals and foods, it is preferred that ceramide-containing particles contain a ceramide in an amount of from 50% by mass to 100% by mass, and more preferably, in an amount of from 75% by mass to 100% by mass. Thus, from the viewpoint of expecting that effects of natural ceramide be attained, it is preferred that natural ceramide be contained in an amount of not less than 50% by mass with respect to the total mass of ceramide contained in a high concentration in the ceramide dispersion, and most preferably in an amount of 100% by mass.
Here, in the ceramide dispersion of the present invention, the oil components contained in the oil phase represent, among the components contained in the oil phase, oil components having a physical property or functionality for application purposes of the ceramide dispersion, such as natural ceramide, the below mentioned ceramide analogues which may be used in combination therewith, as well as a variety of oil components including the below mentioned other oil components (e.g., fat-soluble carotenoids, fat-soluble vitamins, ubiquinones, fatty acids, oils and fats). It is noted that, among the components which may be used for preparing the oil phase, surfactants and water-soluble organic solvents are not included in the oil components of the present invention.
The content of ceramide in the ceramide dispersion is preferably in the range from 0.01% by mass to 5% by mass, and more preferably in the range from 0.1% by mass to 3% by mass. A ceramide dispersion containing a ceramide in the above mentioned range is preferred from the viewpoint of user's skin feel, for example, when the ceramide dispersion is applied to external preparations for skin such as cosmetics.
—Particle Diameter—
The ceramide-containing particles has a volume average particle diameter from 1 nm to 100 nm, preferably from 1 nm to 75 nm, more preferably from 1 nm to 50 nm, more preferably, and most preferably from 1 nm to 30 nm.
By making the particle diameter of ceramide-containing particle from 1 nm to 100 nm, transparency of the ceramide dispersion can be secured. When the ceramide dispersion of the present invention is used for, for example, cosmetics, pharmaceuticals or foods, the transparency of the composition is secured and desired effects such as skin absorbance can be favorably exerted.
The particle diameter of the ceramide-containing particle may be measured with a commercially available particle size distribution meter.
Known examples of the method for measuring particle size distribution include optical microscopy, a confocal laser scanning microscope method, an electron microscopic method, atomic force microscopy, a static light scattering method, laser diffractometry, dynamic light scattering, a centrifugal sedimentation method, electric pulse measurement, a chromatography method, and an ultrasonic attenuation method. Apparatuses based on each of these principles are commercially available.
In the measurement of the particle diameter of the ceramide-containing particle in the invention, it is preferable to use the dynamic light scattering from the viewpoint of particle diameter range and ease of measurement.
Examples of commercially available measuring apparatus using dynamic light scattering include a Nanotrac UPA (manufactured by Nikkiso Co., Ltd.), a dynamic light scattering particle size distribution meter LB-550 (manufactured by HORIBA Ltd.), and a concentrated-system particle diameter analyzer FPAR-1000 (manufactured by Otsuka Electronics Co., Ltd.).
The particle diameter of ceramide-containing particle in the invention is a value measured by using the dynamic light scattering particle size distribution meter LB-550 (manufactured by HORIBA Ltd.). Specifically, a value measured in the following manner is employed.
That is, in the method for measuring the particle diameter of the ceramide-containing particle, a sample divided from the ceramide dispersion of the invention is diluted with pure water so that the concentration of the oil component contained in the sample is 1% by mass and the particle diameter is measured using a quartz cell. The particle diameter may be determined as a median diameter when the refractive index of a sample is 1.600, the refractive index of a dispersion medium is 1.333 (pure water), and the viscosity of pure water is set as the viscosity of the dispersion medium.
Embodiments of the process of containing the ceramide-containing particles in the ceramide dispersion according to the present invention include: 1) a process of forming ceramide-containing particles (oil phase) in advance as solid particles and then dispersing these in a dispersion medium (aqueous phase); and 2) a process of forming a ceramide-containing particle in the system by heating ceramide analogs to change it into a molten state or dissolving a ceramide analog in an appropriate solvent to change it into a liquid state and then adding the resultant to the aqueous phase to disperse it, followed by reducing the temperature to ordinary ambient temperature or removing the solvent. Further, it is preferable that the natural ceramide or the like is prepared so as to be soluble in another oil component or is prepared by dissolving it in an organic solvent.
(Other Oil Components)
The ceramide dispersion of the invention is formed by dispersing a ceramide-containing particle in an aqueous phase as an oil phase. The ceramide dispersion may also have a configuration in which an oil component and/or solvent (may be referred to as “another (other) oil component(s)” in the present specification) different from the ceramide such as natural ceramide described above is contained in the oil phase, and an oil droplet-like dispersed particle containing natural ceramide is present as a natural ceramide-containing particle in the oil component and/or solvent. When this embodiment is used, the average particle diameter of the ceramide-containing particle in the invention means the average particle diameter of an oil droplet-like dispersed particle which contains a ceramide-containing particle.
In this regard, the term “another (other) oil component(s)” refers to an oil component which is not separated from the ceramide at an ordinary temperature. The term “solvent” refers to a solvent which may dissolve the ceramide, and examples thereof include alcohols.
Here, the other oil components usable in the present invention are not particularly limited. The other oil components may be components added as active component in accordance with the intended use of the ceramide dispersion, oil components used for improving dispersion stability or feeling with respect to skin or controlling the properties of a composition containing the ceramide dispersion. Herein below, the other oil components usable in the present invention are described.
(Stenone, Sterol)
The ceramide dispersion according to the present invention may contain at least one of stenone and sterol as other oil components. These compounds are useful in improving the dispersion stability of the ceramide dispersion. Specific examples of stenones usable as the other oil components in the present invention include the following.
Specific examples of sterol include the following.
The stenone compound and the sterol compound can be obtained by synthesis or as a commercially available product.
For example, phytostenone can be obtained as UNIFETH (manufactured by Toyo Hakko Co., Ltd.) and PEO-sterol can be obtained from NIKKOL BPS-20 (manufactured by Nikko Chemicals Co., Ltd.).
Each of the stenone compound and the sterol compound may be used singly, or plural kinds thereof may be used.
In the case of using one stenone compound singly, from the viewpoints of the dispersion stability of the natural-ceramide-containing particles, the content of the stenone compound is preferably 50% by mass or less with respect to the total mass of the oil-phase components contained in the ceramide dispersion, and more preferably 30% by mass or less.
(Oil Component as an Active Component)
In the case of using the ceramide dispersion according to the present invention for the use of a cosmetic product or a pharmaceutical product, it is preferable to include a functional material for a cosmetic product or a pharmaceutical product that is insoluble or poorly soluble in a water-soluble medium, particularly in water, as an oil component.
The oil components usable in the present invention are not particularly limited as long as they are components that are soluble in an oil medium, and insoluble or poorly soluble in an aqueous medium, particularly, water. Preferable examples of the oil components include radical scavengers including carotenoid and an oil-soluble vitamin such as tocopherol, and a fat or oil, such as a coconut oil.
The term “insoluble in an aqueous medium” means that the solubility in 100 mL of an aqueous medium is 0.01 g or less at 25° C. The term “hardly-soluble in an aqueous medium means that the solubility in 100 mL of an aqueous medium is more than 0.01 g and 0.1 g or less at 25° C. The term “functional component” used in the present specification means a component which is expected to induce a certain physiological effect in a living body to which the functional component is applied.
Carotenoids
As the oil component, carotenoids including a natural colorant may be preferably used.
Carotenoids which may be used in the external composition of the invention are colorants of terpenoids ranging in color from yellow to red, and include natural substances such as plants, algae, and bacteria.
Further, carotenoids are not limited to naturally-derived substances. Any carotenoids are included in carotenoids in the invention as long as they are obtained according to the conventional method. For example, many of carotenes of carotenoids described later are also produced by synthesis, and many of commercially available β-carotenes are produced by synthesis.
Examples of the carotenoids include hydrocarbons (carotenes) and oxidized alcohol derivatives thereof (xanthophylls).
Examples carotenoids include actinioerythrol, bixin, canthaxanthin, capsanthin, capsorbin, β-8′-apo-carotenal (apocarotenal), β-12′-apo′-carotenal, α-carotene, β-carotene, “carotene” (mixtures of α- and β-carotenes), γ-carotene, β-cryptoxanthin, lutein, lycopene, violaxanthin, zeaxanthin, and esters of them which have a hydroxyl or carboxyl group.
Many of carotenoids exist in nature in the form of cis- and trans-isomers, and synthetic products are often cis-trans-mixtures.
Carotenoids may be generally extracted from plant materials. These carotenoids have various functions and, for example, lutein extracted from a petal of marigold is widely used as a raw material of a feed of poutly, and has the function of coloring a skin of poutly, and lipid, as well as an egg laid by poutly.
Fats or Oils
Examples of fats or oils used as other oil component include fats or oils which are liquid at a normal temperature (fatty oils) and fats or oils which are solid at a normal temperature (fats).
Examples of liquid fats or oils include an olive oil, a camellia oil, a macadamia nut oil, a castor oil, an avocado oil, an evening primrose oil, a turtle oil, a corn oil, a mink oil, a rapeseed oil, an egg yolk oil, a sesame oil, a persic oil, a wheat germ oil, a sasanqua oil, a flaxseed oil, safflower seed oil a cotton seed oil, a perilla oil, a soybean oil, an arachis oil, a tea seed oil, a kaya oil, a rice bran oil, a chinese wood oil, a Japanese tung oil, jojoba oil, a germ oil, a triglycerol, a glyceryl trioctanoate, a glycerin triisopalmitate, a salad oil, a safflower oil (Carthamus tinctorius oil), a palm oil, a coconut oil, a peanut oil, an almond oil, a hazelnut oil, a walnut oil, and a grape seed oil.
Examples of the solid fats or oils include a beef tallow, a hardened beef tallow, a neatsfoot oil, a beef bone fat, a mink oil, an egg yolk oil, a lard, a horse fat, a mutton tallow, a hardened oil, a cacao butter, a palm oil, a hardened palm oil, a palm oil, a palm hardened oil, a Japan wax, a Japan wax kernel oil, and a hardened castor oil.
Among them, a coconut oil which is a medium chain fatty acid triglyceride is preferably used from a viewpoint of the dispersed particle diameter and stability of the external composition.
In the invention, as the fats or oils, commercially available products may be used. Further, in the invention, the fats or oils may be used alone, or may be used by mixing them.
Examples of a compound having a phenolic hydroxyl group which may be used as other oil component in the invention include polyphenols (e.g. catechin), guaiac butter, nordihydroguaretic acid (NDGA), gallic acid esters, BHT (butylhydroxytoluene), BHA (butylhydroxyanisole), vitamin E group and bisphenols. Examples of gallic acid esters include propyl gallate, butyl gallate and octyl gallate.
Examples of the amine compound include phenylenediamine, diphenyl-p-phenylenediamine and 4-amino-p-diphenylamine, and diphenyl-p-phenylenediamine or 4-amino-p-diphenylamine is more preferable.
Examples of an oil-solubilized derivative of ascorbic acid or erythorbic acid include L-ascorbyl stearate, L-ascorbyl tetraisopalmitate, L-ascorbyl palmitate, erisorbyl palmitate, and erisorbyl tetraisopalmitate.
Among them, a vitamin E group is particularly preferably used from a viewpoint of excellence in safety and function of antioxidant.
The vitamin E group is not particularly limited. Examples of the vitamin E group include a compound group consisting of tocopherol and derivatives thereof, as well as a compound group consisting of tocotrienol and derivatives thereof. These may be used alone or in combination with a plurality of them. Alternatively, the compound selected from the group consisting of tocopherol and derivatives thereof may be used in combination with the compound selected from the group consisting of tocotrienol and derivatives thereof.
Examples of the compound group consisting of tocopherol and derivatives thereof include dl-α-tocopherol, dl-β-tocopherol, dl-γ-tocopherol, dl-δ-tocopherol, acetic acid dl-α-tocopherol, nicotinic acid-dl-α-tocopherol, linolic acid-dl-α-tocopherol, and succinic acid dl-α-tocopherol. Among them, dl-α-tocopherol, dl-β-tocopherol, dl-γ-tocopherol, dl-δ-tocopherol, and mixtures thereof (mixed tocopherol) are more preferable. As tocopherol derivatives, acetic esters of them are preferably used.
Examples of the compound group consisting of tocotrienol and derivatives thereof include α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol. As tocotrienol derivatives, acetic esters thereof are preferably used. Tocotrienol is a tocopherol analog included in wheat, rice bran, and palm oil, has three double bonds in the side chain of tocopherol, and shows excellent antioxidant performance.
The vitamin E group are particularly preferably contained, in the oil phase of the ceramide dispersion as the oil-soluble antioxidant since the antioxidant function of the oil component may be effectively exhibited. Among the vitamin E group, at least one compound selected from the compound group consisting of tocotrienol and derivatives thereof is preferably contained from a viewpoint of the oxidation preventing effect.
In the ceramide dispersion of the present invention, the content of such other oil components used is preferably from 0.1% by mass to 50% by mass with respect to the total mass of the dispersion, more preferably from 0.2% by mass to 25% by mass, and still more preferably from 0.5% by mass to 10% by mass, from the viewpoint of dispersed particle diameter and emulsion stability, in view of application of, for example, pharmaceuticals and cosmetics.
When the content of the oil component is not less than 0.1% by mass as mentioned above, the ceramide dispersion can be easily applied to pharmaceuticals and cosmetics since the efficacy of the effective component can be sufficiently exerted. On the other hand, when the content of the oil component is not more than 50% by mass, increase in dispersed particle diameter and deterioration of emulsion stability are inhibited, whereby a stable composition is obtained.
(2) Fatty Acid Component
The fatty acid component of the present invention is at least one of a fatty acid or a fatty acid salt. By employing such a fatty acid component, fine and stable ceramide-containing particles which contain a ceramide can be obtained. In the present invention, the below-mentioned “surfactant” does not include this fatty acid component.
Fatty acids as the fatty acid component may be those which are generally used, for example, in the field of cosmetics, pharmaceuticals or foods. From the viewpoint of the dispersibility or the like of the ceramide-containing particles, fatty acids having a carbon number of 12 to 20 (C12-C20 fatty acids) are preferred. Among these, a fatty acid which is in a liquid state at normal temperature or at the temperature during dispersion such as lauric acid, oleic acid or isostearic acid is more preferred. Examples of the C12-C20 fatty acids include lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, isostearic acid, linoleic acid, α-linolenic acid and γ-linolenic acid. A fatty acid as the fatty acid component is included in the ceramide dispersion that is the oil phase component.
Since the fatty acid as the fatty acid component is in soluble form irrespective of the melting point of the fatty acid, from the viewpoint of solubility during a mixture process, the fatty acid component may be a fatty acid having any melting point, and may be a saturated fatty acid or an unsaturated fatty acid. Examples of the salt constituting the fatty acid salt include metallic salts such as sodium salts and potassium salts, basic amino acid salts such as L-arginine salts, L-histidine salts and L-lysine salts, alkanolamine salts such as triethanolamine salts. The type of salt may be selected according to the type of fatty acid used, and metallic salts such as sodium are preferred from the viewpoint of solubility and stability of dispersion liquid. Such fatty acid salts as fatty acid components may be employed as an aqueous phase component of the ceramide dispersion because these fatty acids may be dissolved in an aqueous medium.
Fatty acid components in the ceramide dispersion of the present invention may be C12-C20 fatty acids, and examples thereof include fatty acids such as lauric acid, myristic acid, pulmitic acid, palmitoleic acid, stearic acid, oleic acid, 12-hydroxy stearic acid, tall acid, isostearic acid, linoleic acid, α-linolenic acid and γ-linolenic acid, and salts thereof, and these may be used alone or two or more of these may be used in combination. Among others, from the viewpoint of its liquid state at room temperature or dispersion temperature, fatty acid components of the present invention is preferably selected from the group consisting of myristic acid, pulmitic acid, palmitoleic acid, lauric acid, stearic acid, isostearic acid, oleic acid, γ-linolenic acid, α-linolenic acid and linoleic acid, and salts thereof, and oleic acid is particularly preferred.
The amount of the fatty acid component contained in the ceramide dispersion of the invention is preferably the amount which may disperse the ceramide sufficiently. From a viewpoint of preservation stability and transparency of the ceramide dispersion, the amount is preferably from 0.01 to 1.0 times of the total mass of the ceramide. From a viewpoint of preservation stability, the amount is preferably from 0.05 to 0.5 times of the total mass of the ceramide. When the amount of the fatty acid component is 1.0 times or less of the total mass of the ceramide, it is preferable in that excessive separation or precipitation of fatty acid is suppressed. On the other hand, when the amount of the fatty acid component is 0.01 times or more of the total mass of the ceramide, it is preferable in that the fixation of the fatty acid component to the ceramide is sufficient.
From the viewpoint of transparency, it is preferred that the content of fatty acid components in the ceramide dispersion be from 0.01 to 0.5 times the total mass of ceramide. When the content of the fatty acid components is not less than 0.01 times the total mass of ceramide, the stability of the ceramide dispersion improves, but when the content of the fatty acid components is less than 0.01 times the total mass of ceramide, the ceramide cannot be sufficiently dispersed and is deposited. On the other hand, when the content of the fatty acid components is not more than 0.5 times the total mass of ceramide, the transparency of the ceramide dispersion can be attained and release of an excess amount of fatty acids can be inhibited. Therefore, the above range is preferable.
In order to obtain more favorable transparent ceramide, the content of fatty acid components in the ceramide dispersion is preferably from 0.01 times to 0.3 times the total mass of ceramide, and more preferably from 0.03 times to 0.2 times the total mass of ceramide. In order to obtain a ceramide dispersion having a more favorable preservation stability, the content of fatty acid components in the ceramide dispersion is preferably from 0.05 times to 0.5 times the total mass of ceramide, and more preferably from 0.03 times to 0.2 times the total mass of ceramide.
(3) Polyhydric Alcohol
The ceramide dispersion of the present invention contains a polyhydric alcohol in an amount which is five to twenty times the amount of the ceramide.
The polyhydric alcohol has the moisturizing function and the viscosity adjusting function. In addition, the polyhydric alcohol also has the function of reducing the interface tension between water and a fat or oil component, making an interface easily spread, and making easier to form a fine and stable particle.
From the foregoing, inclusion of the polyhydric alcohol in the ceramide dispersion is preferable from a viewpoint that the dispersed particle diameter of the ceramide dispersion may be finer, and the particle diameter may be stably retained for a long period of time in the state where the particle diameter is fine.
In addition, by addition of the polyhydric alcohol, the moisture activity of the ceramide dispersion may be reduced, and proliferation of microorganisms may be suppressed.
Further, by containing a polyhydric alcohol in an amount which is five to twenty times the amount of the ceramide, filtration can be easily performed in a filtration process in the production of the dispersion, thereby improving production efficiency.
The polyhydric alcohol which may be used in the invention is not particularly limited, as long as it is a di- or more hydric alcohol.
Examples of polyhydric alcohol include glycerin, diglycerin, triglycerin, polyglycerin, 3-methyl-1,3-butanediol, 1,3-butylene glycol, isoprene glycol, polyethylene glycol, 1,2-pentanediol, 1,2-hexandiol, propylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, pentaerythritol, neopentyl glycol, maltitol, reduced starch syrup, saccharose, lactitol, palatinit, erythritol, sorbitol, mannitol, xylitol, xylose, glucose, lactose, mannose, maltose, galactose, fructose, inositol, pentaerythritol, maltotriose, sorbitan, trehalose, amylolysis sugar, and amylolysis sugar reduced alcohol. These compounds may be used alone, or in the form of a mixture of plural kinds.
It is preferred that polyhydric alcohol in which the number of hydroxyl groups in one molecule is three or more be used. By this, the interfacial tension between an aqueous solvent and oils or fats components can be lowered more effectively, and more minute and stable particulates can be formed. As the result, in the ceramide dispersion, a higher intestinal absorption can be attained when the ceramide dispersion is used for foods, and a higher skin absorption can be attained when the ceramide dispersion is used for percutaneous pharmaceuticals or cosmetics.
In cases where, among the polyhydric alcohols which satisfy such conditions as described above, any of glycerin, 1,3-butanediol, or a combination thereof is used, ease of filtering is improved, the particle diameter of the dispersed particle in the ceramide dispersion become smaller, and the particle diameter is stably maintained at a small size for the long term, which is particularly preferable.
The content of the polyhydric alcohol is from five to twenty times the total mass of the ceramide. By making the content of the polyhydric alcohol five or more times the total mass of the ceramide, easier filtration in the production process can be attained in addition to the particle diameter, stability and antisepsis described above. By making the content of the polyhydric alcohol 20 or less times the total mass of the ceramide, stickiness of the ceramide when processed into cosmetics can be suppressed; effects commensurate with the content can be relied on; and the viscosity of the dispersion can be set in an appropriate range. From the viewpoint of filterability, transparency and stability over time of the ceramide dispersion liquid, the content of polyhydric alcohol is preferably from five to twenty times the amount of the ceramide, and more preferably from 7.5 to 15 times the amount of the ceramide.
From the viewpoint of dispersion stability, preservation stability, the viscosity of the dispersion and composition, and the filterability, the content of polyhydric alcohol is preferably from 0.1 to 60% by mass based on the total mass of the ceramide dispersion, more preferably from 0.5 to 55% by mass, and still more preferably from 1 to 50% by mass. When the content of polyhydric alcohol is 0.1% or higher by mass, a sufficient preservation stability is easily obtained also by the type and content of fats and oils or the like. On the other hand, when the content of polyhydric alcohol is 60% or lower by mass, an effect can be maximally obtained, and an increase in the viscosity of the ceramide dispersion is easily inhibited, which is preferred.
(4) Polysaccharide Fatty Acid Ester
The ceramide dispersion of the present invention contains a polysaccharide fatty acid ester. Emulsions or dispersions such as the ceramide dispersion of the present invention are generally formulated in a variety of forms of organic salts or inorganic salts in order to stably formulate each of the components having a variety of functions. When organic salts or inorganic salts are increased in the ceramide dispersion, phenomena such as cloudiness, aggregation, precipitation, thickening or separation, which are known as salting-out, are likely to be caused by these salts. In particular, in a formulation in which transparency is prioritized, such salting-out may compromise the transparency, which is not preferred. Since the ceramide dispersion of the present invention contains a polysaccharide fatty acid ester, dispersion stability can be obtained and the so-called salting-out can be favorably inhibited even in cases in which a variety of organic or inorganic salts are added.
An improvement in the stability of the dispersion over time, such as by inhibition of precipitation of the ceramide dispersion, is also possible.
In the polysaccharide fatty acid esters of the present invention, the polysaccharide portion is composed of a sugar unit which is glucose or fructose having an average degree of polymerization from 2 to 140. Examples of the polysaccharide portion include disaccharides such as sucrose, oligosaccharides, inulins (those in which about 2 to 60 fructoses are connected to glucose) and hexa- or higher saccharides such as starch or dextrin. From the viewpoint of the effect of inhibiting a salting-out phenomena such as cloudiness, aggregation, precipitation, thickening or separation of the ceramide dispersion when salts are added, dextrin, inulin or a combination thereof is preferred, and inulin is more preferred. Inulin is an oligosaccharide whose main component is D-fructose. Furanoid fructose unit which represents a structure having furanoid fructose having β-1,2 bond and α-D-glucose having a sucrose bond at a reducing terminal is generally 2 to 60.
From the viewpoint of the effect of inhibiting a precipitation by salts, the fatty acid portion which is esterified with the polysaccharide is preferably a C12-C18 fatty acid, and examples thereof include caprylic acid, caprin acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, isostearic acid, linoleic acid, linolenic acid, ethyl hexanoic acid, behenic acid, behenic acid.
Examples of such polysaccharide fatty acid esters include dextrin fatty acid esters, sucrose fatty acid ester, starch fatty acid esters, oligosaccharide fatty acid esters, inulin fatty acid esters. Among these, inulin fatty acid esters and dextrin fatty acid esters are preferred. Examples of the inulin fatty acid esters include inulin octanoate, inulin decanoate, inulin laurate, inulin myristate, lauryl carbamate, inulin palmitate, inulin stearate, inulin arachidate, inulin behenate, inulin oleate, inulin 2-ethyl hexanoate, inulin isomyristate, inulin isopalmitate, inulin isostearate, inulin isooleate, or a combination there of. From the viewpoint of the stability of the ceramide dispersion, as the polysaccharide fatty acid esters of the present invention, inulin stearate, lauryl carbamate, dextrin palmitate, dextrin palmitate/octanoate and dextrin myristate are preferred, and inulin lauryl carbamate is most preferred.
Although inulin lauryl carbamate has an HLB value of about 8 and have a low solubility for oily components, the dispersibility of the inulin lauryl carbamateis good, and inulin lauryl carbamate also has a low solubility for water, thereby precipitating in an aqueous phase. In an oil-in-water emulsion, by the hydration of the inulin structure, inulin lauryl carbamate is located on the surface of the dispersed particles to form a steric barrier, which forms an emulsion structure in which the steric barrier encloses the dispersed particles in the aqueous phase.
The polysaccharide fatty acid esters can be used alone or two or more of these may be used in combination. The content of the polysaccharide fatty acid esters can be from 0.1 to 2 times the amount of the ceramide in the ceramide dispersion, and from the viewpoint of the stability of the ceramide dispersion, the content of the polysaccharide fatty acid esters is more preferably from 0.5 to 1.5 times the amount of the ceramide in the ceramide dispersion. The amount of polysaccharide fatty acid esters is preferably from 0.05% to 2% by mass based on the total mass of the ceramide dispersion, and more preferably from 0.5% to 1.5% by mass based on the total mass of the ceramide dispersion. In a case where the amount is 0.05% by mass or more, good effects can be expected, and in a case where the amount is 2% by mass or less, the viscosity of the ceramide dispersion can be maintained appropriately, both of which are preferred.
The polysaccharide fatty acid esters may be added to any of an aqueous phase and a oil phase, which can be selected appropriately according to the type of the polysaccharide fatty acid esters selected. For example, inulin lauryl carbamate can be contained in the dispersion of the present invention as an aqueous phase component, and palmitic acid dextrin can be contained in the dispersion of the present invention as an oil phase component.
(5) Alkali Treated Gelatin
From the viewpoint that a precipitation by salts can be favorably inhibited without compromising transparency, the ceramide dispersion of the present invention preferably contains an alkali treated gelatin.
The alkali treated gelatin in the present invention means a gelatin made in such a way that a collagen is pretreated by alkali and then thermally hydrolysed to be solubilized. As the alkali treated gelatin, from the viewpoint of viscosity, that is, ease of handling, and from the viewpoint of the viscosity of the ceramide dispersion liquid, an alkali treated gelatin having a molecular weight of from about 10000 to 200000 is preferred. The gelatin is not particularly limited whether the gelatin is extracted from collagen tissues of mammals or fishes, and collagen from fishes is preferred. Examples of sources of collagen from fishes include skin of tilapia (Oreochromis niloticus), tunny (yellow fin) and shark. Examples of sources of collagen from mammals include pig and cattle.
From the viewpoint of inhibiting a so-called salting-out, the amount of the alkali treated gelatin is preferably from 0.1 to 2 times the mass of the ceramide, and more preferably from 0.3 to 1.5 times the mass of the ceramide. The content of the alkali treated gelatin in the ceramide dispersion is preferably from 0.1% to 2.0% by mass based on the ceramide dispersion, and more preferably from 0.5% to 2% by mass based on the ceramide dispersion. In a case where the content is 0.1% by mass or more, effects of inhibiting a salting-out can be sufficiently expected, and in a case where the content is 2.0% by mass or less, the viscosity of the ceramide dispersion can be maintained appropriately, both of which are preferred.
The alkali treated gelatin can be mixed as ceramide dispersion liquid or an aqueous phase component.
(6) Surfactant
From the viewpoint of dispersion stability and miniaturization of the particles, the ceramide dispersion of the present invention preferably contains surfactants other than the fatty acids mentioned above in an amount of 0 or not more than 0.1 times the total mass of the ceramide.
Since the ceramide dispersion of the present invention contains the fatty acid component as mentioned above, the amount of surfactants other than the fatty acid components can be 0 or not more than 0.1 times the total mass of the ceramide. Here, “0 based on the total mass of the ceramide” means that the ceramide dispersion of the present invention does not contain surfactants other than fatty acid components. Examples of such surfactants of the present invention other than fatty acid components include cationic, anionic, amphoteric and nonionic surfactants.
In cases where nonionic surfactant is contained as such surfactants, from the viewpoint of transparency and stability, the nonionic surfactant may be contained in an amount 0.1 times or less the total mass of the ceramide. On the other hand, from the viewpoint of preservation stability of the ceramide dispersion, surfactants other than the nonionic surfactants are preferably contained in an amount 0.01 times or less the total mass the of ceramide, and most preferably are contained in an amount of 0, that is, are not contained.
Examples of the nonionic surfactant capable be contained in the ceramide dispersion include glycerole fatty acid ester, organic acid monoglyceride, polyglycerole fatty acid ester, propylene glycol fatty acid ester, polyglycerole condensed ricinoleic acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, and polyoxyethylene sorbitan fatty acid ester. These may be used alone or two or more of these may be used in combination. These surfactants are not necessary to be a surfactant which is highly purified such as by distillation, and may be a reaction mixture. These nonionic surfactants can be contained as an oil phase component of the ceramide dispersion of the present invention.
Among the nonionic surfactants, polyglycerol fatty acid ester is preferable from a viewpoint of emulsion stability. Particularly, polyglycerol fatty acid ester with an HLB of form 10 to 16 (hereinafter, may be referred to as the “specific polyglycerol fatty acid ester”) is more preferable. The polyglycerol fatty acid ester may be contained in the oil phase.
Surfactants such as the specific polyglycerole fatty acid ester is preferable since the specific polyglycerol fatty acid ester may reduce the interfacial tension of oil phase/aqueous phase greatly, and thereby the particle diameter of the ceramide-containing particle which is contained in the ceramide dispersion as an oil phase may be smaller.
Herein, HLB is hydrophilicity-hydrophobicity balance which is usually used in the field of surfactants, and a calculation equation which is usually used, for example, Kawakami equation may be used. In the invention, the following Kawakami equation is adopted.
HLB=7+11.7 log(Mw/Mo)
In the equation, Mw is the molecular weight of a hydrophilic group, and Mo is the molecular weight of a hydrophobic group.
Alternatively, numerical values of HLB described in catalogs may be used. As is apparent from the aforementioned equation, a surfactant of an arbitrary HLB value may be obtained by utilizing additivity of HLB.
As for the preferable examples of the polyglycerol fatty acid ester, it is particularly preferable that at least one of them is an ester of a polyglycerin with an average degree of polymerization of 10, and a fatty acid having 8 to 18 carbon atoms (for example, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and linolic acid).
Preferable examples of the polyglycerol fatty acid ester include hexaglycerol monooleate, hexaglycerol monopalmitate, hexaglycerol monomyristate, hexaglycerol monolaurate, decaglycerol monooleate, decaglycerol monostearate, decaglycerol monopalmitate, decaglycerol monomyristate, and decaglycerol monolaurate. The HLB values of these compounds are from 10 to 16.
Among them, decaglycerol monolinoleate (HLB=12), decaglycerol monooleate (HLB=12), decaglycerol monostearate (HLB=12), decaglycerol monopalmitate (HLB=13), decaglycerol monomyristate (HLB=14), decaglycerol monolaurate (HLB=16) or the like is more preferable. As the polyglycerol fatty acid ester, decaglycerol oleate is particularly preferable. In the invention, the specific polyglycerol fatty acid ester may be used alone or in combination of two or more thereof.
As for the surfactant in the invention, one selected from polyglycerol fatty acid ester with an HLB of from 10 to 16 and one or more selected from polyglycerol fatty acid ester with an HLB of from 5 to 15 which has a molecular structure different from the former polyglycerol fatty acid ester may be combined. In this regard, the polyglycerol fatty acid ester with an HLB of from 5 to 15 may be polyglycerol fatty acid ester which is contained in polyglycerol fatty acid esters as described above or may be other polyglycerol fatty acid esters.
In the invention, a preferred embodiment contains, as the surfactant, decaglycerol oleate and polyglycerol fatty acid ester in which the polymerization degree of glycerol is less than 10 and the number of carbon atom in fatty acid is from 12 to 18. A more preferable example of polyglyceryl fatty acid ester in which the degree of polymerization of the glycerol is less than 10 and the number of carbon atoms in fatty acid is from 12 to 18 includes polyglyceryl fatty acid ester which is at least one selected from hexaglycerol fatty acid ester and tetraglycerol fatty acid ester and has an HLB value of form 5.0 to 15.
Examples of hexaglycerol fatty acid ester and tetraglycerol fatty acid ester which are suitably used together with decaglycerol oleate include tetraglycerol monostearate (HLB=6), tetraglycerol monooleate (HLB=6), hexaglycerol monolaurate (HLB=14.5), hexaglycerol monomyristate (HLB=11), hexaglycerol monostearate (HLB=9), and hexaglycerol monooleate (HLB=9).
When decaglycerol oleate is used in combination with hexaglycerol fatty acid ester and/or tetraglycerol fatty acid ester in the invention, the content ratio may be properly determined according to the application form of the ceramide dispersion and (decaglycerol fatty acid ester)/(tetraglycerol fatty acid ester and/or hexaglycerol fatty acid ester) is preferably from 1/0 to 1/1, more preferably 1/0.5, and further preferably 1/0.25.
A commercially available product of polyglycerol fatty acid ester such as a specific polyglycerol fatty acid ester may be used.
Examples of the commercially available product of polyglycerol fatty acid ester include NIKKOL DGMS, NIKKOL DGMO-CV, NIKKOL DGMO-90V, NIKKOL DGDO, NIKKOL DGMIS, NIKKOL DGTIS, NIKKOL Tetraglyn 1-SV, NIKKOL Tetraglyn 1-O, NIKKOL Tetraglyn 3-S, NIKKOL Tetraglyn 5-S, NIKKOL Tetraglyn 5-O, NIKKOL Hexaglyn 1-L, NIKKOL Hexaglyn 1-M, NIKKOL Hexaglyn 1-SV, NIKKOL Hexaglyn 1-O, NIKKOL Hexaglyn 3-S, NIKKOL Hexaglyn 4-B, NIKKOL Hexaglyn 5-S, NIKKOL Hexaglyn 5-O, NIKKOL Hexaglyn PR-15, NIKKOL Decaglyn 1-L, NIKKOL Decaglyn 1-M, NIKKOL Decaglyn 1-SV, NIKKOL Decaglyn 1-50SV, NIKKOL Decaglyn 1-ISV, NIKKOL Decaglyn 1-O, and NIKKOL Decaglyn 1-0V, NIKKOL Decaglyn 1-LN, NIKKOL Decaglyn 2-SV,
NIKKOL Decaglyn 2-ISV, NIKKOL Decaglyn 3-SV, NIKKOL Decaglyn 3-OV, NIKKOL Decaglyn 5-SV, NIKKOL Decaglyn 5-HS, NIKKOL Decaglyn 5-IS, NIKKOL Decaglyn 5-OV, NIKKOL Decaglyn 5-O-R, NIKKOL Decaglyn 7-S, NIKKOL Decaglyn 7-O and NIKKOL Decaglyn 10-SV, NIKKOL Decaglyn 10-IS, NIKKOL Decaglyn 10-OV, NIKKOL Decaglyn 10-MAC, and NIKKOL Decaglyn PR-20 (manufactured by Nikko Chemicals Co., Ltd.), Ryoto Polygly Ester, L-7D, L-10D, M-10D, P-8D, SWA-10D, SWA-15D, SWA-20D, S-24D, S-28D, O-15D, O-50D, B-70D, B-100D, ER-60D, LOP-120DP, DS13W, DS3, HS11, HS9, TS4, TS2, DL15, and D013 (manufactured by Mitsubishi-Kagaku Foods Corporation); Sunsoft Q-17UL, Sunsoft Q-14S, and Sunsoft A-141C (manufactured by Taiyo Kagaku Co., Ltd.); and Poem DO-100 and Poem J-0021 (manufactured by Riken Vitamin Co., Ltd.).
Among them, NIKKOL Decaglyn 1-L, NIKKOL Decaglyn 1-M, NIKKOL Decaglyn 1-SV, NIKKOL Decaglyn 1-50SV, NIKKOL Decaglyn 1-ISV, NIKKOL Decaglyn 1-O, and NIKKOL Decaglyn 1-OV, NIKKOL Decaglyn 1-LN, Ryoto Polygly Ester, L-7D, L-10D, M-10D, P-8D, SWA-10D, SWA-15D, SWA-20D, S-24D, S-28D, O-15D, 0-50D, B-70D, B-100D, ER-60D, and LOP-120DP are preferable.
As for sorbitan fatty acid ester which is another surfactant in the present invention, the number of carbon atoms in fatty acid is preferably 8 or more, more preferably 12 or more. Preferable examples of sorbitan fatty acid ester include sorbitan monocaprylate, sorbitan monolaurate, sorbitan monostearate, sorbitan sesquistearate, sorbitan tristearate, sorbitan isostearate, sorbitan sesquiisostearate, sorbitan oleate, sorbitan sesquioleate, and sorbitan trioleate.
In the invention, these sorbitan fatty acid esters may be used alone, or may be used by mixing them.
Examples of the commercially available product of sorbitan fatty acid ester include NIKKOL SL-10 and SP-10V, SS-10V, SS-10MV, SS-15V, SS-30V, SI-10RV, SI-15RV, SO-10V, SO-15MV, SO-15V, SO-30V, SO-10R, SO-15R, SO-30R, and SO-15EX (manufactured by Nikko Chemicals Co., Ltd.); Solgen 30V, 40V, 50V, 90, and 110 (manufactured by DAI-ICHI KOGYO SEIYAKU CO., LTD.); and RHEODOL AS-10V, AO-10V, AO-15V, SP-L10, SP-P10, SP-S10V, SP-S30V, SP-010V, and SP-030V (manufactured by Kao Corporation).
As for sucrose fatty acid ester, the number of carbon atom in fatty acid is preferably 12 or more, more preferably from 12 to 20.
Preferable examples of sucrose fatty acid ester include sucrose dioleate, sucrose distearate, sucrose dipalmitate, sucrose dimyristate, sucrose dilaurate, sucrose monooleate, sucrose monostearate, sucrose monopalmitate, sucrose monomyristate, and sucrose monolaurate. Among them, sucrose monooleate, sucrose monostearate, sucrose monopalmitate, sucrose monomyristate, and sucrose monolaurate are more preferable.
In the invention, these sucrose fatty acid esters may be used alone, or may be used by mixing them.
Examples of the commercial product of sucrose fatty acid ester include Ryoto sugar ester S-070, S-170, S-270, S-370, S-370F, S-570, S-770, S-970, S-1170, S-1170F, S-1570, S-1670, P-070, P-170, P-1570, P-1670, M-1695, 0-170, 0-1570, OWA-1570, L-195, L-595, L-1695, LWA-1570, B-370, B-370F, ER-190, ER-290, and POS-135 (manufactured by Mitsubishi-Kagaku Foods Corporation); and DK Ester SS, F160, F140, F110, F90, F70, F50, F-A50, F-20W, F-10, F-A10E, Cosmelike B-30, S-10, S-50, S-70, S-110, S-160, S-190, SA-10, SA-50, P-10, P-160, M-160, L-10, L-50, L-160, L-150A, L-160A, R-10, R-20, O-10, and O-150 (manufactured by DAI-ICHI KOGYO SEIYAKU CO., LTD.).
Among them, Ryoto sugar ester S-1170, S-1170F, S-1570, S-1670, P-1570, P-1670, M-1695, 0-1570, L-1695, DK Ester SS, F160, F140, F110, Cosmelike S-110, S-160, S-190, P-160, M-160, L-160, L-150A, L-160A, and O-150 are preferable.
As for polyoxyethylene sorbitan fatty acid ester, the number of carbon atoms of fatty acid is preferably 8 or more, more preferably 12 or more. The length (the number of addition mole) of ethyleneoxide of polyoxyethylene is preferably 2 to 100, more preferably 4 to 50.
Preferable examples of polyoxyethylene sorbitan fatty acid ester include polyoxyethylene sorbitan monocaprylate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan sesquistearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan isostearate, polyoxyethylene sorbitan sesquiisostearate, polyoxyethylene sorbitan oleate, polyoxyethylene sorbitan sesquioleate, and polyoxyethylene sorbitan trioleate.
The polyoxyethylene sorbitan fatty acid esters may be used alone, or may be used by mixing them.
Examples of the commercially available product of polyoxyethylene sorbitan fatty acid ester include NIKKOLTL-10, NIKKOLTP-10V, NIKKOLTS-10V, NIKKOLTS-10MV, NIKKOLTS-106V, NIKKOLTS-30V, NIKKOLTI-10V, NIKKOL TO-10V, NIKKOL TO-10MV, NIKKOL TO-106V, and NIKKOL TO-30V (manufactured byNikko Chemicals Co., Ltd.); RHEODOL TW-L106, TW-L120, TW-P120, TW-S106V, TW-S120V, TW-S320V, TW-O106V, TW-O120V, TW-O320V, TW-IS399C, RHEODOL SUPER SP-L10, and TW-L120 (manufactured by Kao Corporation); and SORGEN TW-20, TW-60V, and TW-80V (manufactured by DAI-ICHI KOGYO SEIYAKU CO., LTD.).
Further, in the present invention, other than the surfactants mentioned above, lecithin may be contained. In a case where lecithin is contained, from the viewpoint of transparency and stability, lecithin can be contained in an amount of from 0.01 to 0.5 times the total mass of the ceramide. In this case, fatty acids are preferably used in combination. Lecithin which can be used for the present invention has glycerin structure, fatty acid residue and phosphate residue as the essential constituents, and base or polyhydric alcohol is linked, which is also referred to as phospholipid. Since lecithin has a hydrophilic group and hydrophobic group in the molecular, conventionally, it is widely used as an emulsifier in the field of foods, pharmaceuticals and cosmetics.
Industrially, lecithin having a purity of 60% or higher is employed, and may be also used in the present invention. From the viewpoint of the formation of an oil drop having a minute particle diameter and stability of a functional oil component, those which are generally referred to as “high purity lecithin” are employed. The purity of the “high purity lecithin” is 80% or higher, and more preferably 90% or higher.
Examples of the lecithin include a variety of known lecithins which are obtained from plants, animals and microorganisms by extraction separation.
Specific examples of such lecithins include, for example, a variety of lecithins obtained from plants such as beans, corn, peanut, rapeseed or wheat, animals such as egg York or cow and microorganisms such as Escherichia coli.
Examples of such lecithins include, in compound name, glycerolecithins such as phosphatidic acid, phosphatidylglycerin, phosphatidylinositol, phosphatidylethanolamine, phosphatidyl methyl ethanolamine, phosphatidylcholine, phosphatidylserine, bis-phosphatidic acid, diphosphatidylglycerin (cardiolipin); sphingolecithins such as sphingomyelin.
In the present invention, other than the high purity lecithins mentioned above, hydrogenated lecithin, enzymatically decomposed lecithin, enzymatically decomposed hydrogenated lecithin or hydroxy lecithin can be used. These lecithins which can be used in the present invention can be used alone or used in a form of a mixture of plural types of lecithins
(7) Good Solvent for Ceramide
The ceramide dispersion of the present invention may further contain a good solvent for ceramide. Such good solvent is not included in “an oil component” herein.
Examples of good solvent for ceramide include a solvent in which at least 0.1% or more by mass of ceramide can be dissolved at a temperature of 25° C. and which is liquid at room temperature. In the present invention, good solvent may be any substance as long as it is oil or fat or solvent in which not less than 0.1% by mass of the ceramide can be dissolved.
The good solvent of the present invention is preferably a water-soluble organic solvent.
The water-soluble organic solvent of the present invention is used as an oil phase containing natural components when mixed with aqueous solution as an aqueous phase of the present invention. This aqueous organic solvent is at the same time a main component of extracting liquid which extracts natural components. That is, in the present invention, the natural components may be used for mixing with an aqueous solution in a state in which the natural components are extracted into an extracting liquid containing water-soluble organic solvent as a main component.
The term “water-soluble organic solvent” to be used in the invention means an organic solvent whose solubility to water (at 25° C.) is 10% by mass or more. The solubility to water is preferably 30% by mass or more, further preferably 50% by mass or more from the viewpoint of the stability of the produced dispersion.
The water-soluble organic solvent may be used alone or a mixture solvent of a plurality of the water-soluble organic solvents may be used. Further, it may be used as a mixed with water. When the mixture with water is used, the content of the water-soluble organic solvent is preferably 50% by volume or more, more preferably 70% by volume or more.
The water-soluble organic solvent is preferably used to mix the oil phase component to prepare the oil phase in the method for producing the ceramide dispersion to de described later. It is preferable that the water-soluble organic solvent is removed after it is mixed with the aqueous phase.
Examples of the water-soluble organic solvent include methanol, ethanol, 1-propanol 2-propanol, 2-butanol, acetone, tetrahydrofuran, acetonitrile, methyl ethyl ketone, dipropylene glycol monomethyl ether, methyl acetate, methyl acetoacetate, N-methylpyrrolidone, dimethylsulfoxide, ethylene glycol, 1,3-butanediol, 1,4-butanediol, propylene glycol, diethylene glycol, triethylene glycol, and mixtures thereof. Among them, ethanol, propylene glycol or acetone is preferable and ethanol or a mixed solution of ethanol and water is particularly preferable when their applications are limited to food products.
(6) Other Components
In accordance with the application of the ceramide dispersion of the present invention, other additives such as a variety of medicinal ingredient, antiseptics, coloring agents which are usually used for their applications may be combined with the ceramide dispersion of the present invention as long as the additives do not impair the effects of the present invention.
When the ceramide dispersion is used for a composition for external use such as an external preparation for skin, examples of the other components include a moisturizing agent such as glycine betaine, xylitol, trehalose, urea, neutral amino acid and basic amino acid; a drug efficacy agent such as allantoin; an organic powder such as cellulose powder, nylon powder, crosslinked silicone powder, crosslinked methylpolysiloxane, porous cellulose powder and porous nylon powder; an inorganic powder such as anhydrous silica, zinc oxide, and titanium oxide; a refreshing agent such as menthol and camphor, a plant extract, a pH buffer, an antioxidant, an ultraviolet absorbing agent, an ultraviolet scattering agent, an antiseptic, a perfume, a fungicide, and a coloring matter.
In the ceramide dispersion of the invention, when a ceramide-containing particle is used for the oil phase together with another oil component, the particle diameter of the dispersed particle contained as the oil phase may be made smaller by factors such as stirring conditions (shearing force, temperature, or pressure) in the method for producing the ceramide dispersion described below, conditions of use of the micro mixer, or the ratio of the oil phase to the aqueous phase, in addition to factors caused by the components contained in the ceramide dispersion, so that fine-grained oil-phase particles with a particle diameter of 100 nm or less may be obtained.
The transparency of the ceramide dispersion of the invention may be roughly determined by visually confirming the appearance. Generally, it may be determined by the turbidity of the ceramide dispersion. The turbidity of the ceramide dispersion may be measured as an absorbance of 660 nm at 25° C. in a cell of 10 mm using UV-VIBLE spectral photometer UV-2550 (manufactured by Shimadzu Corporation). When the turbidity of the ceramide dispersion of the invention is measured using an absorbance of 660 nm and the value is 0.050 or less, the ceramide dispersion is evaluated as a transparent ceramide dispersion of the present invention. The transparency of the ceramide dispersion is preferably from 0.005 or more to 0.040 or less under the same condition described above.
In the ceramide dispersion of the present invention, ceramides are preferably contained in an amount of from 0.1% by mass to 3% by mass based on the total mass of the ceramide dispersion; and the measured absorbance at 660 nm is preferably 0.050 or less, and more preferably from 0.005 to 0.040.
The pH of the ceramide dispersion of the invention is preferably from 6 to 8, more preferably from 6.5 or more to 7.5 or less. When the pH of the ceramide dispersion is within the range, the ceramide dispersion having good dispersion stability and preservation stability is obtained. Various pH regulating agents may be used in order to adjust the pH of the ceramide dispersion to the range.
The pH regulating agent may be added or blended so as to have a pH within a predetermined range of pH values of the ceramide dispersion when the oil phase or aqueous phase is prepared or may be directly added to the obtained ceramide dispersion. Usable examples of the pH regulating agent include an acid such as hydrochloric acid or phosphoric acid; an alkali such as sodium hydroxide; various inorganic salts that are generally used in the field; and a buffer such as lactic acid-sodium lactate, citric acid-sodium citrate and succinic acid-sodium succinate.
The ceramide dispersion of the present invention has excellent filterability. The filterability of the present invention is evaluated by the filtration time when 100 g of the filtrate which has been obtained by performing suction filtration using a membrane filter 5μ having a diameter of 90 mm with a suction power of from 0.03 to 0.05 MPa is further subjected to suction filtration using a membrane filter 0.45μ having a diameter of 90 mm with a suction power of from 0.03 to 0.05 MPa. In a case where all 100 g of the dispersion liquid passes through the filter in 10 seconds according to this evaluation method, the dispersion liquid is evaluated as having filterability. From the viewpoint of production efficiency, it is preferred that all 100 g of the ceramide dispersion of the present invention can pass through the filter in 5 seconds according to this evaluation method.
In the ceramide dispersion of the present invention, in a case where the oil phase component and aqueous phase component are in a salt form or in a case in which the oil phase component and aqueous phase component are added to the ceramide dispersion, precipitation by salts (salting-out) is favorably inhibited. This effect of inhibiting precipitation by salts or the like is determined, for example, by the degree of precipitation when sodium chloride is added to the ceramide dispersion, according to the above-mentioned evaluation of transparency. In this case, the evaluation can be performed such that the ceramide dispersion is left to stand for 30 minutes after mixing in conditions where the amount of sodium chloride added is 1% by mass based on the total mass of the ceramide dispersion and the temperature is about 25° C.
<Method for Producing Ceramide Dispersion>
The ceramide dispersion of the present invention is a transparent ceramide dispersion which includes ceramide-containing particles which are dispersed in an aqueous phase as an oil-phase component; a fatty acid component which is an oil phase component or an aqueous phase component; a polyhyhydric alcohol in an amount from 5 to 20 time s the ceramide; and a polysaccharide fatty acid ester; and the pH is from 6 to 8; and the ceramide dispersion of the present invention is obtained by a production method, the method including mixing an oil phase component containing at least the ceramide with an aqueous phase component at a temperature not higher than 40° C.
According to the method, the oil phase component and the aqueous phase component are mixed at 40° C. or less, whereby the oil phase component is well dissolved and a ceramide dispersion having excellent temporal stability and preservation stability may be obtained.
When an oil phase is prepared, the above-mentioned good solvent for dissolving ceramide, in particular, a water-soluble organic solvent can be favorably used. That is, the production method of the present invention is preferably a method including preparing an oil phase by dissolving the oil phase component containing the ceramide in the good solvent for ceramide; and mixing the obtained oil phase and an aqueous phase containing the aqueous phase component.
Examples of the water-soluble organic solvent to be used for this purpose may include the above described examples.
In the mixing of the aqueous phase component and the oil phase component, known methods such as a high-pressure emulsification method that applies a shearing force of 100 MPa or more or a jet injection method that directly injects the oil phase component into the aqueous phase component may be used. It is preferable to apply a method using a micro mixer in which the oil phase component and the aqueous phase component are independently passed through a micro path in which the cross-section area of the narrowest portion is 1 μm2 to 1 mm2, and then respective phases are mixed from a viewpoint of the particle diameter of the ceramide-containing particle, the dispersion stability, and the preservation stability.
In the mixing, it is preferable that the viscosity of the aqueous phase is 30 mPa·s or less from a viewpoint of finely-dividing of the ceramide-containing particle.
In the present invention, the temperature at the time when the oil phase components and the aqueous phase components are mixed is not higher than 40° C. The temperature of not higher than 40° C. is attained when the oil phase components and the aqueous phase components are mixed, and the set temperature range may be changed as required according to a mixing (emulsifying) method which is applied. In a method using a micro mixer, at least a temperature in the range before mixing and immediately after mixing is not higher than 40° C. For example, the temperature is determined based on each of the temperatures of the aqueous phase components and the oil phase components just before mixing and the temperature measured immediately after dispersion. From the viewpoint of stability of the ceramide dispersion over time, it is preferred that the temperature of the dispersion during mixing be not higher than 35° C.
Examples of the method for producing the ceramide dispersion of the present invention includes: a) preparing an aqueous phase using the aqueous medium (water etc.) containing a fatty acid salt and a polysaccharide fatty acid ester (when both are existent); b) preparing an oil phase using the oil phase component which includes at least a ceramide; and c) mixing and dispersing the oil phase and the aqueous phase by the method described later, using the micro mixer to produce a ceramide dispersion (emulsion) which contains a ceramide-containing particle (a dispersed particle) having a volume average particle diameter of from 1 nm to 100 nm.
The ratio (mass) of the oil phase and the aqueous phase in the emulsification dispersion is not particularly limited. The oil phase/aqueous phase ratio (mass %) is preferably from 0.1/99.9 to 50/50, more preferably from 0.5/99.5 to 30/70, further preferably from 1/99 to 20/80.
When the oil phase/aqueous phase ratio is within the above range, it is preferable in that an active component is sufficiently contained, and practically sufficient emulsion stability is obtained.
In the present invention, a polyhydric alcohol and alkali treated gelatin may be added at any time as long as they are not contained in the ceramide dispersion, and used when an aqueous phase as the aqueous phase component is prepared. The polyhydric alcohol and alkali treated gelatin may exist when mixing (dispersing) an aqueous phase and an oil phase, or may be separately added to the dispersion after mixing the aqueous phase and the oil phase. From the viewpoint of highly developing the stability over time and preservation stability, the polyhydric alcohol and alkali treated gelatin are preferably added when mixing (dispersing) an aqueous phase and an oil phase.
When a composition in powder form is produced using the ceramide dispersion, the composition in powder form may be obtained by adding the process of drying the ceramide dispersion in emulsion form by spray drying and the like.
In the method for producing the ceramide dispersion, the components contained in the oil phase and the aqueous phase is the same as the components of the ceramide dispersion of the invention, and a preferable example and an addition amount thereof are the same as those of the ceramide dispersion, and the preferable combination of the components is also the same.
(Micro Mixer)
In the production method to be applied to the production of the ceramide dispersion of the present invention, it is preferable to take a method of passing the oil phase and the aqueous phase each independently through a micro path in which the cross-section area of the narrowest portion is from 1 μm2 to 1 mm2, and combining and mixing respective components in order to stably form a natural ceramide-containing particle having a particle diameter of from 1 nm to 100 nm.
The mixing of the oil phase and the aqueous phase is preferably mixing by countercurrent collision from a viewpoint of obtaining the finer dispersed particle.
The most suitable device for mixing by countercurrent collision is a countercurrent collision-type micro mixer. The micro mixer mixes mainly two different liquids in a fine space, one of liquids is an organic solvent phase containing a functional oil component, and the other is an aqueous phase which is an aqueous solution.
When the micro mixer is applied to preparation of an emulsion having the small particle diameter which is one of microchemistry processes, a good emulsion or dispersion having relatively low energy and small heat production, having the more uniform particle diameter as compared with a normal stirring emulsification dispersing system or high pressure homogenizer emulsification dispersing, and also having the excellent storage stability is easily obtained. This is an optimal method for emulsifying a natural component which is easily thermally degraded.
A summary of a method of emulsification or dispersing using the micro mixer include dividing the aqueous phase and the oil phase into fine spaces, respectively, and contacting or colliding respective fine spaces. This method is clearly different from a membrane emulsification method or a micro channel emulsification method which is a method in which only one is divided into a fine space, and the other is a bulk and, even when only one is actually divided into a fine space, the effect as in the invention is not obtained. As the known micro mixer, there are a variety of structures. When attention is paid to flow and mixing in a micro path, there are two kinds of a method of mixing while a laminar flow is maintained, and a method of mixing while disturbed, that is, in a disturbed flow. In the method of mixing while a laminar flow is maintained, mixing is effectively performed by making a size of a path depth greater than a path width, thereby, increasing the area of an interface between two liquids as much as possible, and making thicknesses of both layers smaller. Alternatively, a method of adopting a multilayer flow by dividing an entrance for two liquids into many portions, and flowing two liquids alternately has been also devised.
On the other hand, in a method of mixing with the disturbed flow, a method of flowing respective flows at a relatively high speed by dividing them into narrow paths is general. A method of ejecting one of fluids into the other liquid introduced into a fine space using an arrayed micro-nozzle has been also proposed. Alternatively, a method of forcibly contacting liquids flowing at a high speed using various means is good, particularly in the mixing effect. In the former method using a laminar flow, generally, a produced particle is large, and distribution is relatively uniform, on the other hand in the latter method using a disturbed flow, there is a possibility that a very fine emulsion is obtained. In respect of stability and transparency, the method using a disturbed flow is preferable in many cases. As the method using a disturbed flow, a comb tooth type and a collision type are representative. The comb tooth type micro mixer has a structure in which two comb tooth-like paths are faced, and arranged so that one path enters between two the other paths, alternately a representative of which is a mixer manufactured by IMM.
The collision-type micro mixer, represented by a KM mixer, has a structure in which forcible contact is tried utilizing the kinetic energy. Specifically, there is a central collision-type micro mixer disclosed by Nagasawa et al. (“H. Nagasawa et al., Chem. Eng. Technol., 28, No. 3, 324-330 (2005)”, JP-A No. 2005-288254). In the method of counter currently colliding an aqueous phase and an organic solvent phase, since a mixing time is extremely short, and an oil phase droplet is instantly formed, an extremely fine emulsion or dispersion is easily formed.
In the invention, when emulsification is performed by micro-mixing with the collision-type micro mixer, a temperature at emulsification (emulsification temperature) is such that micro-mixing is performed at a temperature of the aforementioned separate fine space of the micro mixer (temperature at micro-mixing part of micro mixer) at preferably 40° C. or lower, more preferably 0° C. to 40° C., particularly preferably 5° C. to 30° C., from a viewpoint of particle diameter uniformity of the resulting emulsion. By adopting the emulsification temperature of 0° C. or higher, since a main component of a dispersing medium is water, the emulsification temperature may be managed, being preferable. A retained temperature of the fine space of the micro mixer is preferably 50° C. or lower. By adopting the retained temperature of 50° C. or lower, management of the retained temperature may be easily controlled, and the micro-bumping phenomenon which adversely influences on emulsification performance may be excluded. It is further preferable that the retained temperature is controlled at a temperature of 40° C. or lower.
In the invention, it is particularly preferable that retained temperatures of the aqueous phase and the oil phase before and after division into the fine space of the micro mixer, and of the fine space of the micro mixer and the separate fine space are higher than room temperature and, after micro-mixing and emulsification, an oil-in-water emulsion obtained with the micro mixer is cooled to a normal temperature after collection.
The cross-sectional area of a narrowest part of the fine space (path) of the micro mixer in the invention is 1 μm2 to 1 mm2 and, from a viewpoint of reducing the emulsion particle diameter and sharpness of the particle diameter distribution, preferably 500 μm2 to 50,000 μm2.
The cross-sectional area of a narrowest part of the fine space (path) of the micro mixer used in the aqueous phase in the invention is particularly preferably 1,000 μm2 to 50,000 μm2 from a viewpoint of mixing stability.
The cross-sectional area of a narrowest portion of the fine space (path) of the micro mixer used in the oil phase is particularly preferably 500 μm2 to 20,000 μm2 from a viewpoint of reducing of the emulsion particle diameter and sharpness of the particle diameter distribution.
When emulsification and dispersing are performed with the micro mixer, the flow rate of the oil phase and the aqueous phase at emulsification and dispersing are different depending on the micro mixer used and, from a viewpoint of reducing of the emulsion particle diameter and sharpness of the particle diameter distribution, the flow rate of the aqueous phase is preferably 10 ml/min to 500 ml/min, more preferably 20 ml/min to 350 ml/min, particularly preferably 50 ml/min to 200 ml/min.
The flow rate of the oil phase, from a viewpoint of reducing of the emulsion particle diameter and sharpness of the particle diameter distribution, is preferably 1 ml/min to 100 ml/min, more preferably 3 ml/min to 50 ml/min, particularly preferably 5 ml/min to 50 ml/min.
The value obtained by dividing flow rates of both phases by the cross-sectional area of a micro channel, that is, the flow speed ratio (Vo/Vw) of both phases is preferably in the range from 0.05 to 5 from a viewpoint of miniaturization of a particle and design of the micro mixer, wherein Vo is the flow speed of an organic solvent phase containing a water-insoluble natural component, and Vw is the flow speed of an aqueous phase. And, the flow speed ratio (Vo/Vw) from 0.1 to 3 is the most preferable range from a viewpoint of further miniaturization of a particle.
In addition, liquid sending pressures of the aqueous phase and the oil phase are preferably 0.030 MPa to 5 MPa and 0.010 MPa to 1 MPa, more preferably 0.1 MPa to 2 MPa and 0.02 MPa to 0.5 MPa, particularly preferably 0.2 MPa to 1 MPa and 0.04 MPa to 0.2 MPa, respectively. By adopting the liquid sending pressure of the aqueous phase of 0.030 MPa to 5 MPa, it is preferable in that the stable solution sending flow rate tends to be maintained. By adopting the liquid sending pressure of the oil phase of 0.010 MPa to 1 MPa, it is preferable in that the uniform mixing property tends to be obtained.
In the invention, the flow rate, the solution sending pressure and the retained temperature are more preferably a combination of respective preferably examples.
Then, a route from introduction of the aqueous phase and the oil phase into the micro mixer to discharge as an O/W emulsion will be explained using an example of a micro device (
As shown in
On a surface opposite to the confluence element 104 of the supply element 102, a cross-section as a path for the oil phase or the aqueous phase in the invention is such that rectangular annular channels 108 and 110 are concentrically formed. In the supply element 102, bores 112 and 114 leading to each annular channel are formed, penetrating in a direction of its thickness (or height) direction.
In the confluence element 104, a bore 116 penetrating in its thickness direction is formed. In this bore 116, when an element is secured thereto in order to construct the micro device 100, an end 120 of the bore 116 situated on a surface of the confluence element 104 opposite to the supply element 102 is opened in the annular channel 108. In an embodiment shown, four bores 116 are formed, and they are arranged at an equal interval in a circumferential direction of the annular channel 108.
In the confluence element 104, a bore 118 is formed, penetrating therethrough, like the bore 116. The bore 118 is formed so as to be opened in the annular channel 110, like the bore 116. Bores 118 are arranged at an equal interval in a circumferential direction of the annular channel 110, and the bore 116 and the bore 118 are arranged so as to be positioned alternately.
On a surface 122 opposite to the discharge element 106 of the confluent element 104, the micro channels 124 and 126 are formed. One end of this micro channel 124 or 126 is an opening part of the bore 116 or 118, the other end is a center 128 of the surface 122, and all micro channels extend from bores towards this center 128, and are converged at a center. A cross-section of the micro channel may be, for example, rectangular.
In the discharge element 106, a bore 130 passing a center thereof and penetrating in a thickness direction is formed. Therefore, this bore is opened in the center 128 of the confluence element 104 at one end, and is opened in the outside of the micro device at the other end.
In the present micro device 100, fluids A and B supplied from the outside of the micro device 100 at ends of bores 112 and 114 are flown into annular channels 108 and 110 via bores 112 and 114, respectively.
The annular channel 108 and the bore 116 are communicated, and the fluid A which has flown into the annular channel 108 enters a micro channel 124 via the bore 116. In addition, the annular channel 110 and the bore 118 are communicated, and the fluid B which has flown into the annular channel 110 enters a micro channel 126 via the bore 118. Fluids
A and B are flown into micro channels 124 and 126, respectively, and are flown towards a center 128, and are converged.
The converged fluids are discharged as a stream C to the outside of the micro device via the bore 130.
Such the micro device 100 may have the following specifications.
Cross-sectional shape of annular channel 108/width/depth/diameter: rectangle/1.5 mm/1.5 mm/25 mm
Cross-sectional shape of annular channel 110/width/depth/diameter: rectangle/1.5 mm/1.5 mm/20 mm
Diameter and length of bore 112: 1.5 mm/10 mm (circular cross-section)
Diameter and length of bore 114: 1.5 mm/10 mm (circular cross-section)
Diameter and length of bore 116: 0.5 mm/4 mm (circular cross-section)
Diameter and length of bore 118: 0.5 mm/4 mm (circular cross-section)
Cross-sectional shape of micro channel 124/width/depth/length/cross-sectional area: rectangle/350 μm/100 μm/12.5 mm/35000 μm2
Cross-sectional shape of micro channel 126/width/depth/length/cross-sectional area: rectangle/50 μm/100 μm/10 mm/5000 μm2
Diameter and length of bore 130: 500 μm/10 mm (circular cross-section)
The size of the micro channel (in
In the invention, the micro mixer disclose in JP-A No. 2004-33901 may be also preferably used.
In
In
In the production method which may be applied to the method for producing the ceramide dispersion, it is preferable that a water-soluble organic solvent which has been used is removed after emulsification and dispersing through the micropath. As a method of removing a solvent, an evaporation method using a rotary evaporator, a flash evaporator, or an ultrasound atomizer, and a membrane separating method such as an ultrafiltration membrane and a reverse osmosis membrane are known, and an ultrafiltration membrane method is particularly preferable.
An ultra filter (abbreviated as UF) is an apparatus by which a stock solution (water, mixed aqueous solution of high-molecular substance, low-molecular substance, and colloidal substance) is pressurized, and water is poured into a UF apparatus, thereby, the stock solution may be separated into two-system solutions of a permeated solution (low-molecular substance) and a concentrated solution (high-molecular substance, colloidal substance), and taken out.
The ultrafiltration membrane is a typical asymmetric membrane made by the Leob-Sourirajan method. The polymer material used includes polyacrylonitrile, polyvinyl chloride-polyacrylonitrile copolymer, polysulfone, polyether sulfone, vinylidene fluoride, aromatic polyamide, or cellulose acetate, or the like. Recently, a ceramic membrane has become to be used. Unlike a reverse osmosis method, in an ultrafiltration method, since pre-treatment is not performed, fouling occurs, in which a polymer is deposited on a membrane surface. For this reason, it is normal to wash the membrane with a chemical or warm water periodically. For this reason, a membrane material is required to have resistance to a chemical and heat resistance. As a membrane module of an ultrafiltration membrane, there are various kinds such as flat membrane type, tubular type, hollow thread type, and spiral type. An index for performance of an ultrafiltration membrane is a fractionation molecular weight, and various membranes having a fractionation molecular weight of 1,000 to 300,000 are commercially available. As the commercially available membrane module, there are Microsa UF (Asahi Kasei Chemicals Corporation), and capillary-type element (trade name: NTU-3306, manufactured by Nitto Denko Corporation), being not limiting.
For removing a solvent from the obtained emulsion, a material of a membrane is particularly preferably polysulfone, polyether sulfone, or aromatic polyamide are particularly preferable from a viewpoint of solvent resistance. As the form of a membrane module, a flat membrane is mainly used at a laboratory scale, and a hollow shred type and spiral type are industrially used, and a hollow shred type is particularly preferable. In addition, a fraction molecular weight is different depending on a kind of an active component and, usually, the range of 5,000 to 100,000 is used.
An operation temperature may be 0° C. to 80° C. and, in view of degradation of an active component, the range of 10° C. to 40° C. is particularly preferable.
As an ultrafiltration device at a laboratory scale, there are ADVANTEC-UHP (ADVANTEC), Flow Type Labotest Unit RUM-2 (Nitto Denko Corporation) using and a flat membrane-typed module. Industrially, respective membrane modules at the size and the number depending on the necessary potency may be arbitrarily combined to construct a plant. As a bench scale unit, RUW-5A (Nitto Denko Corporation) is commercially available.
In the production method which may be applied to the method for producing the ceramide dispersion of the present invention, a process of concentrating the resulting emulsion subsequent to solvent removal may be added. As the concentrating method, the same method and the device as those of solvent removal such as an evaporation method and a filtration membrane method may be used. Also in the case of concentration, an ultrafiltration membrane method is a preferable method. When the same membrane as that of solvent removal may be used, this is preferable and, if necessary, ultrafiltration membranes having different fractionation molecular weights may be also used. Alternatively, a concentration efficacy may be enhanced by operating at a temperature different from that of solvent removal.
The ceramide dispersion (emulsion) obtained by mixing using the above-mentioned micro mixer is oil-in-water emulsion. In the production method of a ceramide composition of the present invention, a volume average particle diameter (median diameter) of dispersed particles of the emulsion is from 1 nm to 100 nm. From the viewpoint of transparency of the obtained emulsion, the diameter is more preferably from 1 nm to 50 nm.
The particle diameter of natural ceramide-containing particle (dispersed particle) can be measured by commercially available particle size distribution meter or the like, and details thereof are as described above.
<Application>
The ceramide dispersion of the present invention can be formed as fine emulsion which has an excellent emollient effect caused by natural ceramide. For this reason, the ceramide dispersion is preferably used as it is or as a component material for a variety of applications according to the functionality of the natural ceramide.
For such applications, the dispersion can be used widely, for example, as pharmaceuticals (external preparations, skin preparations), cosmetics and foods. Here, examples of the pharmaceuticals include parenteral agents such as suppositories and embrocations, and examples of the cosmetics include skin-care cosmetics (skin lotion, essence, milky lotion, cream or the like), sunscreen cosmetics and make-up cosmetics such as lipstick and foundation, but not limited thereto.
When the ceramide dispersion of the present invention is used for external preparations for skin or cosmetics, components which may be added to pharmaceuticals or cosmetics can be suitably added as required.
When the ceramide dispersion of the present invention is used for water-based products such as skin lotion, essence, milky lotion, cream mask pack, pack, shampoo cosmetics, fragrance cosmetics, liquid body shampoo, UV care cosmetics, deodorizing cosmetics, oral care cosmetics, analgesic- or antiphlogistic-containing gel, a medicinal component-containing layer of antiphlogistic-containing patch, a translucent product is obtained and occurrence of disadvantageous events can be inhibited such as deposition of insoluble matter, precipitation or neck ring under severe conditions such as long-term preservation or sterilization.
The present invention will be further specifically explained below by way of Examples, but the invention is not limited to the following Examples as far as it is not departed from the gist thereof. Unless otherwise is indicated, “part” is on a mass basis.
The components described in the oil phase liquid 1 below was stirred at room temperature for about 30 minutes to prepare an oil phase liquid 1. For the aqueous phase liquid 1 described below, inulin lauryl carbamate (INUTEC SP1: manufactured by Siebel Hegner Japan Co., ltd., also the same hereinafter) was added to pure water to be heated to about 50° C., and stirred sufficiently to be dissolved, and the residual components were added, mixed and adjust the temperature of the liquid to 30° C.
<Composition of Aqueous Phase Liquid 1>
The obtained oil phase liquid 1 (oil phase) and aqueous phase liquid 1 (aqueous phase) were micro-mixed (dispersed) in the ratio of 1:7 (by mass) using a KM-type micro mixer 100/100, which is an collision type, to obtain ceramide dispersion liquid 1. The micro mixer was used in the following conditions.
—Micro Channel—
Oil phase side microchannel
Cross-sectional phase/width/depth/length=rectangular/70 μm/100 μm/10 mm
Aqueous phase side microchannel
Cross-sectional phase/width/depth/length=rectangular/490 μm/100 μm/10 mm
—Flow Rate—
An aqueous phase was introduced into an external annulus at the flow rate of 21.0 ml/min, an oil phase was introduced into an internal annulus at the flow rate of 3.0 ml/min, and these were micro-mixed.
The resulting ceramide dispersion liquid lwas repeatedly desolvated to the ethanol concentration of 0.1% by mass or less using EVAPOR (CEP-lab) manufactured by OKAWARA CORPORATION, and this was concentrated and adjusted to the ceramide concentration of 1.0% by mass to obtain a ceramide dispersion A having a pH of 7.4. The ceramide concentration referred herein is the content of the ceramide analog based on the total mass of the ceramide dispersion.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 2 and aqueous phase 2 below. The liquid temperature was adjusted to 28° C., and then, ceramide dispersion liquid 2 was obtained by micro-mixing in the same manner as in Example 1. Then, ceramide dispersion B was obtained by performing the concentration in the same manner as in Example 1 except that 90 parts of the obtained ceramide dispersion liquid 2 and 10 parts of 1,3-butanediol were added to be mixed and stirred sufficiently, and then concentrated.
<Composition of Oil Phase Liquid 2>
<Composition of aqueous phase liquid 2>
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 3 and aqueous phase 3 below. The liquid temperature was adjusted to 40° C., and then, ceramide dispersion liquid 3 was obtained by micro-mixing in the same manner as in Example 1. Then, ceramide dispersion C was obtained by performing the concentration in the same manner as in Example 1 except that 95 parts of the obtained ceramide dispersion liquid 3 and 5 parts of glycerin were added to be mixed and stirred sufficiently, and then concentrated.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 4 and aqueous phase 4 below. The liquid temperature was adjusted to 38° C., and then, ceramide dispersion liquid 4 was obtained by micro-mixing in the same manner as in Example 1. Then, ceramide dispersion D was obtained by performing the concentration in the same manner as in Example 1.
<Composition of Oil Phase Liquid 4>
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 5 and aqueous phase 5 below. The liquid temperature was adjusted to 32° C., and then, ceramide dispersion liquid 5 was obtained by micro-mixing in the same manner as in Example 1. Then, ceramide dispersion E was obtained by performing the concentration in the same manner as in Example 1 except that 95 parts of the obtained ceramide dispersion liquid 5 and parts of 1,3-butanediol were added to be mixed and stirred sufficiently, and then concentrated.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 6 and aqueous phase 6 below. The liquid temperature was adjusted to 26° C., and then, ceramide dispersion liquid 6 was obtained by micro-mixing in the same manner as in Example 1. Then, ceramide dispersion F was obtained by performing the concentration in the same manner as in Example 1.
An oil phase liquid was obtained in the same manner as in Example 1 except that the oil phase liquid 1 was changed to the oil phase liquid 7 below. An aqueous phase liquid 7 was obtained in the same manner as in Example 1 except that the aqueous phase liquid 1 was changed to the aqueous phase liquid 7 below, inulin lauryl carbamate was added to pure water to be completely dissolved at 50° C., then an alkali treated fish gelatin was added and heated to 80° C. to be sufficiently dissolved, then cooled to 29° C. Thereafter, the phases are micro-mixed in the same manner as in Example 1 to obtain ceramide dispersion liquid 7. Then, the concentration was performed in the same way as in Example 1 to obtain ceramide dispersion G.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 8 and aqueous phase 8 below. The liquid temperature was adjusted to 30° C., and then, ceramide dispersion liquid 8 was obtained by micro-mixing in the same manner as in Example 1. To 90 parts of pure water, 10 parts of alkali treated fish gelatin was added, and heated while sufficiently stirring to be dissolved at 80° C. for 30 minutes, then cooled to room temperature to obtain 10% alkali treated fish gelatin. Ceramide dispersion H was obtained by performing the concentration in the same manner as in Example 1 except that, to the ceramide dispersion liquid 8, 5 parts of glycerin and 5 parts of 1,3-butanediol were added while stirring, and further, 10 parts of the obtained 10% alkali treated fish gelatin was added to be mixed and stirred sufficiently, and then concentrated.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 9 and aqueous phase 9 below. The liquid temperature was adjusted to 30° C., and then, ceramide dispersion liquid 9 was obtained by micro-mixing in the same manner as in Example 1. Ceramide dispersion I was obtained by performing the concentration in the same manner as in Example 1.
As the cetylhydroxyproline palmitamide, “CeramideBio” manufactured by Symrise Corporation was used.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 10 and aqueous phase 10 below. The liquid temperature was adjusted to 30° C., and then, ceramide dispersion liquid 10 was obtained by micro-mixing in the same manner as in Example 1. Ceramide dispersion J was obtained by performing the concentration in the same manner as in Example 1.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 11 and aqueous phase 11 below. The liquid temperature was adjusted to 30° C., and then, ceramide dispersion liquid 11 was obtained by micro-mixing in the same manner as in Example 1. Ceramide dispersion K (pH=6.2) was obtained by performing the concentration in the same manner as in Example 1.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 12 and aqueous phase 12 below. The liquid temperature was adjusted to 30° C., and then, ceramide dispersion liquid 12 was obtained by micro-mixing in the same manner as in Example 1. Ceramide dispersion L (pH=6.0) was obtained by performing the concentration in the same manner as in Example 1.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 13 and aqueous phase 13 below. The liquid temperature was adjusted to 30° C., and then, ceramide dispersion liquid 13 was obtained by micro-mixing in the same manner as in Example 1. Then, ceramide dispersion M was obtained by performing the concentration in the same manner as in Example 1.
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 14 and aqueous phase 14 below. The liquid temperature was adjusted to 30° C., and then, ceramide dispersion liquid 14 was obtained by micro-mixing in the same manner as in Example 1. Then, ceramide dispersion N was obtained by performing the concentration in the same manner as in Example 1.
<Composition of oil phase liquid 14>
<Composition of aqueous phase liquid 14>
The components below were mixed in the same manner as in Example 1 except that the oil phase liquid 1 and aqueous phase 1 were changed to the oil phase liquid 15 and aqueous phase 15 below. The liquid temperature was adjusted to 31° C., and then, ceramide dispersion liquid 15 was obtained by micro-mixing in the same manner as in Example 1. Then, ceramide dispersion 0 was obtained by performing the concentration in the same manner as in Example 1.
The particle diameter (volume average particle diameter) of the ceramide-containing particle (or oil droplet-like dispersion particles containing the same) in ceramide dispersion immediately after preparation was measured using a dynamic light scattering particle size distribution meter LB-550 (manufactured by HORIBA Ltd.). In the measurement of the particle diameter, the ceramide-containing particles were diluted with pure water so as to have a concentration of 1% by mass, and the particle diameter was measured using quartz cell. The particle diameter was determined as a median diameter when the refractive index of a sample was 1.600, the refractive index of a dispersion medium was 1.333 (pure water), and the viscosity of pure water was set as the viscosity of the dispersion medium. The results are shown in Table 1.
As the evaluation of stability over time, an evaluation was performed using turbidity by the following method.
Turbidities of the ceramide dispersion A to 0 of Examples and Comparative Examples were measured as the absorbance at 660 nm in 10 mm cell using UV VIBLE Spectrophotometer UV-2550 (manufactured by Simadzu Corporation). (measurement temperature: 25° C.)
Further, each of the ceramide dispersions was stored in a temperature-controlled bath at 40° C. for one month, and then reset the ceramide dispersions at 25° C. to measure the turbidities. The results are shown in Table 2.
The external appearance was observed in terms of the existence or absence of a fine precipitate of the ceramide dispersion and the uniformity of the dispersion liquid, immediately after the ceramide dispersion was prepared and after the ceramide dispersion had been stored in a temperature-controlled bath at 40° C. for one month. Evaluation was performed in the following manner:
A: The whole dispersion was uniform without a precipitate, or no change was observed in the external appearance compared with immediately after the dispersion was prepared.
D: Precipitate, occurrence of separation in the dispersion liquid, or change in the external appearance after one month at 40° C. as compared with immediately after the preparation (unacceptable in terms of commercial value).
4. Salt Resistance
Sample solutions were prepared by adding sodium chloride to ceramide dispersions A to O immediately after preparation and after 1 month of preservation in a thermostatic bath at 40° C., to a salt concentration of 1% by mass and stirring for 30 minutes at about 25° C. The outer appearance of the sample liquid was observed and the turbidity of the dispersion before the addition of sodium chloride and the sample liquid was measured in the same manner as in the above item 2, immediately after preparation and after 1 month of preservation at 40° C. respectively. Evaluations were made as follows:
A: Change of absorbance at 660 nm is no more than 0.005. No precipitation of salt was observed.
B: Change of absorbance at 660 nm is no more than 0.01. No precipitation of salt was observed.
C: Change of absorbance at 660 nm is greater than 0.01. No precipitation of salt was observed.
D: Precipitation of salt was observed.
Explanation and evaluation of ceramide dispersions A to 0 are shown in Table 1 and Table 2. In the tables, the added amounts mean the contents in the final ceramide dispersions A to O.
As apparent from Table 1 and Table 2, it was found that in the ceramide dispersion of the present invention the ceramide-containing particles contained in the ceramide dispersion had a small particle diameter, and that the ceramide dispersion had a good dispersion stability and stability over time.
The ceramide dispersion of the present invention could favorably inhibit salting-out even when salts were added.
In Example 9, ceramide 3B and ceramide 6 as well as ceramide dispersion I including CeramideBio were evaluated. Even in the case of the ceramide dispersion containing only CeramideBio, the same effects were obtained.
The disclosure of Japanese Patent Application No. 2008-298460, which was filed on Nov. 21, 2008, is hereby incorporated by reference in its entirety.
All references, patent applications, and technical standards described in the present specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual reference, patent application or technical standard was specifically and individually indicated to be incorporated herein by reference.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2008-298460 | Nov 2008 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2009/069749 | 11/20/2009 | WO | 00 | 5/20/2011 |
