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WO1997029773A1 - Emulsion et poudre renfermant un vaccin et destinees a une administration orale, et procede de production associe - Google Patents

Emulsion et poudre renfermant un vaccin et destinees a une administration orale, et procede de production associe Download PDF

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Publication number
WO1997029773A1
WO1997029773A1 PCT/JP1997/000351 JP9700351W WO9729773A1 WO 1997029773 A1 WO1997029773 A1 WO 1997029773A1 JP 9700351 W JP9700351 W JP 9700351W WO 9729773 A1 WO9729773 A1 WO 9729773A1
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WO
WIPO (PCT)
Prior art keywords
vaccine
emulsion
oil
amount
oral administration
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PCT/JP1997/000351
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English (en)
Japanese (ja)
Inventor
Katsuhiko Ooyama
Masashi Umemura
Miho Sakurada
Kumiko Kurokawa
Original Assignee
The Nisshin Oil Mills, Ltd.
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Filing date
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Application filed by The Nisshin Oil Mills, Ltd. filed Critical The Nisshin Oil Mills, Ltd.
Priority to AU16711/97A priority Critical patent/AU1671197A/en
Publication of WO1997029773A1 publication Critical patent/WO1997029773A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Emulsion containing vaccine for oral administration Emulsion containing vaccine for oral administration
  • the present invention relates to a vaccine-containing emulsion for oral administration, a vaccine-containing powder for oral administration, and methods for producing the same. More particularly, the present invention relates to a vaccine-containing emulsion for oral administration which is excellent in formulation stability, a vaccine-containing powder for oral administration which can be easily redispersed, and a method for producing them.
  • An immunogen for immunizing a human body or an animal is usually used in a state of being suspended in a buffered physiological saline.
  • Such suspensions are referred to as vaccines, which include inactivated vaccines (eg, typhoid vaccine, 100 days Cough vaccine, rabies vaccine, etc.), attenuated vaccine (eg, pathogen, raw polio vaccine, etc.), detoxified vaccine (eg, diphthene vaccine) Rear toxoid, tetanus toxoid, etc.) are known.
  • inactivated vaccines eg, typhoid vaccine, 100 days Cough vaccine, rabies vaccine, etc.
  • attenuated vaccine eg, pathogen, raw polio vaccine, etc.
  • detoxified vaccine eg, diphthene vaccine
  • an administration agent not by injection has been proposed in, for example, Japanese Patent Application Laid-Open No. 5-294845, but furthermore it is safe and convenient. Development of Oral Drugs That Have Both Properties It has been.
  • micro-fluidizers and ultrasonic emulsifiers are used to emulsify micelles for the purpose of enhancing the immune response and stabilizing the emulsion.
  • Methods have been used for injections and the like [WO90Z148337 (published publication No. 5-5083885) and the like].
  • an immunogen for immunizing a human or an animal and an oil or fat are mixed with at least one hydrophilic non-ionic surfactant in an aqueous medium containing a polyhydric alcohol. And at least one lipophilic nonionic surfactant (provided that the mixing weight ratio is 20: 1 to 1: 1, preferably 9: 1 to 1: 1).
  • an oil-in-water orally-administered emulsion for oral administration which is obtained by emulsification.
  • an actin-containing powder for oral administration which can be obtained by adding two or more kinds of oil droplet interface adsorbents to the above-mentioned vaccine-containing emulsion and drying the same is provided. It is.
  • a hydrophilic and lipophilic non-ionic surfactant (provided that the mixing weight ratio is 20: 1 to 1: 1 and preferably 9: 1 to 1: a step of melt-mixing 1) to obtain a mixture,
  • the method comprises the steps (i) to (iv) described above, wherein an immunogen and an oil droplet surface adsorbent for immunizing a human or animal are simultaneously or separately provided after the step (i). , Which is added before step (ii), during any of steps (ii) to (iv), or after step (iv), and is subjected to a drying treatment.
  • a method for producing a tin-containing powder is provided.
  • the immunogen is also referred to as an antigen, and produces an antibody or a sensitized lymphocyte against a human or animal.
  • a substance that induces humoral immunity or cellular immunity is also referred to as an antigen, and produces an antibody or a sensitized lymphocyte against a human or animal.
  • vaccines include inactive vaccines (eg, influenza vaccine, Japanese encephalitis vaccine, whooping cough vaccine, and triple vaccine vaccine). , Cholera vaccine, pneumococcal vaccine, rosin vaccine, etc.), attenuated vaccines (for example, polio vaccine, measles vaccine, Vaccine vaccine, BCG vaccine, typhus vaccin, pox vaccine, etc., detoxified vaccine (for example, diphtheria vaccine) , Tetanus vaccine, butoxoid, typhoid vaccine, botulinum vaccine, etc.) and component vaccines (Influenza HA vaccine) , Hepatitis B vaccine, non-A non-B hepatitis vaccine, herpes vaccine, AIDS vaccine, cancer vaccine, etc.) Can be listed.
  • inactive vaccines eg, influenza vaccine, Japanese encephalitis vaccine, whooping cough vaccine, and triple vaccine vaccine.
  • Cholera vaccine pneumococcal vaccine, rosin vaccine, etc.
  • immunogens can be lyophilized vaccine solution or vaccine solution, or when this lyophilized product is used, phosphate buffer, physiological saline, It can be used by dissolving it in purified water.
  • the immunogen varies depending on the content or type, etc., the immunogen is contained in an amount of about 0.001 to about 0.1% by weight based on the total amount of the vaccine-containing emulsion. Preferably, about 0.027 to about 0.011% by weight is particularly preferred.
  • the fats and oils are not particularly limited as long as they are pharmaceutically low-toxic and suitable for oral administration. Among them, vegetable oils such as olive oil, soybean oil, sesame oil and the like are preferred.
  • the amount of fats and oils added is about 2 to about 30% by weight, preferably about 2 to about 20% by weight, and more preferably about 5% by weight, based on the total amount of the emulsion containing the vaccine. About 15% by weight. If the oil content of the vaccine-containing emulsion is more than 30% by weight, it may cause digestive problems such as diarrhea when administered orally. If the content is less than 2% by weight, a sufficient effect cannot be obtained, which is not preferable.
  • both the hydrophilic non-ionic surfactant and the lipophilic non-ionic surfactant are simultaneously used. It is necessary to use them.
  • the hydrophilic non-ionic surfactant and the lipophilic non-ionic surfactant can each be used alone or in combination of two or more.
  • the hydrophilic non-ionic surfactant and the lipophilic non-ionic surfactant are preferably in a weight ratio of 20: 1 to 1: 1 and more preferably 9: 1 to 1: 1. , 7: 3 to 1: 1 are more preferred.
  • surfactants are preferably contained in a total amount of about 0.5 to about 4.5% by weight, and preferably about 2.5% by weight, based on the total amount of the emulsion containing the vaccine. ⁇ 3.5% by weight is more preferred.
  • the surfactant is preferably a combination having an HLB value in the range of 7 to 18 when a hydrophilic and lipophilic nonionic surfactant is mixed, and 11 to 14 A range of 5 is more preferred.
  • hydrophilic non-ionic surfactant examples include polyoxyethylene sorbitan fatty acid ester (the number of moles of oxyethylene added to the polyoxyethylene is from 1 to 1).
  • the fatty acid esters are cabronic acid, carboxylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, It is derived from a saturated or unsaturated fatty acid having 6 to 18 carbon atoms such as palmitooleic acid, oleic acid, linoleic acid, linolenic acid, etc.), Polyoxyethylene sorbitol fatty acid esters (the number of moles of oxyethylene added is the same as described above, and the fatty acid esters are the same or mixed fatty acid esters of the same fatty acids as described above).
  • Sucrose fatty acid ester (HLB value is 10 or more, flg fatty acid ester is above The same applies), polyoxyethylene fatty acid ester (the number of moles of added oxyethylene, fatty acid ester is the same as above), and polyoxyethylene fatty acid ester (oxyethylene).
  • the number of moles of added len and fatty acid ester are the same as described above), polyglycerin fatty acid ester (H and B values are 10 or more, and the amount of glycerin in polyglycerin is The number of moles to be added is from 1 to 100, and the fatty acid ester is the same or a mixed fatty acid ester of the same fatty acids as described above .
  • Polyoxyethylene alkyl Ether Alkyl ether is an alkyl ether having 10 to 18 carbon atoms in the same manner as above for the number of moles of added oxyethylene
  • Polyoxyethylene hardened castor oil Olyethylene The number of moles of added len is the same as described above).
  • polyoxyethylene sorbitan fatty acid ester polyoxyethylene alkyl ether
  • polyoxyethylene hydrogenated castor oil are preferred, and specifically, polyoxyethylene.
  • hydrophilic non-ionic surfactants can be used alone or in combination of two or more.
  • polyoxyethylene hardened castor oil and sucrose fatty acid ester polyoxyethylene alkyl ether and polyoxy Silicone bitumen fatty acid ester, polyoxyethylene bitumen fatty acid ester and sucrose fatty acid ester, polyoxyethylene alkyl ether and polyoxyethylene hardened castor oil
  • a combination of a polyoxyethylene alkyl ether and a sucrose fatty acid ester is preferred.
  • lipophilic nonionic surfactants examples include sorbitan fatty acid esters (fatty acid esters are as described above), glycerin fatty acid esters (fatty acid esters are as described above), Glycerin fatty acid ester (HLB value less than 10; fatty acid ester is the same or mixed fatty acid ester of the same fatty acids as above); sucrose fatty acid ester (HLB value less than 10; fatty acid ester Same as above), glycerin / lower mono or dicarboxylic acid / fatty acid ester (one of them)
  • the ester is a fatty acid ester similar to the above, and the other ester is a lower mono- or di-carboxylic acid such as succinic acid, acetic acid, acetic acid, citric acid, tartaric acid, etc.
  • dicarboxylic acid is an ester of which may be substituted with a hydroxyl group, an acetyl group, etc.).
  • Fatty acid esters and glycerin fatty acid esters are preferred, specifically, solvitan sesquioleate and glycerine monostearate.
  • These lipophilic nonionic surfactants can be used alone or in combination of two or more.
  • a combination of sorbitan fatty acid ester and glycerin fatty acid ester is preferable.
  • Preferred examples of the combination of a hydrophilic non-ionic surfactant and a lipophilic non-ionic surfactant include polyoxyethylene sorbitan fatty acid ester and sorbitan. Fatty acid esters, polyoxyethylene alkyl ethers and sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters and glycerin fatty acid esters, polyoxyethylene alkyl ethers And glycerin fatty acid esters. These are preferably combined in such a way that the HLB is in the range of ⁇ to 18 and, among them, the Lauromac mouth goal and the solvent, which are polyoxyethylene alkyl ethers. Preference is given to a combination with bitumen fatty acid ester, solvitan sesquioleate.
  • the vaccine-containing emulsion of the present invention is formed into an emulsion in an aqueous medium containing a polyhydric alcohol.
  • Multivalent Al Due to its water retention function, it is considered that the addition of the surfactant improves the association property of the surfactant and makes it easier for oil droplets to be retained in the surfactant phase. It is also thought that it has helped to lower the interfacial tension, which is essential for the formation of the emulsion. It is thought that this will keep the immunogen in good condition in the emulsion and maintain its effect in oral administration.
  • the polyhydric alcohol include glycerin, polyethylene glycol, propylene glycol, and the like. Glycerin is particularly preferred.
  • the content of the polyhydric alcohol is from about 0.2 to about 1.4% by weight, preferably from about 0.6 to about 1.0% by weight, based on the total amount of the vaccine-containing emulsion. %.
  • the vaccine-containing emulsion of the present invention contains water as a basic medium together with each of the above-mentioned components. Therefore, the vaccine-containing emulsion of the present invention is of the oil-in-water type (o / w). In this case, distilled water or deionized water is preferable as the water. The added amount of water is used to constitute the balance of the content of each component as described above. However, it is preferable to use PBS in consideration of administering the obtained emulsion.
  • the vaccine-containing emulsion of the present invention further contains two or more types of oil droplet surface adsorbents and is subjected to a drying step such as freeze-drying, whereby the vaccine is obtained. It may be in the form of a contained powder.
  • This oil droplet interfacial adsorbent can reproduce fine and uniform emulsions when the vaccine-containing emulsion of the present invention is powdered into a vaccine-containing powder. It is included for the purpose of realizing oil droplets and A compound that is adsorbed on the boundary, has high water dispersibility, and is solid at ordinary temperature. Specific examples include natural polymer compounds such as polysaccharides and proteins, and synthetic polymer compounds such as polyvinyl alcohol.
  • arabia rubber, cyclodextrin, and dextrin are preferred, and a combination of two or three of these is preferred.
  • a combination of Arabic rubber and /? — Cyclodextrin is preferred.
  • the oil droplet surface adsorbent is preferably used in an amount of about 0.8 to about 3 parts by weight, more preferably about 1 part by weight (equal amount), based on 1 part by weight of the fat or oil in the emulsion containing the vaccine. I prefer it.
  • the vaccine-containing emulsion for oral administration of the present invention can be produced, for example, by the following method.
  • a polyhydric alcohol containing a small amount of water is added to the obtained mixture.
  • the ratio of polyhydric alcohol to water is preferably about 1: 9 to 1: 1 by weight, more preferably 1: 4 to 2: 3, and about 3: 7. Is even more preferred.
  • the addition is preferably carried out at room temperature with stirring.
  • a small amount of water and a polyhydric alcohol may be separately added in any order so as to have the above ratio.
  • the fats and oils are not gently stirred into the obtained mixture. Add it.
  • Slow stirring means that natural emulsification is promoted without applying the mechanical pressure of a conventional device such as a microfilter or an ultrasonic emulsifier. Means this.
  • the fats and oils should not be cooled so that the temperature does not rise too quickly. It is preferable to add it by force.
  • the addition is preferably performed gradually.
  • the term “gradually” means a force that can be appropriately adjusted because it differs depending on the manufacturing scale. It is sufficient that the force is not more than about lOOgZ, and 0.1g to 100g. / Min, and more preferably about 1 to 10 g Z min.
  • the immunogen in the present invention may be any of the immunogens after the heating and melting and mixing of the nonionic surfactant (i) in the above-mentioned step. Specifically, in any one of the step of adding a polyhydric alcohol containing a small amount of water (ii), the step of adding fats and oils (iii), the step of adding water (iv), or It may be added before step (ii) or after step (iV). However, it is preferred to add it as much as possible in the subsequent step, and most preferably to add it after step (iV) or step (iV).
  • hydrophilic and lipophilic non-ionic surfactants A polyhydric alcohol and a small amount of water are melted and mixed at a temperature higher than the melting point of the nonionic surfactant, generally at room temperature to 70 to obtain a mixture, and the fats and oils are moderated By gradually adding the mixture while stirring, and adding and mixing a predetermined amount of water, a fine and stable oil-in-water emulsion can be obtained.
  • the immunogen may be added at any step after the melting and mixing, but is preferably added after the step (iV) or after the step (iV), if possible. Is the most preferred.
  • the above-mentioned method uses natural emulsifying power, so that it has a vaccine effect ⁇ the use of oils and fats or surfactants for extracting it, as compared with the conventional emulsion method using mechanical pressure.
  • the addition amount can be reduced, and it is excellent in safety, and also excellent in cost of manufacturing equipment and the like. Furthermore, it is excellent in preventing the deactivation of vaccines.
  • the resulting vaccine-containing emulsion can be used as it is as an orally administered drug.
  • powder for enteric formulation to prevent inactivation of vaccine due to stomach acid, or to improve storage stability.
  • the oil-drop surface adsorbent is added to the vaccine-containing emulsion obtained as described above in its original form, or in the form of a suspension or the like, and mixed.
  • the polyvalent alpha is added.
  • an oil droplet interfacial adsorbent may be added.
  • the immunogen may be added together with the oil droplet surface adsorbent or separately after the oil droplet surface adsorbent is added.
  • the oil droplet interfacial adsorbent is added in this way, it can be made into a powder by subjecting it to, for example, a freeze drying method, a spray drying method, a dehydration drying method, or the like.
  • the freeze-drying method is preferred.
  • water or PBS is added to the obtained emulsion vaccine to obtain an emulsion. It is preferable to adjust the amount of fats and oils to 1 to 5% by weight, preferably about 2% by weight, based on the total amount of cutin.
  • the vaccine-containing powder obtained in this way can be easily redispersed in an aqueous medium. It can be used in the form of granules, tablets, pills, microcapsules, hard or soft capsules, and the like.
  • vaccine-containing emulsions can be used in the form of hard or soft capsules.
  • These preparations are preferably enteric-coated preparations in order to expect a sufficient effect of the vaccine.
  • a pharmaceutically acceptable excipient or carrier eg, monosaccharides such as glucose, lactose, etc.
  • Disaccharides eg., monosaccharides such as glucose, lactose, etc.
  • Polysaccharides such as pullulan and dextrin, starches such as corn starch and potato starch
  • binders eg, methylcellulose, histamine
  • Doxypropyl cellulose polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.
  • disintegrants for example, carboxymethylcellulose
  • Various additives such as ruboxime methylcellulose sodium, crystalline cellulose, partially pregelatinized starch, etc., and lubricants (eg, magnesium stearate, talc, etc.) are appropriately used.
  • microcapsules are appropriately selected and used in order to obtain microcapsules.
  • Hard or soft capsules are generally formed of gelatin.
  • film-forming agent used for enteric solubilization of each preparation for example, those known in the art can be appropriately selected and used.
  • methacrylic acid / methacrylic acid alkyl ester copolymers hydroxypropyl propyl cellulose phthalate, hydroxypropyl propyl cellulose acetyl cellulose succinate, Carboxymethyl ethylcellulose, cellulose acetate phthalate, refined shellac, white shellac, ethylcellulose, aminoalkyl methyl acrylate polymer, etc.
  • Enteric solubilization is generally performed after preparation of each preparation in advance.
  • Each of the above-mentioned preparations can be produced using a method known in the art.
  • the oral dosage of the vaccine-containing emulsion and the vaccine-containing powder of the present invention varies depending on the type of the immunogen used, but usually, the immunogen is administered once per adult. Is about 12.5 to 10000 (g) It is preferable to use it in the amount.
  • the dose varies depending on other components, the number of doses, the sex, age, etc. of the recipient. For example, when influenza is used as an immunogen, it usually contains 12.5-100 000 g of influenza once per adult. If the dose is given orally and no increase in antibody titer is observed, additional dose can be given 2 to 4 weeks later.
  • the vaccine-containing emulsion and the vaccine-containing powder for oral administration of the present invention and the production method thereof will be described with reference to Examples, but the present invention is not limited thereto. is not.
  • an aqueous solution of influenza enzyme (A / Guizhou / 54 / 89H3N2, the same applies hereinafter) is gradually added and mixed, and the oil content becomes 10% by weight.
  • dilution was performed with a phosphate buffer (PBS) to obtain an emulsion containing influen- vacactin with an antigen amount of 27 ⁇ g / l.
  • PBS phosphate buffer
  • an aqueous solution of influenzae protein is gradually added and mixed, and diluted with PBS so that the oil amount becomes 10% by weight, and the antigen amount is adjusted to 27%.
  • An emulsion containing g / m 1 of influenza enquinone was obtained.
  • an aqueous solution of influenzae tactic vaccine is gradually added and mixed, and diluted with PBS so that the oil amount becomes 10% by weight, and the antigen amount is 27 / xg.
  • An emulsion containing 1 / ml of the influenza enzyme was obtained.
  • influenza enzyme vaccine aqueous solution was gradually added and mixed, and diluted with PBS so that the oil amount became 30% by weight.
  • the antigen amount was 27 g / An emulsion containing m1 influenzawacchin was obtained.
  • a mixture of 13.5 g of lauromacrogol and 13.5 g of sorbisoen sesquioleate was heated and melted at 60 ° C, and then added with 3.6 g of glycerin. g and a small amount of water were mixed at room temperature. Here, 180 g of soybean oil was gradually added with stirring.
  • influenzae protein is gradually added and mixed, and diluted with PBS so that the oil amount becomes 30% by weight, and the antigen capacity is 27 g.
  • An influenza enzymatic emulsion containing Zml was obtained.
  • influenza enzyme vaccine aqueous solution is gradually added and mixed, and diluted with PBS so that the oil amount becomes 30% by weight, and the antigen amount is adjusted to 27 g / An emulsion containing m1 influenza vaccine was obtained.
  • influenzaein evening vaccine solution was gradually added and mixed, and diluted with PBS so that the oil amount became 10% by weight, and the antigen amount was adjusted to 27 g / An emulsion containing m1 influenza vaccine was obtained.
  • aqueous solution of influenza intact vaccine is gradually added and mixed, and diluted with PBS so that the oil amount becomes 10% by weight.
  • an emulsion containing influenza enzyme with an antigen amount of 27 g / m 1 was obtained.
  • influenza enzyme vaccine aqueous solution is gradually added and mixed, and diluted with PBS so that the oil amount becomes 30% by weight, and the antigen amount is adjusted to 27 X g
  • An emulsion containing / m 1 of influenza actin was obtained.
  • influenza enzyme vaccine Furthermore, an aqueous solution of influenza enzyme vaccine is gradually added and mixed, and diluted with PBS so that the oil amount becomes 10% by weight, and the antigen amount is 27 g. Influenza enquinone-containing emulsion was obtained.
  • an aqueous solution of influenzae protein is gradually added and mixed, and diluted with PBS so that the oil amount becomes 30% by weight, and the antigen amount is adjusted to 27% by weight.
  • An emulsion containing u-S / m1 of influenza enquintin was obtained.
  • influenza enzymatic vaccine solution was gradually added and mixed, and diluted with PBS so that the oil amount became 30% by weight, and the antigen amount was adjusted to 27 gm 1.
  • an influenza enzyme-containing emulsion was obtained.
  • Polyoxyethylene sorbitan monooleate (trade name: TO-10M; manufactured by Nikko Chemicals, the same applies hereinafter) 24.3 g and sesquioleate sorbitan The mixture was heated and melted at 60 ° C., and 1.2 g of glycerin and a small amount of water were mixed at room temperature. Here, 60 g of soybean oil was gradually added with stirring.
  • Example 15 An aqueous solution of influenzae protein is gradually added and mixed, and diluted with PBS so that the oil amount becomes 10% by weight, and the antigen amount is adjusted to 27%. An emulsion containing ug / m 1 of influenza enzyme was obtained.
  • Example 15 An emulsion containing ug / m 1 of influenza enzyme was obtained.
  • Polyoxyethylene sorbitan monooleate (12.6 g) and glycerine monostearate (trade name: MGS-B; manufactured by Nikko Chemicals, Inc.) 5.4 g were mixed and heated and melted at 60, and 3.6 g of glycerin and a small amount of water were mixed at room temperature. Here, 60 g of soybean oil was gradually added with stirring.
  • influenza enzyme vaccine aqueous solution was gradually added and mixed, and diluted with PBS so that the oil amount became 10% by weight, and the antigen amount was adjusted to 27 g / Thus, an emulsion containing m 1 influenza wax was obtained.
  • influenza intact vaccine aqueous solution is gradually added and mixed, and diluted with PBS so that the oil amount becomes 10% by weight, and the antigen amount is adjusted to the ml amount of the antigen.
  • An emulsion containing fluen- zactin was obtained.
  • soybean oil While cooling, 6 Og of soybean oil was gradually stirred and mixed. Further, the oil was diluted with PBS so as to have an oil amount of 10% by weight to obtain an emulsion containing influenza enquintin having an antigen amount of 27 g / ml.
  • a rubber (dispersed in Sanei Pharmaceutical Trading Co., Ltd., manufactured by Sanei Pharmaceutical Co., Ltd.) dispersed in water so that the oil power becomes 2% by weight was added to the emulsion containing 30 ml of the influenzawacchin-containing emulsion prepared in Example 1.
  • 1.35 g and ⁇ -cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd .; the same applies hereinafter) (1.65 g) were added thereto, followed by stirring and mixing. This was freeze-dried to obtain an emulsion containing powdered influenza vaccin.
  • Example 20 An aqueous solution of influenza enzyme vaccine is gradually added and mixed, and diluted with PBS so that the oil amount becomes 2% by weight, and the antigen amount is adjusted to 5.4 ng / m 2. Thus, an emulsion containing 1 influenza vaccine was obtained. This was freeze-dried to obtain an emulsion containing powdered influenza vaccine.
  • Example 20
  • an aqueous solution of influenzae protein is gradually added and mixed, and diluted with PBS so that the oil amount becomes 2% by weight, and the antigen amount is adjusted to 5.4 g / antigen.
  • ml of emulzine containing influenza enquin was obtained. This was freeze-dried to obtain an emulsion containing powdered influenza vaccine.
  • Polyoxyethylene sorbitan monooleate 24.3 g, sorbitan sesquioleate 2.7 g, glycerin 3.6 g and a small amount of water Were mixed and heated and melted at 60 ° C. To this, 79 g of arabia rubber and 12.7 g of 3-cyclodextrin dispersed in water were added and mixed with stirring. 60 g of soybean oil was gradually added to this mixture with stirring.
  • influenza enzyme vaccine aqueous solution is gradually added and mixed, and the mixture is diluted with PBS so that the oil amount becomes 2% by weight, and the antigen amount is 5.4 ug / m 1.
  • An emulsion containing INFLUENWA ACTIN was obtained.
  • an influenza enzyme vaccine aqueous solution is gradually added and mixed, and diluted with PBS so that the oil amount becomes 2% by weight, and the antigen amount is adjusted to 5.4 / xg. Z ml of the influenza enantione containing emulsion was obtained. This was freeze-dried to obtain an emulsion containing powdered influenza vaccin.
  • Polyoxyethylene hardened castor oil (trade name: HCO — 60: manufactured by Nikko Chemicals) 8. lg, 0.9 g of solvitan sesquioleate, and sugar-powered prill Mix 9.0 g of acid ester (trade name: SM-880: manufactured by Mitsubishi Chemical Foods Co., Ltd.), heat and melt at 6, mix 3.6 g of glycerin and a small amount Of water were mixed at room temperature.
  • 60 g of soybean oil manufactured by Nakarai Tesk was gradually added with stirring.
  • Example 2 4 An aqueous solution of influenza enzyme vaccine was gradually added and mixed, and diluted with PBS so that the oil amount became 10% by weight, and the antigen amount was adjusted to 2%. An emulsion containing 7 g / m 1 of influenza enzyme was obtained.
  • Example 2 4 An aqueous solution of influenza enzyme vaccine was gradually added and mixed, and diluted with PBS so that the oil amount became 10% by weight, and the antigen amount was adjusted to 2%. An emulsion containing 7 g / m 1 of influenza enzyme was obtained.
  • Example 2 4 An emulsion containing 7 g / m 1 of influenza enzyme was obtained.
  • Example 18 When the powdered influenza vaccine-containing emulsion lg prepared in Example 18 was dissolved in water or 900 g of PBS, it was promptly dissolved within 30 minutes. It re-dispersed, and no oil was found 1 hour after re-dispersion.
  • a centrifugal flow-type coating granulator (SPIR-A-FLOW: manufactured by Freund Sangyo Co., Ltd.) was added to the emulsion containing powdered influenza enquin obtained in Example 18. ) And enteric coating was applied.
  • Table 2 shows the formulation of the enteric coating solution when applying the enteric coating.
  • the enteric coating amount was adjusted so that the content of HPMC-AS was about 15% by weight based on the powdered influenza emulsion-iodinated vaccine.
  • the obtained emulsion preparation containing enteric powder influenza vaccin was suitable for the disintegration test according to the disintegration test method of the Japanese Pharmacopoeia method in accordance with the section on enteric preparations.
  • Example 18 The emulsion containing powdered influenza en- quatin obtained in Example 18 was filled in a hard capsule, and the PAN coating apparatus (HI—CORTER.48N type: Freon) was used. Enteric coating was applied to the product. Enteric coating formulation was performed in the same manner as above.
  • the influenzawacutin-containing emulsion prepared in Example 1 was applied to a mouse (ddY female, 6 to 7 weeks old: 10 mice per group, the same applies hereinafter) at a dose of 27 g / ml via lml.
  • Primary immunization Blood was collected 3 weeks after administration, a secondary immunization was performed under the same conditions as the primary immunization, and blood was collected 2 weeks later (5 weeks after the primary immunization). Blood bleeding obtained 3 and 5 weeks after these immunizations was evaluated.
  • Table 3 shows the results of evaluation of the amount of these specific antibodies in the blood by measuring the HI titer (hemarginitin-in-hip-pass assay). Generally, this HI titer is considered to be effective (antibody amount capable of protecting infection) above 128 HI.
  • the influenzazawacin-containing emulsion prepared in Example 2 was orally administered (primary immunization) with 27 g of Zml to the mouse. Blood was collected 3 weeks after the administration, a secondary immunization was performed under the same conditions as the primary immunization, and blood was collected 2 weeks later (5 weeks after the primary immunization). Serum obtained 3 and 5 weeks after these immunizations was used for evaluation. The amounts of specific antibodies in the blood were evaluated by measuring the HI titer. The results are shown in Table 4.
  • the emulsion containing influenza vaccine prepared in Example 3 The mouse was orally administered with 27 ml of izg Zml (primary immunization). Blood was collected three weeks after administration, and the obtained serum was used for evaluation. The amount of specific antibodies in these blood was evaluated by measuring the HI titer. Table 5 shows the results.
  • influenza warpactin-containing emulsion prepared in Example 4 was orally administered (primary immunization) to the mouse with 27 ml of Zml in an amount of lml. Blood was collected 3 weeks after administration, and the obtained serum was used for evaluation. The amount of specific antibodies in these blood was evaluated by measuring the HI titer. Table 6 shows the results.
  • the emulsion containing the influenza vaccine prepared in Example 5 was orally administered (primary immunization) to the mouse with 27 ml of Z ml in an amount of 1 ml. Blood was collected 3 weeks after administration, and the obtained serum was used for evaluation. The amount of specific antibodies in the blood was evaluated by measuring the HI titer. Was performed. Table 7 shows the results.
  • the influenza enzym- cin-containing emulsion prepared in Example 6 was orally administered (primary immunization) with 27 ig Zml to the mouse. Three weeks after administration, blood was collected, and the obtained serum was used for evaluation. The amount of the specific antibody in the blood was evaluated by measuring the HI titer. Table 8 shows the results.
  • the emulsion containing the influenza warpactin prepared in Example 7 was orally administered (primary immunization) to the mouse with 1 ml / 27 / xg Z ml. Three weeks after administration, blood was collected, and the obtained serum was used for evaluation. The amount of specific antibodies in these blood was evaluated by measuring the HI titer. Table 9 shows the results. [Table 9]
  • Test Example 8 The mice were administered orally (primary immunization) with 27 wg Zml of the emulsion containing influenzacactin prepared in Example 23 to the mouse at 27 wg Zml. Blood was collected 3 weeks after administration, a secondary immunization was performed under the same conditions as the primary immunization, and blood was collected 2 weeks later (5 weeks after the primary immunization). The sera obtained 3 and 5 weeks after these immunizations were used for evaluation.
  • Example 18 Using the sample of Example 18 to confirm the antigenicity of the emulsion before pulverization and the redispersion emulsion after pulverization in vitro, it was confirmed that the influenza enzyme was used. The amount of antigen was almost the same as that of the control solution. Thus, it is considered that there is no decrease in antigenicity due to powderization. • experimental method
  • Each sample was prepared with PBS so as to be 5 CCA nom 1, a calibration curve was prepared using an influenza vaccine solution, and the working curve was determined from the absorbance measured by the ELISA method.
  • the antigen amount of the sample was calculated using the antigen amount of the tin solution as a theoretical value.
  • the primary antibody is anti-HA protein (mouse IgG clone G7G12) 10 g / m1 (X200, in PBS (1)). ) was added in 50 ⁇ 1 wells, coated, and left for 1 ⁇ with 4.
  • Block Ace (X4, distilled water) was added to 200 1 1 ⁇ Z well and left at 4 for 1 ⁇ .

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Abstract

On prépare cette émulsion de type huile dans eau, contenant un vaccin et destinée à une administration orale, en émulsifiant un immunogène, lequel peut servir à immuniser l'homme ou l'animal, avec une matière grasse, et ce dans un milieu aqueux contenant un alcool polyhydrique, en utilisant au moins un tensioactif non ionique et hydrophile, ainsi qu'au moins un tensioactif non ionique et lipophile. On décrit également une poudre contenant un vaccin, destinée à une administration orale et obtenue par séchage de l'émulsion.
PCT/JP1997/000351 1996-02-13 1997-02-10 Emulsion et poudre renfermant un vaccin et destinees a une administration orale, et procede de production associe WO1997029773A1 (fr)

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AU16711/97A AU1671197A (en) 1996-02-13 1997-02-10 Vaccine-containing emulsion and vaccine-containing powder for oral administration and process for producing the same

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JP2548296 1996-02-13
JP8/25482 1996-02-13

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
WO2004039399A1 (fr) * 2002-11-01 2004-05-13 Glaxosmithkline Biologicals S.A. Composition immunogene
WO2004108156A1 (fr) * 2003-06-06 2004-12-16 Changchun Institute Of Biological Products Vaccin combine a injection intradermique contenant hevac et bcg et son procede de preparation
JP2006512401A (ja) * 2001-06-05 2006-04-13 ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン ナノエマルジョンワクチン
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US8877208B2 (en) 2008-05-23 2014-11-04 The Regents Of The University Of Michigan Multivalent nanoemulsion vaccines
US8962026B2 (en) 2008-09-26 2015-02-24 The Regents Of The University Of Michigan Nanoemulsion therapeutic compositions and methods of using the same
US9839685B2 (en) 2006-04-13 2017-12-12 The Regents Of The University Of Michigan Methods of inducing human immunodeficiency virus-specific immune responses in a host comprising nasally administering compositions comprising a naonemulsion and recombinant GP120 immunogen
US10138279B2 (en) 2006-04-13 2018-11-27 Regents Of The University Of Michigan Compositions and methods for Bacillus anthracis vaccination

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JPH05294845A (ja) * 1991-11-25 1993-11-09 Nisshin Oil Mills Ltd:The 免疫原組成物
JPH05508385A (ja) * 1989-05-25 1993-11-25 カイロン　コーポレイション サブミクロン油滴乳剤を含んで成るアジュバント製剤
JPH06507172A (ja) * 1991-04-19 1994-08-11 アフィニティー　バイオテック，インコーポレイテッド 転換可能なミクロエマルジョン処方剤
WO1995011700A1 (fr) * 1993-10-29 1995-05-04 Pharmos Corp. Emulsions submicroniques utilisees comme adjuvants de vaccin

Patent Citations (4)

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JPH05508385A (ja) * 1989-05-25 1993-11-25 カイロン　コーポレイション サブミクロン油滴乳剤を含んで成るアジュバント製剤
JPH06507172A (ja) * 1991-04-19 1994-08-11 アフィニティー　バイオテック，インコーポレイテッド 転換可能なミクロエマルジョン処方剤
JPH05294845A (ja) * 1991-11-25 1993-11-09 Nisshin Oil Mills Ltd:The 免疫原組成物
WO1995011700A1 (fr) * 1993-10-29 1995-05-04 Pharmos Corp. Emulsions submicroniques utilisees comme adjuvants de vaccin

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6660286B1 (en) 1997-01-07 2003-12-09 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6667048B1 (en) 1997-01-07 2003-12-23 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6982282B2 (en) 1997-01-07 2006-01-03 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
JP2013253086A (ja) * 2001-06-05 2013-12-19 Regents Of The Univ Of Michigan ナノエマルジョンワクチン
JP2006512401A (ja) * 2001-06-05 2006-04-13 ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン ナノエマルジョンワクチン
JP2010195788A (ja) * 2001-06-05 2010-09-09 Regents Of The Univ Of Michigan ナノエマルジョンワクチン
US8409587B2 (en) 2002-11-01 2013-04-02 Glaxosmithkline Biologicals S.A. Immunogenic composition
WO2004039399A1 (fr) * 2002-11-01 2004-05-13 Glaxosmithkline Biologicals S.A. Composition immunogene
US7579003B2 (en) 2003-06-06 2009-08-25 Changchun Institute Of Biological Products HBsAg-BCG combined vaccine for intracutaneous injection and preparation method thereof
WO2004108156A1 (fr) * 2003-06-06 2004-12-16 Changchun Institute Of Biological Products Vaccin combine a injection intradermique contenant hevac et bcg et son procede de preparation
US9839685B2 (en) 2006-04-13 2017-12-12 The Regents Of The University Of Michigan Methods of inducing human immunodeficiency virus-specific immune responses in a host comprising nasally administering compositions comprising a naonemulsion and recombinant GP120 immunogen
US10138279B2 (en) 2006-04-13 2018-11-27 Regents Of The University Of Michigan Compositions and methods for Bacillus anthracis vaccination
US8877208B2 (en) 2008-05-23 2014-11-04 The Regents Of The University Of Michigan Multivalent nanoemulsion vaccines
US9415006B2 (en) 2008-05-23 2016-08-16 The Regents Of The University Of Michigan Immunogenic compositions comprising nanoemulsion and hepatitis B virus immunogen and methods of using the same
US8962026B2 (en) 2008-09-26 2015-02-24 The Regents Of The University Of Michigan Nanoemulsion therapeutic compositions and methods of using the same
US9259407B2 (en) 2008-09-26 2016-02-16 The Regents Of The University Of Michigan Nanoemulsion therapeutic compositions and methods of using the same

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