WO2005034914A1 - Emulsified solution containing psysiological activation material, a method for preparing thereof, and a method for administration thereof - Google Patents
Emulsified solution containing psysiological activation material, a method for preparing thereof, and a method for administration thereof Download PDFInfo
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- WO2005034914A1 WO2005034914A1 PCT/KR2004/002652 KR2004002652W WO2005034914A1 WO 2005034914 A1 WO2005034914 A1 WO 2005034914A1 KR 2004002652 W KR2004002652 W KR 2004002652W WO 2005034914 A1 WO2005034914 A1 WO 2005034914A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- the present invention relates to a technique for delivering an oral drag to an animal using oil globule absorption action that was recently known from reports published by the present inventors. More particularly, the present invention relates to a novel emulsion containing a physiologically active material developed to be suitable for an effective use of oil globule absorption action in a digestive tract of a certain animal, preparation and administration methods thereof.
- Hei 11-255664 discloses a technique in w hich, a s a n e ffective i ngredient o f a n i mmune e nhancer for oral administration, peptidoglycan having a molecular weight of less than 10,000 is administered to mammals, fish and crustaceans (specifically, Black Tiger shrimp) as it is or in the form of a feed to which peptidoglycan was added.
- Hei 8-504811 discloses a physiologically acceptable drug delivery emulsion comprising emulsified particles of a fluorochemical (specifically, perfluorocarbons such as perfiuorodecalin) and oil in water, a surfactant and a drug solubilized in the emulsion. That is, an emulsion system can be found in the above-mentioned two patent references wherein up to 30% by weight of liquid fatty oil such as triglyceride, as a matrix, up to 75% by weight of a fluoro compound and up to 20% by weight of a drug solution were dispersed by the action of the surfactant. Meanwhile, Japanese Patent Publication Laid-Open No.
- Hei 7-53404 discloses a lipophilic-hydrophilic mixture in which an antigenic material and one adjuvant are lipophilic, and another adjuvant side is hydrophilic.
- a dispersoid water droplets, 30% by weight
- a dispersion medium 70% by weight of oil
- the present inventors found a surprising oil globule absorption action that very fine size oil globules are absorbed at epithelium of intestinal tracts in the body as they are, in the digestive tract of fish or the like, and disclosed a thesis, entitled "Histological study on egg yolk abso ⁇ tion and nutrient intake in a digestive tract of Fry and Juvenile Pagrus major or Girella punctata" in Miyazaki et al., the First Report I, pages 15-27 (1998), Faculty of Bioresources, Mie University, Japan. Further, a new fact is additionally found that the same type of oil globule absorption action also occurs in some mammals.
- the present inventors have created the present invention based on the idea that taking advantage of such oil globule absorption action probably makes it possible to construct an oral drug delivery means whereby vaccines, immune activators and pharmacologically active material can be ingested to animals at greatly high efficiency in a simplified manner. Meanwhile, such an idea has two essential requirements: one that applicable subjects should be limited to animals in which the oil globule abso ⁇ tion action was confirmed in digestive tracts thereof, and another that small and fine oil globules, which will be orally administered to concerned animals, should have a predetermined particle diameter such that the oil globule abso ⁇ tion action can be occurred. Conventional arts including the above-mentioned Japanese Patent Publications had not disclosed and considered such requirements.
- an oil-in-water emulsion containing a physiologically active material wherein fine oil globules as the target for oil globule abso ⁇ tion action in animal digestive tracts are dispersed in the emulsion, the physiologically active material is contained in oil droplets of the emulsion having fine oil globules dispersed therein, and the physiologically active material is embedded into an oil phase in the form of a very fine dispersion phase as it is or together with a small amount of water, by action of an oil-soluble emulsifier present in the fine oil globules.
- an oil-in-water emulsion containing a physiologically active material wherein fine oil globules as the target for oil globule abso ⁇ tion action in animal digestive tracts are dispersed in the emulsion, the physiologically active material is contained in oil droplets of the emulsion having fine oil globules dispersed therein, and the p hysiologically a ctive m aterial i s d issolved or suspended lipophilically i n fine oil globules.
- an oil-in-water emulsion containing a physiologically active material wherein fine oil globules as the target for oil globule abso ⁇ tion action in animal digestive tracts are dispersed in the emulsion, the physiologically active material is contained in oil droplets of the emulsion having fine oil globules dispersed therein, and the physiologically active material is present in the form that is enclosed within the fine oil globules having a micelle structure formed by a lipid bilayer.
- a process for preparing an emulsion containing a physiologically active material comprising: mixing and emulsifying a physiologically active material, an aqueous solution or aqueous suspension thereof and an oil-soluble emulsifier added emulsion to prepare an oily emulsification phase; and mixing and emulsifying the oily emulsification phase and water containing a water soluble emulsifier added thereto to prepare an oil-in-water emulsion in which the oily emulsification phase is dispersed in water as a fine oil globule that is the target for oil globule abso ⁇ tion action in animal digestive tracts.
- a method for administering an emulsion containing a physiologically active material comprising: orally administering a physiologically active material containing emulsion having fine oil globules dispersed therein to an animal, wherein the fine oil globules are prepared such that oil droplets in the emulsion contain the physiologically active material and at the same time, the fine oil globules become a target for oil globule abso ⁇ tion action in animal digestive tracts.
- a method for administering an emulsion containing a physiologically active material comprising: impregnating a physiologically active material containing emulsion having fine oil globules dispersed therein into a feed or pellet for a feed; and allowing animals to ingest the impregnated material, wherein the fine oil globules arc prepared such that oil droplets in the emulsion contain the physiologically active material and at the same time, the fine oil globules become a target for oil globule abso ⁇ tion action in animal digestive tracts.
- the physiologically active material in an oil-in- water emulsion in which fine oil globules, having an average particle diameter suitable for the target of oil globule abso ⁇ tion action in animal digestive tracts, were dispersed, the physiologically active material is embedded into an oil pl as*; in the form of very fine dispersion phase as it is, or together with a small amount of water, by action of an oil- soluble emulsifier, in respective fine oil globules.
- the very fine dispersion phase of physiologically active material (or between physiologically active material and a small amount of water) is stably dispersed in the oil phase of fine oil globules that are dispersoids, in a state that the respective dispersion phases maintain oil-soluble emulsifiers at the interfaces with a dispersoid.
- the respective fine oil globules are stably dispersed in water which is the dispersoid, while maintaining a water-soluble emulsifier at the interface with the dispersoid (water).
- physiologically active material containing emulsion is an oil-in-water type
- dispersion state of fine oil globules as oil droplets is stable, and since fine oil globules have an average particle diameter suitable as the target of oil globule abso ⁇ tion action in animal digestive tracts, it is possible to take advantage of oil globule abso ⁇ tion action in digestive tracts of animal of interest and also possible to be ingested into the animal body at high efficiency.
- physiologically active material form a very fine dispersion phase by themselves or together with a small amount of water, thus being embedded into the oil phase.
- physiologically active materials can be at least one selected from the group consisting of vaccines, immune activators, nutritional materials, pharmacologically active materials, natural pigments and minerals.
- vaccines such as pathogenic viruses, or crushed materials of bacteria or parasites
- immune activators such as glucan, fucoidan and lipopolysaccharide (LPS).
- physiologically active polypeptides such as antibodies, nutritional materials such as vitamins, or pharmacologically a ctive m aterial su ch a s a ntibiotics, h ormones a nd i nterferones.
- natural pigments or minerals such as organic or inorganic calcium, iron and magnesium.
- physiologically active materials are very finely dispersed as they are or together with a small amount of water, concentration of physiologically active materials in the fine dispersion phase is very high, even though it is not 100%, and thus a drug dissociation effect is dramatically increased.
- a structureof (1) is a particle structure created by the present inventors for effective practice of the first invention and detailed description thereof was discussed in the seventh invention, but the particle structure of fine oil globule is not disintegrated even by intestinal lipase of animals and further, it is possible to very finely disperse physiologically active materials in fine oil globules regardless of their affinity.
- an average particle diameter of the fine oil globules suitable for oil globule abso ⁇ tion action cannot be uniformly specified in response to kinds of animals of interest, for example, it is preferably within a range of 1 to 60 ⁇ m, and more preferably 1 to 20 ⁇ m. It is also not possible to specifically limit a particle size distribution of fine oil globules (a degree of particle diameter of the respective fine oil globules), but it is ideal to have as narrow a particle size distribution as possible, within the above-mentioned average particle diameter range.
- Fine oil globules there is no need to limit specific particle structure of fine oil globules if it is within a range suited for oil globule abso ⁇ tion action, but the following three particle structures may be ideally exemplified: (1) Physiologically active materials form a very fine dispersion phase as they are or together with a small amount of water, by the oil-soluble emulsifier in fine oil globules; (2) Lipophilic physiologically active materials are dissolved or suspended in fine oil globules; and (3) Fine oil globules have a micelle structure formed by a lipid bilayer and physiologically active materials were put inside thereof.
- the second structure is made by dissolving or finely suspending a lipophilic physiologically active material in the emulsion and using the resulting emulsion and water (preferably, reusing the emulsifier) to constitute an oil-in-water emulsion.
- the third structure is constitution of the micelle structure formed by the lipid bilayer in water (an aqueous solution of physiologically active materials was put inside thereof).
- Preparation of the second and third particle structures, or preparation of an emulsion containing fine oil globules having such particle structures dispersed therein can b e e asily c arried o ut u sing su itable m ethods se lected from k nown o r w ell k nown methods.
- b e e asily c arried o ut u sing su itable m ethods se lected from k nown o r w ell k nown can be anticipated.
- the third structure has a vesicular particle structure, commonly called ribosome, but when a limiting membrane (lipid bilayer) is disintegrated by action of lipase in animal intestinal tract, there are disadvantages in that such structure cannot maintain the oil globule structure, and oil globule abso ⁇ tion action cannot be employed, i the case of the second particle structure, since it is an oil globule (oil ball), the oil globule structure is not easily disrupted by a ction o f lipase, b ut t here a re d isadvantages i n that i t is g enerally difficult to finely disperse physiologically active materials in oil globules except when oil-soluble physiologically active materials are dissolved in oil globules, and further it is difficult to formulate oil globules having a predetermined fine average particle diameter.
- lipid bilayer lipid bilayer
- oil globule abso ⁇ tion action cannot
- the process for preparing a physiologically active material containing emulsion essentially involves a first emulsification process and a second emulsification process. Provided that any optional pretreatment process, intermediate process or post-treatment process may be added in addition to the first and second processes.
- a physiologically active material, an aqueous solution or aqueous suspension thereof and an oil-soluble emulsifier added emulsion are mixed and emulsified to prepare an oily emulsification phase embedded into a oil phase.
- the oily emulsification phase is prepared wherein physiologically active material is embedded into the oil phase in the form of very fine dispersion phase as it is or together with a small amount of water.
- physiologically active material is used as an aqueous solution or aqueous suspension thereof, in the first emulsification process, it is ideal to minimize water content (that is, a high concentration aqueous solution or high density aqueous suspension of physiologically active material).
- an important technical point in the first emulsification process is in that physiologically active material and aqueous solution thereof (phase a) are emulsified by mixing with an oil-soluble emulsifier added emulsion (phase b).
- the mixing ratio of phases a and b need not uniformly defined, but the ratio may be optionally selected within a range of phase a : b of 1 : 99 to 99:1 by weight ratio. Where a weight ratio of phase a : phase b is outside the above-mentioned range or the oil-soluble emulsifier is not added to phase b, it is likely to fail to prepare physiologically active material- embedded fine oil globules, as described above.
- amount of the oil-soluble emulsifier added to phase b is preferably within the range of 1 to 5% by weight.
- oil-soluble emulsifiers are those having an HLB (Hydrophilic Lipophilic Balance) value of less than 6, more preferably less than 2.
- HLB Hydrophilic Lipophilic Balance
- the emulsifier is preferably a non-ionic surfactant.
- the oily emulsification phase prepared in the first emulsification process, and a water soluble emulsifier added water are mixed and emulsified to prepare an oil-in-water emulsion whereby the oily emulsification phase has an average particle diameter suitable for a target of oil globule abso ⁇ tion action in animal digestive tracts and is dispersed in water as the fine oil globule.
- a technical point in the second emulsification process is in that the water- soluble emulsifier added water (phase d) are mixed and emulsified to the oily emulsification phase (phase c) prepared in the first emulsification process.
- the mixing ratio of phases c and d need not be specified, but the ratio may be optionally selected within a range of phase c : d of 3 : 1 to 1:3 based on a weight ratio.
- the weight ratio of phase c : phase d is outside the above-mentioned range or the water-soluble emulsifier is not added to phase d, it is likely to fail to prepare a physiologically active material containing emulsion relating to the present invention.
- amount of the water-soluble emulsifier added to phase d is preferably within a range of 0.5 to 1.3% by weight.
- the water-soluble emulsifiers are those having an HLB (Hydrophilic Lipophilic Balance) value of more than 10, and more preferably more than 12.
- HLB Hydrophilic Lipophilic Balance
- the non- ionic surfactant is ideal, as described above.
- the ideal water-soluble emulsifiers satisfying such conditions mention may be made of decaglyceryl di-stearate, glyceryl isostearate, decaglyceryl monoisostearate and ethyleneglycol monooleate.
- an emulsification operation may be performed by using known ultrasonication, a homogenizer or a mixer.
- a particle diameter of fine oil globules in the physiologically active material containing emulsion and a degree of fine dispersion of the physiologically active material in the fine oil globules may be adjusted by suitably selecting operation conditions of an emulsification means.
- the physiologically active material or aqueous solution thereof was mixed with the emulsion and then the oil-soluble emulsifier was added to the resulting emulsion so as to form an oily emulsification phase wherein physiologically active material was embedded into the oil phase in the form of very fine dispersion phase as it is or together with a small amount of water upon using known emulsion formation means such as ultrasonication and use of homogenizer.
- fine oil globules are prepared wherein oil droplets in an oil-in-water emulsion contain a physiologically active material and at the same time, fine oil globules have an average particle diameter suitable for the target of oil globule abso ⁇ tion action in animal digestive tracts, and the resulting emulsion is orally administered to animals whose digestive tracts exhibit oil globule abso ⁇ tion action, except for humans.
- emulsions constituting oil droplets for example, surfactants used in emulsion formation (including oil- soluble emulsifier and water-soluble emulsifier used in preparing the physiologically active material containing emulsion as described above) or pellet for a feed should be all non-toxic or physiologically safe to subject animals. Further, it will be ideal to use materials which are nutritionally beneficial to the subject animals. In an administration method of physiologically active material related to the present invention, there is no need to specifically limit oral administration methods of an oil-in-water emulsion.
- physiologically active material may be mixed and imbibed into an animal feed.
- physiologically active material is impregnated into animal feed pellet (porous feed pellet is particularly ideal) and ingested as it is or after drying.
- animal feed pellet a variety of commercially available products may be optionally utilized. According to such oral administration methods, there is no surgical invasion stress due to blood vessel injection to animals except for humans as an administration subject and thus it is easily applicable to fish, crustaceans and shellfish.
- physiologically active materials can be ingested into the animal body at considerably high efficiency in a simplified manner.
- Example 1 As a physiologically active material, formalin-killed bacteria of E. coli was used to an aqueous suspension (First solution) containing a high density of the dead bacteria. Meanwhile, in the case of liver oil of cuttlefish, as the oil-soluble emulsifier,
- hexaglyceryl linoleate (Oxygen Food #818R, Taiyou Chemical Industry Co., Ltd, Japan) was added to prepare an emulsion (Second solution). Then, as the first emulsification treatment, the first solution and second solution were mixed in a weight ratio of 90:10, and subjected to sufficient emulsification treatment using a sonicator so as to form an oily emulsification phase (Third solution) embedded in an oil phase in which a high density suspension of formalin-killed bacteria of E. coli forms a very fine dispersion phase.
- the water-soluble emulsifier 1% by weight of decaglyceryl distearate (Oxygen Food Q-182S, Taiyou Chemical Industry Co., Ltd, Japan) was added to water (Fourth solution).
- the third solution and fourth solution were mixed in a weight ratio of 2:1 and sufficiently stirred using a mixer to prepare a physiologically active material containing emulsion in which the oily emulsification phase was dispersed in water as fine oil globule.
- Upon observing a particle diameter of fine oil globules included in the prepared physiologically active material containing emulsion it was approximately 5 to 10 ⁇ m.
- the prepared physiologically active material containing emulsion was stored in a refrigerator for about one week and when observing again the particle diameter of fine oil globules, the particle diameter thereof was approximately 5 to 10 ⁇ m. From these results, it was confirmed that dispersion state of fine oil globules was stable.
- administered group refers to 5 olive flounders (Paralichthys olivaceus) relating to Examples while “control group” refers to 5 olive flounders (Paralichthys olivaceus) relating to Comparative Examples.
- control group refers to 5 olive flounders (Paralichthys olivaceus) relating to Comparative Examples.
- numbers of column “Fish” refer to Sample Nos. of 5 olive flounders of the administered group and control group, respectively.
- This example also used formalin-killed bacteria of Edwardsiella tarada.
- An aqueous suspension (First solution) containing the dead bacteria at a concentration of 10 9 cells/ml was prepared and then a second solution was prepared using the same method as described in Example 1. Then, the first solution and second solution were mixed in a weight ratio of 99:1, and subjected to sufficient emulsification treatment using an so- ⁇ cator so as to form an oily emulsification phase (Third solution of group 1) embedded in an oil phase in which a high density suspension of formalin-killed bacteria of E. coli forms a very fine dispersion phase.
- the first solution and the second solution were mixed in a weight ratio of 90:10 and the resulting mixture was subjected to emulsification treatment as described above to form an oily emulsification phase (Third solution of group 2).
- a fourth solution was prepared in the same method as Example 1, the third solution and fourth solution were mixed in a weight ratio of 2:1 relative to the third solution of group 1 and the third solution of group 2 and sufficiently stirred using a mixer to prepare a physiologically active material containing emulsion ([the physiologically active material containing emulsion of group 1] and [the physiologically active material containing emulsion of group 2]) in whi ⁇ h the oily emulsification phase was dispersed in water as fine oil globule.
- the p hysiologically active material c ontaining emulsion o f group 1 and the physiologically active material containing emulsion of group 2 were impregnated in a commercially available porous pellets for a fish feed in an appropriate amount.
- the porous pellets were fed such that a fish feeds for 13 days, consecutively such that emulsion intake is 0.05 ml/day/lOOg of fish body.
- Each 10 olive flounders (Paralichthys olivaceus) (average body weight: 100 g) were allowed to freely feed for 3 days.
- olive flounder (Paralichthys olivaceus) in which the physiologically active material containing emulsion of group 1 was fed was designated “group A” and olive flounder (Paralichthys olivaceus) in which the physiologically active material containing emulsion of group 2 was fed was designated “group B”.
- group A olive flounder
- group B olive flounder
- antibody titer of antibodies of Edwardsiella tarada in sera of olive flounders (Paralichthys olivaceus) obtained was determined as an agglutination value.
- immune activators and pharmacologically active materials and various physiologically active materials can be imbibed into various aquacultured or ornamental fish and aquatic crustaceans, or mammal in which oil globule abso ⁇ tion action occurs, at very significantly high efficiency by a simple method.
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Abstract
The p resent invention r elates to a t echnique f or d elivering an oral drug to an animal using oil globule absorption action that was recently known from the reports by the present inventors. The present invention provides a process for preparing an emulsion containing a physiologically active material so as to effectively use the oil globule absorption action in a digestive tract of a certain animal and an emulsion containing the physiologically active material prepared using the same, thereby an oral drug delivery means can be provided whereby the physiolo ically active materials including immune activators and pharmacologically active materials can be ingested into animals, at very significantly high efficiency by a simple method.
Description
[DESCRIPTION] [Invention Title]
EMULSIFIED SOLUTION CONTAINING PS YSIO-LOGICAL ACTIVATION MATERIAL, A METHOD FOR PREPARING THEREOF, AND A METHOD FOR ADMINISTRATION THEREOF
[Technical Field]
The present invention relates to a technique for delivering an oral drag to an animal using oil globule absorption action that was recently known from reports published by the present inventors. More particularly, the present invention relates to a novel emulsion containing a physiologically active material developed to be suitable for an effective use of oil globule absorption action in a digestive tract of a certain animal, preparation and administration methods thereof.
[Background Art]
From old times, in order to prevent particular diseases of mammals such as humans, rabbits, mice and livestock, there have been sometimes proposed a method of administering vaccines or immune activators against the concerned diseases. Recently, there have been increasing trials to prevent/treat the diseases by administering a variety of physiologically active materials, in addition to vaccines and materials having pharmacological actions, to aquacultured animals. Blood vessel injection (intravenous injection), which has been traditionally conducted to mammals except for humans, is a drug delivery method by which excellent effects can be theoretically anticipated, but has a disadvantage of causing organisms to suffer with a certain degree of surgical invasion stress, and further such a method is not easily applicable to fish, crustaceans and shellfish. As a result, oral administration methods have been prevailing as the methods of administering physiologically active materials for fish, crustaceans and shellfish. For such reasons, upon designing oral preparations, there has been currently studying
various forms of emulsion preparations taking consideration into the fact that one or more physiologically active materials to be administered and respective aids used in combination thereof have different affinity (hydrophilic or lipophilic) and at the same time, in taking consideration of stability of oral preparations. For example, Japanese Patent Publication Laid-Open No. Hei 11-255664 discloses a technique in w hich, a s a n e ffective i ngredient o f a n i mmune e nhancer for oral administration, peptidoglycan having a molecular weight of less than 10,000 is administered to mammals, fish and crustaceans (specifically, Black Tiger shrimp) as it is or in the form of a feed to which peptidoglycan was added. In addition, Japanese Patent Publication Laid-Open No. Hei 8-504811 discloses a physiologically acceptable drug delivery emulsion comprising emulsified particles of a fluorochemical (specifically, perfluorocarbons such as perfiuorodecalin) and oil in water, a surfactant and a drug solubilized in the emulsion. That is, an emulsion system can be found in the above-mentioned two patent references wherein up to 30% by weight of liquid fatty oil such as triglyceride, as a matrix, up to 75% by weight of a fluoro compound and up to 20% by weight of a drug solution were dispersed by the action of the surfactant. Meanwhile, Japanese Patent Publication Laid-Open No. Hei 7-53404 discloses a lipophilic-hydrophilic mixture in which an antigenic material and one adjuvant are lipophilic, and another adjuvant side is hydrophilic. Specifically, in a water-in-oil emulsion, a dispersoid (water droplets, 30% by weight) contains the antigenic material and adjuvant by inclusion of an emulsifier in a dispersion medium (70% by weight of oil) as matrix. However, where physiologically active materials are orally administered, a conventional problem has been previously recognized in that administration effects thereof cannot be sufficiently expressed. For example, as can be seen from the disclosure of the above-mentioned Japanese Patent Publication Laid-Open No. Hei 11- 255664, it is pointed out that oral administration of physiologically active materials cannot exhibit sufficient effects on fish. This is because, although the reason is not fully clarified, when orally administering unlike blood vessel injection, probably since the materials are absorbed through the digestive tract, thus considering as being connected with that physiologically active materials are digested before being absorbed,
or not sufficiently absorbed in the digestive tract. That is, in common sense, oil (fat) is degraded to fatty acid and glycerin and absorbed at a molecular level in digestive tracts of animals. However, the present inventors found a surprising oil globule absorption action that very fine size oil globules are absorbed at epithelium of intestinal tracts in the body as they are, in the digestive tract of fish or the like, and disclosed a thesis, entitled "Histological study on egg yolk absoφtion and nutrient intake in a digestive tract of Fry and Juvenile Pagrus major or Girella punctata" in Miyazaki et al., the First Report I, pages 15-27 (1998), Faculty of Bioresources, Mie University, Japan. Further, a new fact is additionally found that the same type of oil globule absorption action also occurs in some mammals.
[Disclosure] [Technical Problem]
Therefore, the present inventors have created the present invention based on the idea that taking advantage of such oil globule absorption action probably makes it possible to construct an oral drug delivery means whereby vaccines, immune activators and pharmacologically active material can be ingested to animals at greatly high efficiency in a simplified manner. Meanwhile, such an idea has two essential requirements: one that applicable subjects should be limited to animals in which the oil globule absoφtion action was confirmed in digestive tracts thereof, and another that small and fine oil globules, which will be orally administered to concerned animals, should have a predetermined particle diameter such that the oil globule absoφtion action can be occurred. Conventional arts including the above-mentioned Japanese Patent Publications had not disclosed and considered such requirements. Further, even though the above-mentioned Japanese reference of the present inventors reported the oil globule absoφtion action, there is no mention of availability of oil globule absoφtion action as the oral drug delivery means and no specific practice method.
[Technical Solution]
In accordance with a first aspect of the present invention, there is provided an oil-in-water emulsion containing a physiologically active material, wherein fine oil globules as the target for oil globule absoφtion action in animal digestive tracts are dispersed in the emulsion, the physiologically active material is contained in oil droplets of the emulsion having fine oil globules dispersed therein, and the physiologically active material is embedded into an oil phase in the form of a very fine dispersion phase as it is or together with a small amount of water, by action of an oil-soluble emulsifier present in the fine oil globules. In accordance with a second aspect of the present invention, there is provided an oil-in-water emulsion containing a physiologically active material, wherein fine oil globules as the target for oil globule absoφtion action in animal digestive tracts are dispersed in the emulsion, the physiologically active material is contained in oil droplets of the emulsion having fine oil globules dispersed therein, and the p hysiologically a ctive m aterial i s d issolved or suspended lipophilically i n fine oil globules. In accordance with a third aspect of the present invention, there is provided an oil-in-water emulsion containing a physiologically active material, wherein fine oil globules as the target for oil globule absoφtion action in animal digestive tracts are dispersed in the emulsion, the physiologically active material is contained in oil droplets of the emulsion having fine oil globules dispersed therein, and the physiologically active material is present in the form that is enclosed within the fine oil globules having a micelle structure formed by a lipid bilayer. In accordance with a fourth aspect of the present invention, there is provided a process for preparing an emulsion containing a physiologically active material, comprising: mixing and emulsifying a physiologically active material, an aqueous solution or aqueous suspension thereof and an oil-soluble emulsifier added emulsion to prepare
an oily emulsification phase; and mixing and emulsifying the oily emulsification phase and water containing a water soluble emulsifier added thereto to prepare an oil-in-water emulsion in which the oily emulsification phase is dispersed in water as a fine oil globule that is the target for oil globule absoφtion action in animal digestive tracts. In accordance with a fifth aspect of the present invention, there is provided a method for administering an emulsion containing a physiologically active material, comprising: orally administering a physiologically active material containing emulsion having fine oil globules dispersed therein to an animal, wherein the fine oil globules are prepared such that oil droplets in the emulsion contain the physiologically active material and at the same time, the fine oil globules become a target for oil globule absoφtion action in animal digestive tracts. In accordance with a sixth aspect of the present invention, there is provided a method for administering an emulsion containing a physiologically active material, comprising: impregnating a physiologically active material containing emulsion having fine oil globules dispersed therein into a feed or pellet for a feed; and allowing animals to ingest the impregnated material, wherein the fine oil globules arc prepared such that oil droplets in the emulsion contain the physiologically active material and at the same time, the fine oil globules become a target for oil globule absoφtion action in animal digestive tracts.
Now, embodiments for carrying out the first through sixth aspects of the present invention are described, including best mode.
Emulsion containing physiologically active material
In connection with a physiologically active material containing emulsion in accordance with the first through third aspects of the present invention, in an oil-in- water emulsion in which fine oil globules, having an average particle diameter suitable for the target of oil globule absoφtion action in animal digestive tracts, were dispersed,
the physiologically active material is embedded into an oil pl as*; in the form of very fine dispersion phase as it is, or together with a small amount of water, by action of an oil- soluble emulsifier, in respective fine oil globules. In fine oil globules, the very fine dispersion phase of physiologically active material (or between physiologically active material and a small amount of water) is stably dispersed in the oil phase of fine oil globules that are dispersoids, in a state that the respective dispersion phases maintain oil-soluble emulsifiers at the interfaces with a dispersoid. And, the respective fine oil globules are stably dispersed in water which is the dispersoid, while maintaining a water-soluble emulsifier at the interface with the dispersoid (water). Since the physiologically active material containing emulsion is an oil-in-water type, dispersion state of fine oil globules as oil droplets is stable, and since fine oil globules have an average particle diameter suitable as the target of oil globule absoφtion action in animal digestive tracts, it is possible to take advantage of oil globule absoφtion action in digestive tracts of animal of interest and also possible to be ingested into the animal body at high efficiency. Further, by the action of the oil-soluble emulsifier in fine oil globules, physiologically active material form a very fine dispersion phase by themselves or together with a small amount of water, thus being embedded into the oil phase. Therefore, upon receiving action of lipase in the intestinal tract of animal, although a portion of fine oil globule surface was digested, the particle structure of fine oil globule was maintained without disintegration, unlike a micelle structure, and thus is favorably absorbed by intestinal epithelium. In addition, since physiologically active materials are dispersed in oil by action of the oil-soluble emulsifier, they can be embedded into fine oil globules in a very finely dispersed state, regardless of their affinity (hydrophilic or lipophilic) and further it will be easily possible to prepare an oil globule having a predetermined fine average particle diameter. More specifically, any physiologically active material can be employed as long as their affinity is water soluble, hydrophilic, oil-soluble and lipophilic. Preferably, as category of superior position concept, physiologically active materials may be at least one selected from the group consisting of vaccines, immune activators, nutritional materials, pharmacologically active materials, natural pigments and minerals. For example, mention may be made of vaccines such as pathogenic viruses, or crushed
materials of bacteria or parasites, and immune activators such as glucan, fucoidan and lipopolysaccharide (LPS). In addition, it is possible to use physiologically active polypeptides such as antibodies, nutritional materials such as vitamins, or pharmacologically a ctive m aterial su ch a s a ntibiotics, h ormones a nd i nterferones. In order to impart desired colors to animals of interest, it is also possible to utilize natural pigments or minerals such as organic or inorganic calcium, iron and magnesium. Meanwhile, characteristic of fine oil globules i ncluded in the physiologically active material containing emulsion is in that physiologically active materials form a very fine dispersion phase in fine oil globules by action of the oil-soluble emulsifier (that is, embedded into the oil phase). Also, since physiologically active materials are very finely dispersed as they are or together with a small amount of water, concentration of physiologically active materials in the fine dispersion phase is very high, even though it is not 100%, and thus a drug dissociation effect is dramatically increased. Based on comparison of those characteristics as described above, a structureof (1) is a particle structure created by the present inventors for effective practice of the first invention and detailed description thereof was discussed in the seventh invention, but the particle structure of fine oil globule is not disintegrated even by intestinal lipase of animals and further, it is possible to very finely disperse physiologically active materials in fine oil globules regardless of their affinity. Meanwhile, although an average particle diameter of the fine oil globules suitable for oil globule absoφtion action cannot be uniformly specified in response to kinds of animals of interest, for example, it is preferably within a range of 1 to 60 μm, and more preferably 1 to 20 μm. It is also not possible to specifically limit a particle size distribution of fine oil globules (a degree of particle diameter of the respective fine oil globules), but it is ideal to have as narrow a particle size distribution as possible, within the above-mentioned average particle diameter range. Further, there is no need to limit specific particle structure of fine oil globules if it is within a range suited for oil globule absoφtion action, but the following three particle structures may be ideally exemplified: (1) Physiologically active materials form a very fine dispersion phase as they are or together with a small amount of water, by the oil-soluble emulsifier in fine oil globules;
(2) Lipophilic physiologically active materials are dissolved or suspended in fine oil globules; and (3) Fine oil globules have a micelle structure formed by a lipid bilayer and physiologically active materials were put inside thereof.
Among them, the second structure is made by dissolving or finely suspending a lipophilic physiologically active material in the emulsion and using the resulting emulsion and water (preferably, reusing the emulsifier) to constitute an oil-in-water emulsion. The third structure is constitution of the micelle structure formed by the lipid bilayer in water (an aqueous solution of physiologically active materials was put inside thereof). Preparation of the second and third particle structures, or preparation of an emulsion containing fine oil globules having such particle structures dispersed therein can b e e asily c arried o ut u sing su itable m ethods se lected from k nown o r w ell k nown methods. Although there is no limit to kind or particle structure of oil globule as the target for oil globule absoφtion action, for example structures (1) through (3) are representatively exemplified which stability of oil globule dispersion can be anticipated. According to relative evaluation of particle structure of (1) through (3), the third structure has a vesicular particle structure, commonly called ribosome, but when a limiting membrane (lipid bilayer) is disintegrated by action of lipase in animal intestinal tract, there are disadvantages in that such structure cannot maintain the oil globule structure, and oil globule absoφtion action cannot be employed, i the case of the second particle structure, since it is an oil globule (oil ball), the oil globule structure is not easily disrupted by a ction o f lipase, b ut t here a re d isadvantages i n that i t is g enerally difficult to finely disperse physiologically active materials in oil globules except when oil-soluble physiologically active materials are dissolved in oil globules, and further it is difficult to formulate oil globules having a predetermined fine average particle diameter. Now, among physiologically active material containing emulsions capable of providing such high concentration or finely dispersed state of physiologically active materials, a process for preparing the first particle structure will be described in detail. The process for preparing a physiologically active material containing emulsion
essentially involves a first emulsification process and a second emulsification process. Provided that any optional pretreatment process, intermediate process or post-treatment process may be added in addition to the first and second processes. In the first emulsification process, a physiologically active material, an aqueous solution or aqueous suspension thereof and an oil-soluble emulsifier added emulsion are mixed and emulsified to prepare an oily emulsification phase embedded into a oil phase. That is, according to the first emulsification process, the oily emulsification phase is prepared wherein physiologically active material is embedded into the oil phase in the form of very fine dispersion phase as it is or together with a small amount of water. Meanwhile, when the physiologically active material is used as an aqueous solution or aqueous suspension thereof, in the first emulsification process, it is ideal to minimize water content (that is, a high concentration aqueous solution or high density aqueous suspension of physiologically active material). Further, an important technical point in the first emulsification process is in that physiologically active material and aqueous solution thereof (phase a) are emulsified by mixing with an oil-soluble emulsifier added emulsion (phase b). Here, the mixing ratio of phases a and b need not uniformly defined, but the ratio may be optionally selected within a range of phase a : b of 1 : 99 to 99:1 by weight ratio. Where a weight ratio of phase a : phase b is outside the above-mentioned range or the oil-soluble emulsifier is not added to phase b, it is likely to fail to prepare physiologically active material- embedded fine oil globules, as described above. Herein, amount of the oil-soluble emulsifier added to phase b is preferably within the range of 1 to 5% by weight. Although there is no particular limit to kinds of the oil-soluble emulsifiers as long as they do not pose problems associated with toxicity and physiological safety, preferred are those having an HLB (Hydrophilic Lipophilic Balance) value of less than 6, more preferably less than 2. In addition, the emulsifier is preferably a non-ionic surfactant. As the preferred oil-soluble emulsifiers satisfying such conditions, mention may be made of hexaglyceryllinoleate, polyoxyethylenelaurylether, lecithin and polyoxyethyleneoleylether.
In the second emulsification process, the oily emulsification phase prepared in
the first emulsification process, and a water soluble emulsifier added water are mixed and emulsified to prepare an oil-in-water emulsion whereby the oily emulsification phase has an average particle diameter suitable for a target of oil globule absoφtion action in animal digestive tracts and is dispersed in water as the fine oil globule. A technical point in the second emulsification process is in that the water- soluble emulsifier added water (phase d) are mixed and emulsified to the oily emulsification phase (phase c) prepared in the first emulsification process. Here, the mixing ratio of phases c and d need not be specified, but the ratio may be optionally selected within a range of phase c : d of 3 : 1 to 1:3 based on a weight ratio. Where the weight ratio of phase c : phase d is outside the above-mentioned range or the water-soluble emulsifier is not added to phase d, it is likely to fail to prepare a physiologically active material containing emulsion relating to the present invention. Herein, amount of the water-soluble emulsifier added to phase d is preferably within a range of 0.5 to 1.3% by weight. Although there is no particular limit to kinds of the water-soluble emulsifiers as long as they do not pose problems associated with toxicity and physiological safety, preferred are those having an HLB (Hydrophilic Lipophilic Balance) value of more than 10, and more preferably more than 12. In addition, as the type of emulsifier, the non- ionic surfactant is ideal, as described above. As the ideal water-soluble emulsifiers satisfying such conditions, mention may be made of decaglyceryl di-stearate, glyceryl isostearate, decaglyceryl monoisostearate and ethyleneglycol monooleate. In the first and second emulsification processes, an emulsification operation may be performed by using known ultrasonication, a homogenizer or a mixer. In the emulsification operation, a particle diameter of fine oil globules in the physiologically active material containing emulsion and a degree of fine dispersion of the physiologically active material in the fine oil globules may be adjusted by suitably selecting operation conditions of an emulsification means. Meanwhile, as described above, first the physiologically active material or aqueous solution thereof was mixed with the emulsion and then the oil-soluble emulsifier was added to the resulting emulsion so as to form an oily emulsification phase wherein physiologically active material was embedded into the oil phase in the form of very fine dispersion phase as it is or together with a small amount of water upon
using known emulsion formation means such as ultrasonication and use of homogenizer.
Administration method of physiologically active material In an administration method of physiologically active material related to the present invention, fine oil globules are prepared wherein oil droplets in an oil-in-water emulsion contain a physiologically active material and at the same time, fine oil globules have an average particle diameter suitable for the target of oil globule absoφtion action in animal digestive tracts, and the resulting emulsion is orally administered to animals whose digestive tracts exhibit oil globule absoφtion action, except for humans. In this connection, provided that various materials as used herein, for example, emulsions constituting oil droplets, surfactants used in emulsion formation (including oil- soluble emulsifier and water-soluble emulsifier used in preparing the physiologically active material containing emulsion as described above) or pellet for a feed should be all non-toxic or physiologically safe to subject animals. Further, it will be ideal to use materials which are nutritionally beneficial to the subject animals. In an administration method of physiologically active material related to the present invention, there is no need to specifically limit oral administration methods of an oil-in-water emulsion. For example, it is possible to inject the physiologically active material into the oral cavity using a syringe, and in the case of mammals, a so lution itself may be imbibed. In addition, physiologically active material may be mixed and imbibed into an animal feed. Among those methods, more preferably, physiologically active material is impregnated into animal feed pellet (porous feed pellet is particularly ideal) and ingested as it is or after drying. As the feed pellet, a variety of commercially available products may be optionally utilized. According to such oral administration methods, there is no surgical invasion stress due to blood vessel injection to animals except for humans as an administration subject and thus it is easily applicable to fish, crustaceans and shellfish. Meanwhile, as described above, by satisfaction of two requirements, that is, one that applicable subjects is limited to animals in which the oil globule absoφtion action in digestive tracts thereof was confirmed, and another that fine oil globules, which is orally
administered to subject animals, should have a predetermined average particle diameter suitable for oil globule absoφtion action, and at the same time, by inclusion of physiologically active materials, which is a desired material of drug delivery, in fine oil globules which are oil droplets of an oil-in-water emulsion, fine oil globules containing physiologically active material are absorbed into the body at intestinal epithelium as their original form, in the digestive tract of the orally administered subject animal and as a result, disadvantages exhibited by the conventional oral administration methods can be avoided that physiologically active materials are digested before being absorbed, or not sufficiently absorbed in the digestive tracts. Therefore, physiologically active materials can be ingested into the animal body at considerably high efficiency in a simplified manner. Meanwhile, as the subject animals for the administration method of a physiologically active material related to the present invention, preferred are animals in which the oil globule absoφtion action in digestive tracts thereof was confirmed, that is aquatic animals or terrestrial mammals, except humans. More specifically, animals in which the oil globule absoφtion action in digestive tracts thereof was confirmed, for example, mention may be made of mammals such as rabbits, rats, dogs, cats, cows and pigs, except humans, and birds, amphibians, reptile, various fish including aquacultured fishes or ornamental fish, shellfish and aquatic crustaceans (shrimp, crab).
[Best Mode]
Now, the present invention will be described in more detail with reference to the following Examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and sprit of the present invention.
EXAMPLES
Example 1
As a physiologically active material, formalin-killed bacteria of E. coli was used to an aqueous suspension (First solution) containing a high density of the dead bacteria. Meanwhile, in the case of liver oil of cuttlefish, as the oil-soluble emulsifier,
5% by weight of hexaglyceryl linoleate (Oxygen Food #818R, Taiyou Chemical Industry Co., Ltd, Japan) was added to prepare an emulsion (Second solution). Then, as the first emulsification treatment, the first solution and second solution were mixed in a weight ratio of 90:10, and subjected to sufficient emulsification treatment using a sonicator so as to form an oily emulsification phase (Third solution) embedded in an oil phase in which a high density suspension of formalin-killed bacteria of E. coli forms a very fine dispersion phase. Next, as the water-soluble emulsifier, 1% by weight of decaglyceryl distearate (Oxygen Food Q-182S, Taiyou Chemical Industry Co., Ltd, Japan) was added to water (Fourth solution). And, as the second emulsification treatment, the third solution and fourth solution were mixed in a weight ratio of 2:1 and sufficiently stirred using a mixer to prepare a physiologically active material containing emulsion in which the oily emulsification phase was dispersed in water as fine oil globule. Upon observing a particle diameter of fine oil globules included in the prepared physiologically active material containing emulsion, it was approximately 5 to 10 μm. The prepared physiologically active material containing emulsion was stored in a refrigerator for about one week and when observing again the particle diameter of fine oil globules, the particle diameter thereof was approximately 5 to 10 μm. From these results, it was confirmed that dispersion state of fine oil globules was stable.
Example 2
In this example, formalin-killed bacteria of Edwardsiella tarada, which is a pathogenic bacteria of olive flounder (Paralichthys olivaceus), was used. An aqueous suspension (First solution) containing the dead bacteria at a concentration of 107 cells/ml was prepared and then a physiologically active material containing emulsion was prepared using the same method as described in Example 1. Then, an appropriate amount of the prepared physiologically active material containing emulsion was impregnated in a commercially available porous pellet for a fish
feed. 15 olive flounders (Paralichthys olivaceus) were fed with the porous pellet for a fish feed for 13 days, consecutively such that emulsion intake is 10 μl/day/lOOg of fish body. On day 23 after completion of an intake period, blood was collected from the arteries of 5 olive flounders (Paralichthys olivaceus) and then the sera thus obtained were determined on antibody titer of antibodies of Edwardsiella tarada as agglutination value. The determined results are presented in Table 1 below. Hereinafter, the "administered group" refers to 5 olive flounders (Paralichthys olivaceus) relating to Examples while "control group" refers to 5 olive flounders (Paralichthys olivaceus) relating to Comparative Examples. Further, numbers of column "Fish" refer to Sample Nos. of 5 olive flounders of the administered group and control group, respectively.
Table 1
Table 2
As can be confirmed from Table 2, there was no dead fish in both administered group and control group until 6 days lapsed from injection, but at the point of day 14, sum of dead fish was 5(viability of 50%) in the control group. It can be seen from the above-described results that the administered group exhibited excellent results compared to the control group, in both antibody titer determination and viability after injection of live bacteria.
Example 3
This example also used formalin-killed bacteria of Edwardsiella tarada. An aqueous suspension (First solution) containing the dead bacteria at a concentration of 109 cells/ml was prepared and then a second solution was prepared using the same method as described in Example 1. Then, the first solution and second solution were mixed in a weight ratio of 99:1, and subjected to sufficient emulsification treatment using an so-ύcator so as to form an oily emulsification phase (Third solution of group 1) embedded in an oil phase in which a
high density suspension of formalin-killed bacteria of E. coli forms a very fine dispersion phase. In addition, the first solution and the second solution were mixed in a weight ratio of 90:10 and the resulting mixture was subjected to emulsification treatment as described above to form an oily emulsification phase (Third solution of group 2). Next, a fourth solution was prepared in the same method as Example 1, the third solution and fourth solution were mixed in a weight ratio of 2:1 relative to the third solution of group 1 and the third solution of group 2 and sufficiently stirred using a mixer to prepare a physiologically active material containing emulsion ([the physiologically active material containing emulsion of group 1] and [the physiologically active material containing emulsion of group 2]) in whiςh the oily emulsification phase was dispersed in water as fine oil globule. Next, the p hysiologically active material c ontaining emulsion o f group 1 and the physiologically active material containing emulsion of group 2 were impregnated in a commercially available porous pellets for a fish feed in an appropriate amount. The porous pellets were fed such that a fish feeds for 13 days, consecutively such that emulsion intake is 0.05 ml/day/lOOg of fish body. Each 10 olive flounders (Paralichthys olivaceus) (average body weight: 100 g) were allowed to freely feed for 3 days. Hereinafter, olive flounder (Paralichthys olivaceus) in which the physiologically active material containing emulsion of group 1 was fed was designated "group A" and olive flounder (Paralichthys olivaceus) in which the physiologically active material containing emulsion of group 2 was fed was designated "group B". Next, with regard to olive flounders (Paralichthys olivaceus) related to group A and group B, on day 23 after completion of an intake period, antibody titer of antibodies of Edwardsiella tarada in sera of olive flounders (Paralichthys olivaceus) obtained was determined as an agglutination value. The results are presented in column "bacterial body embedded-oil globule administered group" of Table 3 below. Numbers of column "Fish" in Table 3 refer to Sample Nos. of 10 olive flounders (Paralichthys olivaceus) related to group A and group B. Meanwhile, as the control group, formalin-killed bacteria of Edwardsiella tarada and liver oil of cuttlefish and an oil-soluble emulsifier in the same amount as "group A" in Example 3 were used to prepare a simple miscible oily solution, as described above. This oily solution does not undergo the process corresponding to the second
emulsification treatment, and thus is not encompassed by physiologically active material containing emulsion related to the present invention. This oily solution was impregnated into porous pellet as described above and administered to 10 Olive flounder (Paralichthys olivaceus), and antibody production was measured. Olive flounder (Paralichthys olivaceus) that was fed with this oily solution served as "Group D". Evaluation results are presented in column "Group D" in Table 3. In addition, 10 normal Olive flounders (Paralichthys olivaceus) in which formalin-killed bacteria of Edwardsiella tarada and emulsion were not administered in any manner served as "group C" and evaluation of antibody production was carried out using the same method. Evaluation results are presented in column "Group C" of Control group in Table 3.
Table 3
[Industrial Applicability]
As described above, immune activators and pharmacologically active materials and various physiologically active materials can be imbibed into various aquacultured or ornamental fish and aquatic crustaceans, or mammal in which oil globule absoφtion action occurs, at very significantly high efficiency by a simple method. Although the preferred embodiments of the present invention have been disclosed for illustrative puφoses, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.
Claims
[Claim 1] An oil-in-water emulsion containing a physiologically active material, wherein fine oil globules as the target for oil globule aosoφtion action in animal digestive tracts are dispersed in the emulsion, the physiologically active material is contained in oil droplets of the emulsion having fine oil globules dispersed therein, and the physiologically active material is embedded into an oil phase in the form of a very fine dispersion phase as it is or together with a small amount of water, by action of an oil-soluble emulsifier present in the fine oil globules.
[Claim 2] An oil-in-water emulsion containing a physiologically active material, wherein fine oil globules as the target for oil globule absoφtion action in animal digestive tracts are dispersed in the emulsion, the physiologically active material is contained in oil droplets of the emulsion having fine oil globules dispersed therein, and the p hysiologically a ctive m aterial i s d issolved or suspended lipophilically i n fine oil globules.
[Claim 3] An oil-in-water emulsion containing a physiologically active material, wherein fine oil globules as the target for oil globule absoφtion action in animal digestive tracts are dispersed in the emulsion, the physiologically active material is contained in oil droplets of the emulsion having fine oil globules dispersed therein, and the physiologically active material is present in the form that is enclosed within the fine oil globules having a micelle structure formed by a lipid bilayer.
[Claim 4] The emulsion as set forth in any one of claims 1 through 3, wherein the average particle diameter of the fine oil globules is within a range of 1 to 60 μm.
[Claim 5] The emulsion as set forth in any one of claims 1 through 3, wherein the physiologically active materials is at least one selected from the group consisting of vaccines, immune activators, nutritional materials, pharmacologically a ctive materials, natural pigments and minerals.
[Claim 6] A process for preparing an emulsion containing a physiologically active material, comprising: mixing and emulsifying a physiologically active material, an aqueous solution or aqueous suspension thereof and an oil-soluble emulsifier added emulsion to prepare an oily emulsification phase; and mixing and emulsifying the oily emulsification phase and water containing a water soluble emulsifier added thereto to prepare an oil-in- water emulsion in which the oily emulsification phase is dispersed in water as a fine oil globule that is the target for oil globule absoφtion action in animal digestive tracts.
[Claim 7] A method for administering an emulsion containing a physiologically active material, comprising: orally administering a physiologically active material containing emulsion having fine oil globules dispersed therein to an animal, wherein the fine oil globules are prepared such that oil droplets in the emulsion contain the physiologically active material and at the same time, the fine oil globules become a target for oil globule absoφtion action in animal digestive tracts.
[Claim 8] A method for administering an emulsion containing the physiologically active material, comprising: impregnating a physiologically active material containing emulsion having fine oil globules dispersed therein into a feed or pellet for a feed; and allowing animals to ingest the impregnated material, wherein the fine oil globules are prepared such that oil droplets in the emulsion contain the physiologically active material and at the same time, the fine oil globules become a target for oil globule absoφtion action in animal digestive tracts.
[Claim 9 ] The method as set forth in claim 7 or 8, wherein the animal is an aquatic animal or terrestrial mammal. [Claim 10] The method as set forth in claim 7 or 8, wherein the physiologically active material is at least one selected from the group consisting of vaccines, immune activators, nutritional materials, pharmacologically active materials, natural pigments and minerals.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003354482A JP2005119986A (en) | 2003-10-15 | 2003-10-15 | Method for administering physiologically active substance, emulsion containing physiologically active substance, and method for producing emulsion containing physiologically active substance |
| JP2003-354482 | 2003-10-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005034914A1 true WO2005034914A1 (en) | 2005-04-21 |
Family
ID=34431189
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2004/002652 Ceased WO2005034914A1 (en) | 2003-10-15 | 2004-10-15 | Emulsified solution containing psysiological activation material, a method for preparing thereof, and a method for administration thereof |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP2005119986A (en) |
| KR (1) | KR20060123119A (en) |
| CN (1) | CN1867319A (en) |
| WO (1) | WO2005034914A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105707485A (en) * | 2016-01-15 | 2016-06-29 | 东北农业大学 | Feed additive reducing fat globule particle sizes in sow milk |
| US20170215457A1 (en) | 2014-07-21 | 2017-08-03 | Sevecom S.P.A. | Powdered emulsion for animal feed |
| US11213052B2 (en) | 2011-06-10 | 2022-01-04 | Sevecom S.P.A. | Use of emulsifiers in association with vegetable oleins in an animal feed |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009225748A (en) * | 2008-03-25 | 2009-10-08 | Mikasa:Kk | Method for rearing animal |
| CN102573802A (en) * | 2009-08-12 | 2012-07-11 | 希格默伊德药业有限公司 | Immunomodulatory compositions comprising a polymer matrix and an oil phase |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0073006A2 (en) * | 1981-08-21 | 1983-03-02 | William Gough Tucker | Medicinal composition and method of making same |
| JPH0517344A (en) * | 1991-03-25 | 1993-01-26 | Dai Ichi Seiyaku Co Ltd | Lipid membranous structure for oral use |
| US5885590A (en) * | 1991-06-27 | 1999-03-23 | Hunter; Robert L. | Oral vaccines comprising multiple emulsions and methods of preparation |
| WO1999060012A1 (en) * | 1998-05-21 | 1999-11-25 | Isis Pharmaceuticals, Inc. | Compositions and methods for non-parenteral delivery of oligonucleotides |
-
2003
- 2003-10-15 JP JP2003354482A patent/JP2005119986A/en active Pending
-
2004
- 2004-10-15 WO PCT/KR2004/002652 patent/WO2005034914A1/en not_active Ceased
- 2004-10-15 KR KR1020067007210A patent/KR20060123119A/en not_active Withdrawn
- 2004-10-15 CN CNA2004800301817A patent/CN1867319A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0073006A2 (en) * | 1981-08-21 | 1983-03-02 | William Gough Tucker | Medicinal composition and method of making same |
| JPH0517344A (en) * | 1991-03-25 | 1993-01-26 | Dai Ichi Seiyaku Co Ltd | Lipid membranous structure for oral use |
| US5885590A (en) * | 1991-06-27 | 1999-03-23 | Hunter; Robert L. | Oral vaccines comprising multiple emulsions and methods of preparation |
| WO1999060012A1 (en) * | 1998-05-21 | 1999-11-25 | Isis Pharmaceuticals, Inc. | Compositions and methods for non-parenteral delivery of oligonucleotides |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11213052B2 (en) | 2011-06-10 | 2022-01-04 | Sevecom S.P.A. | Use of emulsifiers in association with vegetable oleins in an animal feed |
| US20170215457A1 (en) | 2014-07-21 | 2017-08-03 | Sevecom S.P.A. | Powdered emulsion for animal feed |
| US11185092B2 (en) | 2014-07-21 | 2021-11-30 | Sevecom S.P.A. | Powdered emulsion for animal feed |
| CN105707485A (en) * | 2016-01-15 | 2016-06-29 | 东北农业大学 | Feed additive reducing fat globule particle sizes in sow milk |
| CN105707485B (en) * | 2016-01-15 | 2019-03-08 | 东北农业大学 | A feed additive for reducing fat globule particle size in sow milk |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2005119986A (en) | 2005-05-12 |
| KR20060123119A (en) | 2006-12-01 |
| CN1867319A (en) | 2006-11-22 |
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