WO2020111248A1 - Vaccine preparation - Google Patents
Vaccine preparation Download PDFInfo
- Publication number
- WO2020111248A1 WO2020111248A1 PCT/JP2019/046846 JP2019046846W WO2020111248A1 WO 2020111248 A1 WO2020111248 A1 WO 2020111248A1 JP 2019046846 W JP2019046846 W JP 2019046846W WO 2020111248 A1 WO2020111248 A1 WO 2020111248A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fatty acid
- acid ester
- vaccine preparation
- antigen
- aqueous phase
- Prior art date
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Definitions
- the present invention relates to a vaccine preparation capable of excellent immunity induction by transdermal administration.
- cancer immunotherapy has attracted attention as an effective method with few side effects.
- cancer vaccine therapy that induces antibody production and cell-mediated immunity against cancer cells has few side effects and can be used in combination with the above three major therapies. There is.
- the skin has a strong immune function to resist the invasion of foreign substances from the outside, and Langerhans cells present in the epidermis are more strongly cytotoxic than other dendritic cells. It has been reported that a response can be induced (see Non-Patent Documents 1 and 2). Therefore, if the vaccine preparation can be transdermally administered and the antigen can be permeated from the skin surface and delivered to the Langerhans cells, effective induction of an immune response can be expected. Further, the transdermal administration of the vaccine preparation can be performed by the patient himself and is non-invasive, so that there is an advantage that the administration is simple and the burden on the patient is small. As described above, the vaccine preparation for transdermal administration can be expected to overcome the drawbacks of the injection preparation and achieve both excellent vaccine effect and convenience.
- the stratum corneum located in the outermost layer of the epidermis prevents foreign substances from entering from the outside as a strong biological barrier, and can only penetrate oil-soluble substances or low molecular weight substances having a molecular weight of 500 Da or less (non-patent reference) Reference 3).
- protein antigens and peptide antigens generally used as vaccines are hydrophilic and have a high molecular weight, it is difficult to deliver them even to Langerhans cells existing under the stratum corneum just by applying them to the skin.
- the hydrophilic gel patch containing an antigen has an overwhelmingly low utilization rate of the antigen as compared with an injection (see Non-Patent Document 4).
- An object of the present invention is to provide a vaccine preparation capable of excellent immunity induction by transdermal administration.
- the inventors of the present invention have conducted extensive studies to solve the above problems, and include an aqueous phase in which an antigen is dissolved, a glycerin fatty acid ester and/or a polyglycerin fatty acid ester, and an oil phase, and the aqueous phase is the oil phase. It has been found that the vaccine preparation dispersed in A. can induce immunity superior to that by injection when administered transdermally. The present invention has been completed by further studies based on such findings.
- Item 1 A vaccine preparation for transdermal administration, comprising an aqueous phase in which an antigen is dissolved, a glycerin fatty acid ester and/or a polyglycerin fatty acid ester, and an oil phase, wherein the aqueous phase is dispersed in the oil phase.
- Item 2. Item 2. The vaccine preparation for transdermal administration according to Item 1, wherein the origin of the antigen is a cancer cell, a pathogenic virus, a pathogenic bacterium, a pathogenic organism, or pollen.
- Item 3. Item 3. The vaccine preparation for transdermal administration according to Item 1 or 2, wherein the antigen is an antigen peptide or an antigen protein.
- Item 4. The vaccine preparation for transdermal administration according to any one of Items 1 to 3, wherein the glycerin fatty acid ester is glyceryl monooleate.
- Item 5. The vaccine preparation for transdermal administration according to any one of Items 1 to 4, wherein the content of the glycerin fatty acid ester and/or the polyglycerin fatty acid ester is 0.1 to 30% by weight.
- a vaccine preparation for transdermal administration of a composition comprising an aqueous phase in which an antigen is dissolved, glycerin fatty acid ester and/or polyglycerin fatty acid ester, and an oil phase, wherein the aqueous phase is dispersed in the oil phase
- Item 7 An immune-inducing effective amount of a composition containing an aqueous phase in which an antigen is dissolved, glycerin fatty acid ester and/or polyglycerin fatty acid ester, and an oil phase, the aqueous phase being dispersed in the oil phase,
- An immunity-inducing method comprising the step of transdermal administration to an animal in need.
- transdermal administration enables superior immunity induction over injection administration, and thus is excellent in allergen immunotherapy for allergy such as cancer immunotherapy, infectious disease prevention, and pollinosis. It is possible to exert a therapeutic or preventive effect. Further, since the vaccine preparation of the present invention can effectively induce immunity by transdermal administration, it can be used in a non-invasive, safe and simple manner.
- FIG. 3 is a diagram schematically showing a schedule of an immunity induction experiment in Test Example 1.
- FIG. 5 is a diagram showing the results of measuring the tumor volume over time in the immunity induction experiment in Test Example 1.
- tumors taken out 14 days after transplantation were stained with APC-labeled anti-CD8 antibody and DAPI, and observed with a fluorescence microscope.
- FIG. FIG. 6 is a diagram schematically showing a schedule of an immunity induction experiment in Test Example 2.
- FIG. 8 is a diagram schematically showing a schedule of an immunity induction experiment in Test Example 3.
- FIG. 8 is a diagram showing the results of measuring the serum concentration of anti-influenza A(H3N2) antibody in the transdermal administration group of Example 3 and the transdermal administration group of Comparative Example 3 in the immunity induction experiment in Test Example 3.
- the vaccine preparation of the present invention is a vaccine preparation for transdermal administration, comprising an aqueous phase in which an antigen is dissolved, a glycerin fatty acid ester and/or a polyglycerin fatty acid ester, and an oil phase, the aqueous phase being the oil phase. It is characterized by being dispersed.
- the vaccine preparation of the present invention will be described in detail.
- the aqueous phase is composed of a solution in which the antigen is dissolved.
- the hydrophilic portion of the glycerin fatty acid ester and/or the polyglycerin fatty acid ester is associated with the water phase, and the water phase is in a WO emulsion form in which the water phase is dispersed in the oil phase.
- a reverse micelle coated with glycerin fatty acid ester and/or polyglycerin fatty acid ester around the aqueous phase is formed and emulsified, or around the aqueous phase, glycerin fatty acid ester and/or polyglycerin fatty acid ester is formed. It is presumed that the aqueous phase is in an emulsified state in which it is emulsified particles even if the glycerin fatty acid ester is not completely covered.
- each component contained in the aqueous phase will be described.
- the antigen used in the present invention is not particularly limited as long as it is capable of inducing an immune response in vivo as an immunogen of a vaccine and is water-soluble.
- the antigen protein refers to a protein that is specifically expressed or present in a pathogen or an allergen and induces an immune response.
- the antigen peptide refers to a peptide derived from an antigen protein (for example, an antigen protein having a reduced molecular weight).
- the antigen protein and the antigen peptide may be those capable of inducing antigen-specific T cells by directly forming a complex with the MHC molecule (HLA molecule) on the cell surface of the antigen-presenting cell.
- HLA molecule MHC molecule
- a peptide fragment that is taken up into cells and then decomposed into cells binds to MHC molecules to form a complex, and the complex is presented on the cell surface to generate antigen-specific T cells. It may be inducible.
- an antigen peptide is a suitable example of the antigen.
- the number of amino acid residues of the antigen peptide is not particularly limited, but examples thereof include 2 to 50, preferably 7 to 31, and more preferably about 8 to 20.
- the origin of the antigen is not particularly limited, but examples thereof include cancer cells, pathogenic viruses, pathogenic bacteria, pathogenic organisms, pollen, and the like.
- As the origin of the antigen specifically, melanoma, pancreatic cancer, lung cancer, osteosarcoma, colon cancer, colon cancer, gastric cancer, rectal cancer, liver cancer, breast cancer, bladder cancer, prostate cancer, cervical cancer, head and neck cancer, bile duct cancer.
- Cancer cells such as solid cancers such as gallbladder cancer, oral cancer, brain tumors, and blood cancers such as leukemia and malignant lymphoma; influenza virus, avian influenza virus, parainfluenza virus, adenovirus, SARS virus, AIDS virus, cytomegalo Viral, hepatitis virus, Japanese encephalitis virus, measles virus, rubella virus, varicella-zoster virus, polio virus, papilloma virus, herpes virus, mumps virus, rotavirus, cholera virus, rabies virus, HIV and other pathogenic viruses; diphtheria , Tetanus, tubercle bacillus, pneumococcus, meningococcus, staphylococcus, aeruginosa, pertussis, anthrax, salmonella and other pathogenic bacteria; malaria parasites, mites and other pathogenic organisms; cedar pollen, Examples include pollen such as cypress pollen and bir
- the content of the antigen in the aqueous phase is, for example, 0.001 to 60% by weight, preferably 0.001 to 50% by weight, more preferably 0.001 to 40% by weight. %, more preferably 0.1 to 25% by weight, particularly preferably 0.1 to 5% by weight.
- the content of the antigen in the vaccine preparation of the present invention may be appropriately set according to the type of the antigen, the condition of the patient, the dose, etc., but is, for example, 0.0001 to 5% by weight, preferably 0.0001 to 3. 5% by weight, more preferably 0.0001 to 2.5% by weight, particularly preferably 0.01 to 2% by weight.
- the aqueous phase contains an aqueous phase base for dissolving the antigen.
- the type of aqueous phase base is not particularly limited as long as it can dissolve the antigen, and examples thereof include water, a monohydric lower alcohol, and a mixed solution thereof.
- the water used as the aqueous phase base may be purified water, ultrapure water, or the like, as well as a buffer solution, physiological saline, or the like.
- Examples of monohydric lower alcohols used as the aqueous phase base include monohydric alcohols having 2 to 5 carbon atoms.
- Examples thereof include ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-amyl alcohol, sec-amyl alcohol, isoamyl alcohol, tert-amyl alcohol and neopentyl alcohol.
- These monohydric lower alcohols may be contained alone or in combination of two or more.
- a preferable embodiment of the aqueous phase base is a mixed solution of water and a monohydric lower alcohol, more preferably a mixed solution of water and isopropanol.
- another preferable embodiment of the aqueous phase base is water or an aqueous solution (buffer solution, physiological saline, etc.) containing no monohydric lower alcohol.
- the mixing ratio of these is not particularly limited, but for example, 1 to 50 parts by weight of the monohydric lower alcohol per 1 part by weight of water.
- the ratio is preferably 1 to 45 parts by weight, more preferably 1 to 40 parts by weight, and particularly preferably 1 to 20 parts by weight.
- the content of the aqueous phase base in the aqueous phase is, for example, 40 to 99.999% by weight.
- the lower limit of the content of the aqueous phase base in the aqueous phase is preferably 50% by weight or more, more preferably 60% by weight or more, and further preferably 95% by weight. The above is mentioned.
- the upper limit of the content of the aqueous phase base in the aqueous phase is preferably 99.9% by weight or less, more preferably 99% by weight or less.
- the content of the aqueous phase base in the aqueous phase is preferably 50 to 99.999% by weight, more preferably 60 to 99.999% by weight, and further preferably 75 to 99.9% by weight. , Particularly preferably 95 to 99.9% by weight.
- the content of the aqueous phase base in the vaccine preparation of the present invention is, for example, 0.1 to 50% by weight. From the viewpoint of inducing even more excellent transdermal immunity, the content of the aqueous phase base in the vaccine preparation of the present invention is preferably 0.1 to 40% by weight, more preferably 0.1 to 30% by weight, and further preferably Is 0.5 to 30% by weight, particularly preferably 5 to 20% by weight.
- the glycerin fatty acid ester and/or the polyglycerin fatty acid ester plays a part or all in association with the aqueous phase, plays a role of dispersing the aqueous phase in the oil phase and emulsifying, and transdermal administration. Plays a role in enabling superior immunity induction.
- Glycerin fatty acid ester is a monoester, diester, or triester of fatty acid and glycerin.
- the number of carbon atoms of the fatty acid constituting the glycerin fatty acid ester is, for example, 6 to 24, preferably 8 to 22 and more preferably 12 to 18.
- Specific examples of the glycerin fatty acid ester include glyceryl monomyristate, glyceryl monostearate, glyceryl monoisostearate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, and glyceryl distearate.
- monoesters of fatty acids and glycerin are preferable, and glyceryl monooleate is more preferable.
- Polyglycerin fatty acid ester is an ester of fatty acid and polyglycerin.
- the number of ester bonds (the number of fatty acids bound to one molecule of polyglycerin) is, for example, 1 to 10, preferably 1 to 6, and more preferably 1 to 3.
- the carbon number of the fatty acid constituting the polyglycerin fatty acid ester is, for example, 6 to 24, preferably 8 to 22, and more preferably 12 to 18.
- the degree of polymerization of polyglycerin that constitutes the polyglycerin fatty acid ester is, for example, 2 to 30, and preferably 2 to 10.
- polyglycerin fatty acid ester polyglyceryl-2 stearate (diglyceryl monostearate), polyglyceryl-2 oleate (diglyceryl monooleate), polyglyceryl-4 oleate (tetraglyceryl monooleate), Polyglyceryl oleate-10 (decaglyceryl monooleate), polyglyceryl-5 trioleate (pentaglyceryl trioleate), polyglyceryl-10 trioleate (decaglyceryl trioleate), polyglyceryl-10 palmitate (monopalmitic acid) Decaglyceryl), polyglyceryl-2 isostearate, polyglyceryl-2 triisostearate, polyglyceryl-4 stearate, polyglyceryl tristearate-6, polyglyceryl pentastearate-10, polyglyceryl pentahydroxystearate-10, polyglyceryl pentaisostearate- 10, polyglyceryl-10 penta
- one of the glycerin fatty acid ester and the polyglycerin fatty acid ester may be used alone, or two or more thereof may be used in combination.
- glycerin fatty acid ester and polyglycerin fatty acid ester from the viewpoint of inducing even more excellent transdermal immunity, preferably glycerin fatty acid ester, more preferably monoester of fatty acid and glycerin, more preferably glyceryl monooleate. Can be mentioned.
- the ratio of the aqueous phase (dissolved liquid) to the glycerin fatty acid ester and/or polyglycerin fatty acid ester is, for example, the total amount of glycerin fatty acid ester and/or polyglycerin fatty acid ester per 1 part by weight of the aqueous phase.
- aqueous phase dissolved liquid
- the ratio of the aqueous phase (dissolved liquid) to the glycerin fatty acid ester and/or polyglycerin fatty acid ester is, for example, the total amount of glycerin fatty acid ester and/or polyglycerin fatty acid ester per 1 part by weight of the aqueous phase.
- At 0.5 to 200 parts by weight preferably 0.5 to 75 parts by weight, more preferably 0.5 to 50 parts by weight, further preferably 0.5 to 40 parts by weight, particularly preferably 0.5 to 3 parts by weight. Parts.
- the content of glycerin fatty acid ester and/or polyglycerin fatty acid ester in the vaccine preparation of the present invention is, for example, 0.1 to 30% by weight, preferably 0.25 to 27.5% by weight, more preferably 0.5. Up to 25% by weight.
- the oil phase serves as a dispersion medium for the aqueous phase, and is formed of an oil phase base such as liquid oil, solid oil and higher alcohol.
- -Liquid oil is an oil that maintains a liquid form at 25°C.
- the liquid oil used in the present invention may be one normally used in cosmetics and external medicines, for example, avocado oil, camellia oil, macadamia atsutu oil, olive oil, almond oil, soybean oil, jojoba oil, Vegetable oils such as cottonseed oil, rapeseed oil, sesame oil, perilla oil, cinnamon oil, corn oil, peanut oil, sunflower oil, cacao oil, mint oil, bergamot oil, fennel oil, etc.; fatty acids such as oleic acid, isostearic acid; ethylhexanoic acid Cetyl, ethylhexyl palmitate, octyldodecyl myristate, neopentyl glycol diethylhexanoate, glyceryl tri-2-ethylhexanoate, octyldodecyl o
- Solid oil is an oil that maintains a solid form at 25°C.
- the solid oil used in the present invention may be one normally used for cosmetics and external medicines, for example, candelilla wax, rice bran wax, beeswax, cotton wax, carnauba wax, lanolin, shellac wax, ozokerite, ceresin, Polyethylene wax, microcrystalline wax, paraffin, petrolatum, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, 12-hydroxystearic acid, undecylenic acid, myristyl myristate, cetyl myristate, stearyl stearate, cetyl stearate.
- Solid oils such as cetyl palmitate, cholesteryl stearate, cholesteryl oleate, dextrin palmitate, inulin stearate, hydrogenated jojoba oil, ceresin wax, solid paraffin wax, polyethylene wax and silicone wax. These solid oils may be used alone or in combination of two or more.
- Higher alcohol is a monohydric alcohol having 6 or more carbon atoms in one molecule.
- the number of carbon atoms in one molecule in the higher alcohol used in the present invention may be 6 or more, preferably 6 to 34, more preferably 14 to 22.
- the higher alcohol used in the present invention may be one normally used in cosmetics and external medicines, for example, lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, cetostearyl alcohol, cetanol, oleyl.
- Examples thereof include linear higher alcohols such as alcohols; branched higher alcohols such as nostearyl glycerin ether (batyl alcohol). These higher alcohols may be used alone or in combination of two or more.
- liquid oil is preferable.
- the ratio of the water phase and the oil phase is, for example, 1 to 1000 parts by weight, preferably 1.5 to 1000 parts by weight, and more preferably 2 to 1 part by weight of the oil phase.
- the amount is 1000 parts by weight, more preferably 2.5 to 200 parts by weight, and particularly preferably 2.5 to 10 parts by weight.
- the content of the oil phase in the vaccine preparation of the present invention is not particularly limited and may be appropriately set according to the type of the oil phase base used, for example, 40 to 99.8% by weight, preferably 50 to 99.7% by weight, more preferably 55 to 99.4% by weight.
- the vaccine preparation of the present invention may contain an adjuvant in order to further improve the induction of transdermal immunity.
- the adjuvant include CpG oligodeoxynucleotide, Freund, aluminum hydroxide (Alum), alum and the like.
- the vaccine preparation of the present invention may contain other bases and additives required for formulation and the like, in addition to the above-mentioned components, if necessary.
- additives are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, for example, preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), Flavoring agents (citral, 1,8-cionele, citronellal, farnesol, etc.), colorants (tar pigments (brown 201, blue 201, yellow 4, yellow 403, etc.), cacao pigments, chlorophyll, aluminum oxide, etc.
- thickeners (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, etc.), pH adjusters (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid) , Sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agent (sodium dl-pyrrolidonecarboxylate solution, D-sorbitol solution, macrogol, etc.), stabilizer (dibutylhydroxytoluene, butylhydroxy) Anisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary
- the water-soluble component may be added to the water-soluble fraction, and the lipophilic component may be added to the oil phase. It may be set appropriately according to
- the vaccine preparation of the present invention is a water-in-oil type (W/O type) emulsified form in which an aqueous phase is dispersed in an oil phase.
- the vaccine preparation of the present invention may be further dispersed in an aqueous phase according to a conventional method to give a W/O/W type preparation.
- the dosage form of the vaccine preparation of the present invention is not particularly limited as long as it can be applied transdermally, and examples thereof include creams, ointments, gels, poultices, lotions, liniments, and aerosols. Can be mentioned. Of these, creams, ointments, emulsions and lotions are preferable.
- the vaccine preparation of the present invention can be produced according to a known formulation method for emulsified preparations.
- the components to be contained are divided into a water-soluble component and an oil component, a solution containing the water-soluble component (aqueous phase component), an oil component and a glycerin fatty acid ester and/or Examples include a method of preparing a mixed solution containing a polyglycerin fatty acid ester (oil phase component and glycerin fatty acid ester and/or polyglycerin fatty acid ester), and emulsifying them according to a known method.
- a solution in which an antigen is dissolved in an aqueous phase base, and a mixed solution containing glycerin fatty acid ester and/or polyglycerin fatty acid ester and an oil phase base are prepared, and the solution and the mixed solution are mixed.
- the vaccine formulation of the present invention can be produced by mixing and emulsifying.
- the vaccine formulation of the present invention is transdermally administered and used to induce immunity.
- the conventional vaccine preparation for general transdermal administration has a drawback that the antigen utilization rate is low and immunity cannot be sufficiently induced, but the vaccine preparation of the present invention induces immunity superior to injection administration by transdermal administration. It is possible to produce an effect.
- the vaccine preparation of the present invention is used for cancer immunotherapy, infectious disease prevention, allergen immunotherapy for allergies such as hay fever, etc., depending on the type of antigen contained, but it can be suitably used for cancer immunotherapy. ..
- the subject of administration of the vaccine preparation of the present invention is not particularly limited as long as it is an animal for which the immunity induction is required, and examples thereof include humans, monkeys, mice, rats, dogs, rabbits, cats, cows, horses, goats and the like. Mammals: Birds such as chickens and ostriches are mentioned.
- the dose of the vaccine preparation of the present invention is appropriately set according to the type of antigen used, symptoms of the subject to be administered, age, body weight, etc., but when the subject animal is a human, it is usually administered once a day.
- the antigen may be transdermally administered in an amount equivalent to 3 to 12 mg/kg once to several times, preferably once a day (primary immunization).
- the vaccine preparation of the present invention may be re-administered usually 1 to 2 weeks after the initial immunization under the same conditions as the initial immunization (boost).
- the skin site to which the vaccine preparation of the present invention is administered is not particularly limited, but, for example, in the case of humans, the upper arm, chest, back, etc. may be mentioned, and in the case of non-human animals, the back, ear. An intermediary part and the like can be mentioned.
- Test example 1 Preparation of formulation Each formulation having the composition shown in Table 1 was prepared by the following method.
- Example 1 and Comparative Example 1 A predetermined amount of melanoma antigen peptide (K-TRP-2, amino acid sequence: KKKGSVYDFFVWL, tyrosinase-related protein 2 at the N-terminal side of the peptide consisting of amino acids 180 to 188) was added to an aqueous phase base (purified water and isopropanol). A lysate was prepared by dissolving a glycine residue and a peptide to which three lysine residues were added.
- K-TRP-2 amino acid sequence: KKKGSVYDFFVWL, tyrosinase-related protein 2 at the N-terminal side of the peptide consisting of amino acids 180 to 188
- a predetermined amount of a surfactant (glyceryl monooleate or polyoxyethylene sorbitan monooleate (Tween 80)) was added to liquid oil (isopropyl myristate) and heated at 70° C. for 10 minutes to completely dissolve it. . While stirring a predetermined amount of the solution, the solution was dropped little by little. By stirring this until it reached room temperature, a vaccine formulation in a water-in-oil emulsified form containing melanoma antigen peptide (a form in which the water phase was dispersed in the oil phase and emulsified by the reverse micelle) was obtained.
- a surfactant glyceryl monooleate or polyoxyethylene sorbitan monooleate (Tween 80)
- aqueous vaccine preparation was obtained by adding a predetermined amount of a predetermined amount of melanoma antigen peptide (K-TRP-2) to a phosphate buffer (PBS) and dissolving it.
- K-TRP-2 melanoma antigen peptide
- PBS phosphate buffer
- mice C57BL/6N, female were divided into four test groups shown in Table 2 (6 mice per group), and the first day (Day-14) under the conditions shown in Table 2 Immunization, one week later (Day -7), booster immunization was performed.
- the amount of each component administered in each of the primary immunization and the booster immunization is as shown in Table 1.
- mice melanoma cells (B16F10) suspended in HBSS( ⁇ ) medium at 1.0 ⁇ 10 6 cells/ml was transplanted subcutaneously to each mouse. (Day 0).
- the major axis and minor axis of the tumor were measured every 2 days from 5 days after the transplantation of mouse melanoma cells, and the tumor volume was calculated based on the following formula.
- Example 14 14 days after the transplantation of mouse melanoma cells, the tumor was taken out from the skin, the tumor was cut to a thickness of 20 ⁇ m, and placed on a slide glass. It was stained with a phycocyanin (APC)-labeled anti-CD8 antibody and DAPI (4′,6-diamidino-2-phenylindole) (Day 14).
- APC phycocyanin
- Fig. 1 shows the experimental schedule
- Fig. 2 shows the results of measuring the tumor volume over time
- Fig. 3 shows the results of staining the tumors taken out 14 days after transplantation with the APC-labeled anti-CD8 antibody and DAPI.
- FIG. 2 shows the tumor volume in the subcutaneous administration group of Comparative Example 1 and the subcutaneous administration group of Comparative Example 2, the tumor volume was large and the induction of cancer immunity was insufficient as compared with the injection administration group of Reference Example 1.
- the tumor volume was smaller than that in the injection administration group of Reference Example 1, and cancer immunity could be effectively induced.
- FIG. 1 shows the experimental schedule
- Fig. 2 shows the results of measuring the tumor volume over time
- Fig. 3 shows the results of staining the tumors taken out 14 days after transplantation with the APC-labeled anti-CD8 antibody and DAPI.
- polyglyceryl-10 trioleate or polyglyceryl isostearate-2 was used to prepare a vaccine preparation for transdermal administration.
- excellent induction of cancer immunity was confirmed even with a vaccine preparation for transdermal administration using polyglyceryl-10 trioleate or polyglyceryl isostearate-2.
- a vaccine preparation for transdermal administration is prepared by replacing the aqueous phase base from a mixed solution of a phosphate buffer and isopropanol with a phosphate buffer alone. When an immunity induction experiment similar to that was conducted, excellent induction of cancer immunity was confirmed.
- a vaccine preparation in which a water-soluble fraction containing a solution in which an antigen is dissolved in water and a glycerin fatty acid ester and/or a polyglycerin fatty acid ester are dispersed in an oil phase is effective for immunity by transdermal administration. It was confirmed that it can be induced.
- Test example 2 1. Preparation of formulation Each formulation having the composition shown in Table 3 was prepared by the following method.
- Example 2 A solution was prepared by dissolving a predetermined amount of pollen antigen peptide (pepA, amino acid sequence: SMKVTVAFNQFGP) in an aqueous phase base (purified water and isopropanol). Separately, a predetermined amount of a surfactant (glyceryl monooleate) was added to a liquid oil (isopropyl myristate) and heated at 70° C. for 10 minutes to completely dissolve it. While stirring a predetermined amount of the solution, the solution was dropped little by little.
- pepA pollen antigen peptide
- aqueous phase base purified water and isopropanol
- a surfactant glyceryl monooleate
- a vaccine formulation in a water-in-oil emulsified form (form in which the water phase was dispersed in the oil phase by the reverse micelle and emulsified) containing the pollen antigen peptide was obtained.
- aqueous vaccine preparation was obtained by adding a predetermined amount of a predetermined amount of pollen antigen peptide (pepA) to a phosphate buffer (PBS) and dissolving it.
- pepA pollen antigen peptide
- PBS phosphate buffer
- mice B10.S, female mice were bred for 1 week in an environment where they could freely ingest water and food, and then acclimatized, and then 10 ⁇ g of pollen antigen extract and Inject? 200 ⁇ l of a phosphate buffer solution (PBS) containing 4 mg of Alum Adjuvant (Thermo Fisher Scientific) was subcutaneously administered to the roots of both legs once a week for a total of 3 times to prepare a pollinosis model mouse. Histamine (20 ng/head) was intranasally administered 6 days after the third subcutaneous administration, and from the next day, pollen exposure was performed once a day for 5 days.
- PBS phosphate buffer solution
- Alum Adjuvant Thermo Fisher Scientific
- the pollen solution was prepared by dissolving a cedar pollen extract (trade name "Cedar pollen extract-Cj", manufactured by LSS Co., Ltd.) in a PBS solution to a concentration of 0.1 mg/mL in both nostrils. By nasal exposure of 10 ⁇ L each.
- a cedar pollen extract trade name "Cedar pollen extract-Cj", manufactured by LSS Co., Ltd.
- PBS solution a concentration of 0.1 mg/mL in both nostrils.
- IgE antibody titer in the blood was measured by ELISA. Twelve mice were selected from the 5th to 34th pollinosis model mice in descending order of IgE antibody titers, and the two groups (1 group) shown in Table 4 were selected so that the average IgE antibody titers in each group were the same. 6 animals) and were bred for 8 days in a normal environment, and then subjected to the initial immunization and booster immunization under the conditions shown in Table 4.
- Histamine (20 ng/head) was intranasally administered 6 days after the completion of the second booster immunization (completion of a total of 3 immunizations), and from the next day, pollen exposure was performed once a day for 5 days.
- a pollen solution prepared by dissolving a cedar pollen extract (trade name “Sugi pollen extract-Cj”, manufactured by ELS Co., Ltd.) in a PBS solution to a concentration of 0.1 mg/mL was applied to both nostrils. By nasal exposure of 10 ⁇ L each.
- blood was collected from the tail of the mouse, and the spleen was extracted.
- Serum was prepared from the obtained blood, and serum concentrations of Crij1-specific IgE antibody and IgG1 antibody were measured by ELISA.
- the obtained spleen was ground and subjected to hemolytic treatment, and then cells were collected by removing impurities with a 70 ⁇ m cell strainer. After culturing the obtained cells in a PRMI1640 medium containing 10% inactivated FBS (fetal bovine serum), 50 ⁇ M 2-mercaptoethanol, and 1% antibiotic/antimycotic mixed solution at 37° C. for 3 days, The culture medium (spleen cell culture medium) was collected. The cytokine (IL-4 and IL-5) concentration in the obtained culture solution was measured by ELISA.
- FIG. 4 shows the experimental schedule
- FIG. 5 shows the results of measuring the serum concentrations of Crij1-specific IgE antibody and IgG1 antibody and the cytokine (IL-4 and IL-5) concentrations in the spleen cell culture medium.
- the antibody concentration in the serum was lower than that in the transdermal administration group of Comparative Example 3, and it was confirmed that the production amount of cytokines involved in allergic reaction can be suppressed. It was
- Test example 3 Preparation of formulation Each formulation having the composition shown in Table 5 was prepared by the following method.
- Example 3 A solution was prepared by dissolving a predetermined amount of influenza virus antigen protein (Influenza A H3N2 (A/Aichi/1968) Hemagglutinin/HA Protein (His tag), Sino Biological) in an aqueous phase base (purified water and isopropanol). did. Separately, a predetermined amount of a surfactant (glyceryl monooleate) was added to a liquid oil (isopropyl myristate) and heated at 70° C. for 10 minutes to completely dissolve it. While stirring a predetermined amount of the solution, the solution was dropped little by little.
- influenza virus antigen protein Influenza A H3N2 (A/Aichi/1968) Hemagglutinin/HA Protein (His tag), Sino Biological
- a predetermined amount of a surfactant glyceryl monooleate
- a vaccine formulation in a water-in-oil emulsified form (form in which the water phase was dispersed in the oil phase by the reverse micelle and emulsified) containing the pollen antigen peptide was obtained.
- a vaccine preparation in a water-in-oil emulsified form (form in which an aqueous phase is dispersed in an oil phase by reverse micelles and emulsified) is prepared in the same manner as in Example 3 except that the influenza virus antigen protein is not included. Obtained.
- mice Female mice were bred for 1 week in an environment where they could freely ingest water and food and acclimated, and then divided into two test groups shown in Table 6 (per group). , 6), and the initial immunization and booster immunization were performed under the conditions shown in Table 6.
- the animals were raised in a normal environment for 3 weeks. Blood was collected from the tail of the mouse once a week from the day of the first immunization. Serum was prepared from the obtained blood and the serum concentration of anti-influenza A(H3N2) antibody was measured by ELISA.
- FIG. 6 shows the experimental schedule
- FIG. 7 shows the measurement results of the serum concentration of anti-influenza A(H3N2) antibody.
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Abstract
The purpose of the present invention is to provide a vaccine preparation that can induce excellent immunity through transdermal administration. This vaccine preparation includes: an aqueous phase having an antigen dissolve therein; glycerin fatty acid ester and/or poly-glycerin fatty acid ester; and an oil phase, wherein the aqueous phase is dispersed in the oil phase. The vaccine preparation can, when being administered transdermally, induce excellent immunity in a manner better than administration through injection.
Description
本発明は、経皮投与によって優れた免疫誘導が可能なワクチン製剤に関する。
The present invention relates to a vaccine preparation capable of excellent immunity induction by transdermal administration.
がんの治療法として、外科手術、放射線療法、及び化学療法の三大療法が確立されているが、近年、副作用が少なく有効な手法としてがん免疫療法が注目を浴びている。がん免疫療法の中でも、がん細胞に対する抗体産生や細胞性免疫を誘導するがんワクチン療法は、副作用が少なく、更に前記三大療法と併用することも可能であり、近年、注目を浴びている。
The three major therapies, surgery, radiation therapy, and chemotherapy, have been established as cancer treatment methods, but in recent years, cancer immunotherapy has attracted attention as an effective method with few side effects. Among cancer immunotherapy, cancer vaccine therapy that induces antibody production and cell-mediated immunity against cancer cells has few side effects and can be used in combination with the above three major therapies. There is.
また、従来、感染症の予防には、人為的な疑似感染により、特定の病原体に対する抗体産生や細胞性免疫を誘導するワクチン免疫法が広く利用されている。
In addition, conventionally, for the prevention of infectious diseases, a vaccine immunization method that induces antibody production against specific pathogens and cell-mediated immunity by artificial artificial infection has been widely used.
このようにがんの治療や感染症の予防には、ワクチンの投与によって獲得免疫を誘導する手法が有効であり、従来、ワクチン製剤が精力的に研究されている。但し、従来開発されているワクチン製剤の大半は注射製剤であり、このような注射製剤では、投与に医療従事者を必要としたり、注射による痛みを伴ったりする欠点がある。
In this way, for the treatment of cancer and prevention of infectious diseases, the method of inducing adaptive immunity by administering a vaccine is effective, and conventionally, vaccine preparations have been vigorously studied. However, most of vaccine formulations that have been conventionally developed are injectable formulations, and such injectable formulations have the drawback that they require medical personnel for administration and are accompanied by pain due to injection.
一方、皮膚には外部からの異物の侵入に抵抗するための強力な免疫機能が備わっており、表皮に存在するランゲルハンス細胞には、他の樹状細胞と比較して強力に細胞障害性T細胞応答を誘導できることが報告されている(非特許文献1及び2参照)。そのため、ワクチン製剤を経皮投与して抗原を皮膚表面から浸透させランゲルハンス細胞へと送達することができれば、効果的な免疫応答の誘導が期待できる。また、ワクチン製剤の経皮投与は、患者自身で行うことができ、しかも非侵襲性であるため、投与が簡便で患者への負担が少ないという利点がある。このように、経皮投与用のワクチン製剤は、注射製剤の欠点を払拭し、優れたワクチン効果と利便性を両立させることが期待できる。
On the other hand, the skin has a strong immune function to resist the invasion of foreign substances from the outside, and Langerhans cells present in the epidermis are more strongly cytotoxic than other dendritic cells. It has been reported that a response can be induced (see Non-Patent Documents 1 and 2). Therefore, if the vaccine preparation can be transdermally administered and the antigen can be permeated from the skin surface and delivered to the Langerhans cells, effective induction of an immune response can be expected. Further, the transdermal administration of the vaccine preparation can be performed by the patient himself and is non-invasive, so that there is an advantage that the administration is simple and the burden on the patient is small. As described above, the vaccine preparation for transdermal administration can be expected to overcome the drawbacks of the injection preparation and achieve both excellent vaccine effect and convenience.
しかしながら、表皮の最外層に位置する角層は、強力な生体バリアとして外部からの異物の侵入を防いでおり、油溶性物質又は分子量500Da以下の低分子量の物質しか浸透することができない(非特許文献3参照)。一般にワクチンとして用いるタンパク質抗原やペプチド抗原は親水性且つ高分子量であるため、皮膚に塗布しただけでは角層の下に存在するランゲルハンス細胞まで送達することは困難である。実際、抗原を含有させた親水性ゲルパッチでは、注射剤に比べて抗原の利用率が圧倒的に低くなることが報告されている(非特許文献4参照)。また、従来、マイクロニードルを用いた経皮ワクチン製剤によって、経皮投与による免疫誘導能を向上させる試みもなされているが、このようなワクチン製剤は、製造工程が煩雑になり、製造コストの増大を招くという欠点がある。このような従来技術を背景として、マイクロニードルを利用せずとも、優れた免疫誘導が可能な経皮投与用ワクチンの開発が切望されている。
However, the stratum corneum located in the outermost layer of the epidermis prevents foreign substances from entering from the outside as a strong biological barrier, and can only penetrate oil-soluble substances or low molecular weight substances having a molecular weight of 500 Da or less (non-patent reference) Reference 3). Since protein antigens and peptide antigens generally used as vaccines are hydrophilic and have a high molecular weight, it is difficult to deliver them even to Langerhans cells existing under the stratum corneum just by applying them to the skin. In fact, it has been reported that the hydrophilic gel patch containing an antigen has an overwhelmingly low utilization rate of the antigen as compared with an injection (see Non-Patent Document 4). In addition, conventionally, attempts have been made to improve the immunity-inducing ability by transdermal administration by a transdermal vaccine preparation using microneedles, but such a vaccine preparation complicates the manufacturing process and increases the manufacturing cost. Has the drawback of inviting. Against the background of such conventional techniques, development of a vaccine for transdermal administration capable of excellent immunity induction without using microneedles has been earnestly desired.
本発明の目的は、経皮投与によって優れた免疫誘導が可能なワクチン製剤を提供することである。
An object of the present invention is to provide a vaccine preparation capable of excellent immunity induction by transdermal administration.
本発明者等は、前記課題を解決すべく鋭意検討を行ったところ、抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、当該水相が当該油相に分散しているワクチン製剤は、経皮投与すると、注射投与を凌ぐ、優れた免疫誘導が可能になることを見出した。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。
The inventors of the present invention have conducted extensive studies to solve the above problems, and include an aqueous phase in which an antigen is dissolved, a glycerin fatty acid ester and/or a polyglycerin fatty acid ester, and an oil phase, and the aqueous phase is the oil phase. It has been found that the vaccine preparation dispersed in A. can induce immunity superior to that by injection when administered transdermally. The present invention has been completed by further studies based on such findings.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項1. 抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散している、経皮投与用ワクチン製剤。
項2. 前記抗原の由来が、がん細胞、病原性ウイルス、病原性細菌、病原性生物、又は花粉である、項1に記載の経皮投与用ワクチン製剤。
項3. 前記抗原が抗原ペプチド又は抗原タンパク質である、項1又は2に記載の経皮投与用ワクチン製剤。
項4. 前記グリセリン脂肪酸エステルが、モノオレイン酸グリセリルである、項1~3のいずれかに記載の経皮投与用ワクチン製剤。
項5. 前記グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルの含有量が0.1~30重量%である、項1~4のいずれかに記載の経皮投与用ワクチン製剤。
項6. 抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散している組成物の、経皮投与用ワクチン製剤の製造のための使用。
項7. 抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散している組成物の免疫誘導に有効な量を、免疫誘導が求められている動物に対して経皮投与する工程を含む、免疫誘導方法。 That is, the present invention provides the inventions of the following modes.
Item 1. A vaccine preparation for transdermal administration, comprising an aqueous phase in which an antigen is dissolved, a glycerin fatty acid ester and/or a polyglycerin fatty acid ester, and an oil phase, wherein the aqueous phase is dispersed in the oil phase.
Item 2. Item 2. The vaccine preparation for transdermal administration according to Item 1, wherein the origin of the antigen is a cancer cell, a pathogenic virus, a pathogenic bacterium, a pathogenic organism, or pollen.
Item 3. Item 3. The vaccine preparation for transdermal administration according to Item 1 or 2, wherein the antigen is an antigen peptide or an antigen protein.
Item 4. Item 4. The vaccine preparation for transdermal administration according to any one of Items 1 to 3, wherein the glycerin fatty acid ester is glyceryl monooleate.
Item 5. Item 5. The vaccine preparation for transdermal administration according to any one of Items 1 to 4, wherein the content of the glycerin fatty acid ester and/or the polyglycerin fatty acid ester is 0.1 to 30% by weight.
Item 6. For the production of a vaccine preparation for transdermal administration of a composition comprising an aqueous phase in which an antigen is dissolved, glycerin fatty acid ester and/or polyglycerin fatty acid ester, and an oil phase, wherein the aqueous phase is dispersed in the oil phase Use of.
Item 7. An immune-inducing effective amount of a composition containing an aqueous phase in which an antigen is dissolved, glycerin fatty acid ester and/or polyglycerin fatty acid ester, and an oil phase, the aqueous phase being dispersed in the oil phase, An immunity-inducing method, comprising the step of transdermal administration to an animal in need.
項1. 抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散している、経皮投与用ワクチン製剤。
項2. 前記抗原の由来が、がん細胞、病原性ウイルス、病原性細菌、病原性生物、又は花粉である、項1に記載の経皮投与用ワクチン製剤。
項3. 前記抗原が抗原ペプチド又は抗原タンパク質である、項1又は2に記載の経皮投与用ワクチン製剤。
項4. 前記グリセリン脂肪酸エステルが、モノオレイン酸グリセリルである、項1~3のいずれかに記載の経皮投与用ワクチン製剤。
項5. 前記グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルの含有量が0.1~30重量%である、項1~4のいずれかに記載の経皮投与用ワクチン製剤。
項6. 抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散している組成物の、経皮投与用ワクチン製剤の製造のための使用。
項7. 抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散している組成物の免疫誘導に有効な量を、免疫誘導が求められている動物に対して経皮投与する工程を含む、免疫誘導方法。 That is, the present invention provides the inventions of the following modes.
本発明のワクチン製剤によれば、経皮投与によって、注射投与を凌ぐ優れた免疫誘導が可能になるので、がん免疫療法、感染症予防、花粉症等のアレルギーに対するアレルゲン免疫療法等において、優れた治療又は予防効果を奏することができる。また、本発明のワクチン製剤は、経皮投与によって免疫を有効に誘導できるので、非侵襲的、安全、且つ簡便な方法で使用することができる。
According to the vaccine preparation of the present invention, transdermal administration enables superior immunity induction over injection administration, and thus is excellent in allergen immunotherapy for allergy such as cancer immunotherapy, infectious disease prevention, and pollinosis. It is possible to exert a therapeutic or preventive effect. Further, since the vaccine preparation of the present invention can effectively induce immunity by transdermal administration, it can be used in a non-invasive, safe and simple manner.
本発明のワクチン製剤は、経皮投与されるワクチン製剤であって、抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散していることを特徴とする。以下、本発明のワクチン製剤について詳述する。
The vaccine preparation of the present invention is a vaccine preparation for transdermal administration, comprising an aqueous phase in which an antigen is dissolved, a glycerin fatty acid ester and/or a polyglycerin fatty acid ester, and an oil phase, the aqueous phase being the oil phase. It is characterized by being dispersed. Hereinafter, the vaccine preparation of the present invention will be described in detail.
[水相]
本発明のワクチン製剤において、水相は、抗原が溶解した溶解液で構成される。本発明のワクチン製剤において、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルの親水性部分が水相に会合した状態になって、当該水相が油相に分散したWO乳化形態になっている。本発明のワクチン製剤では、水相の周りをグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルで被覆された逆ミセルを形成して乳化した状態、或は水相の周りをグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルが完全に被覆せずとも水相が乳化粒子になった乳化状態になっていると推測される。以下、水相に含まれる各成分について説明する。 [Water phase]
In the vaccine preparation of the present invention, the aqueous phase is composed of a solution in which the antigen is dissolved. In the vaccine preparation of the present invention, the hydrophilic portion of the glycerin fatty acid ester and/or the polyglycerin fatty acid ester is associated with the water phase, and the water phase is in a WO emulsion form in which the water phase is dispersed in the oil phase. In the vaccine preparation of the present invention, a reverse micelle coated with glycerin fatty acid ester and/or polyglycerin fatty acid ester around the aqueous phase is formed and emulsified, or around the aqueous phase, glycerin fatty acid ester and/or polyglycerin fatty acid ester is formed. It is presumed that the aqueous phase is in an emulsified state in which it is emulsified particles even if the glycerin fatty acid ester is not completely covered. Hereinafter, each component contained in the aqueous phase will be described.
本発明のワクチン製剤において、水相は、抗原が溶解した溶解液で構成される。本発明のワクチン製剤において、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルの親水性部分が水相に会合した状態になって、当該水相が油相に分散したWO乳化形態になっている。本発明のワクチン製剤では、水相の周りをグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルで被覆された逆ミセルを形成して乳化した状態、或は水相の周りをグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルが完全に被覆せずとも水相が乳化粒子になった乳化状態になっていると推測される。以下、水相に含まれる各成分について説明する。 [Water phase]
In the vaccine preparation of the present invention, the aqueous phase is composed of a solution in which the antigen is dissolved. In the vaccine preparation of the present invention, the hydrophilic portion of the glycerin fatty acid ester and/or the polyglycerin fatty acid ester is associated with the water phase, and the water phase is in a WO emulsion form in which the water phase is dispersed in the oil phase. In the vaccine preparation of the present invention, a reverse micelle coated with glycerin fatty acid ester and/or polyglycerin fatty acid ester around the aqueous phase is formed and emulsified, or around the aqueous phase, glycerin fatty acid ester and/or polyglycerin fatty acid ester is formed. It is presumed that the aqueous phase is in an emulsified state in which it is emulsified particles even if the glycerin fatty acid ester is not completely covered. Hereinafter, each component contained in the aqueous phase will be described.
・抗原
本発明で使用される抗原は、ワクチンの免疫原として、生体内で免疫応答を誘導し得るものであり、且つ水溶性であることを限度として特に制限されないが、抗原タンパク質及び抗原ペプチドが挙げられる。本発明において、抗原タンパク質とは、病原体やアレルギー源において特異的に発現又は存在しており、免疫応答を誘導するタンパク質のことをいう。また、抗原ペプチドとは、抗原タンパク質に由来するペプチド(例えば、抗原タンパク質を低分子化したもの)のことをいう。本発明において、抗原タンパク質及び抗原ペプチドには、抗原提示細胞の細胞表面のMHC分子(HLA分子)との複合体を直接形成することにより抗原特異的T細胞を誘導可能なものであってもよく、また、細胞内に取り込まれ、その後細胞内分解されて生じたペプチド断片がMHC分子と結合して複合体を形成し、当該複合体が細胞表面に提示されることにより抗原特異的T細胞を誘導可能なものであってもよい。 -Antigen The antigen used in the present invention is not particularly limited as long as it is capable of inducing an immune response in vivo as an immunogen of a vaccine and is water-soluble. Can be mentioned. In the present invention, the antigen protein refers to a protein that is specifically expressed or present in a pathogen or an allergen and induces an immune response. In addition, the antigen peptide refers to a peptide derived from an antigen protein (for example, an antigen protein having a reduced molecular weight). In the present invention, the antigen protein and the antigen peptide may be those capable of inducing antigen-specific T cells by directly forming a complex with the MHC molecule (HLA molecule) on the cell surface of the antigen-presenting cell. In addition, a peptide fragment that is taken up into cells and then decomposed into cells binds to MHC molecules to form a complex, and the complex is presented on the cell surface to generate antigen-specific T cells. It may be inducible.
本発明で使用される抗原は、ワクチンの免疫原として、生体内で免疫応答を誘導し得るものであり、且つ水溶性であることを限度として特に制限されないが、抗原タンパク質及び抗原ペプチドが挙げられる。本発明において、抗原タンパク質とは、病原体やアレルギー源において特異的に発現又は存在しており、免疫応答を誘導するタンパク質のことをいう。また、抗原ペプチドとは、抗原タンパク質に由来するペプチド(例えば、抗原タンパク質を低分子化したもの)のことをいう。本発明において、抗原タンパク質及び抗原ペプチドには、抗原提示細胞の細胞表面のMHC分子(HLA分子)との複合体を直接形成することにより抗原特異的T細胞を誘導可能なものであってもよく、また、細胞内に取り込まれ、その後細胞内分解されて生じたペプチド断片がMHC分子と結合して複合体を形成し、当該複合体が細胞表面に提示されることにより抗原特異的T細胞を誘導可能なものであってもよい。 -Antigen The antigen used in the present invention is not particularly limited as long as it is capable of inducing an immune response in vivo as an immunogen of a vaccine and is water-soluble. Can be mentioned. In the present invention, the antigen protein refers to a protein that is specifically expressed or present in a pathogen or an allergen and induces an immune response. In addition, the antigen peptide refers to a peptide derived from an antigen protein (for example, an antigen protein having a reduced molecular weight). In the present invention, the antigen protein and the antigen peptide may be those capable of inducing antigen-specific T cells by directly forming a complex with the MHC molecule (HLA molecule) on the cell surface of the antigen-presenting cell. In addition, a peptide fragment that is taken up into cells and then decomposed into cells binds to MHC molecules to form a complex, and the complex is presented on the cell surface to generate antigen-specific T cells. It may be inducible.
経皮吸収の効率を高めてより一層優れた経皮免疫を誘導させるという観点から、抗原の好適な一例として、抗原ペプチドが挙げられる。抗原ペプチドのアミノ酸残基数については、特に制限されないが、例えば、2~50個、好ましくは7~31個、より好ましくは8~20個程度が挙げられる。
From the viewpoint of enhancing the efficiency of percutaneous absorption and inducing even better transdermal immunity, an antigen peptide is a suitable example of the antigen. The number of amino acid residues of the antigen peptide is not particularly limited, but examples thereof include 2 to 50, preferably 7 to 31, and more preferably about 8 to 20.
抗原の由来については、特に制限されないが、例えば、がん細胞、病原性ウイルス、病原性細菌、病原性生物、花粉等が挙げられる。抗原の由来として、具体的には、メラノーマ、膵癌、肺癌、骨肉腫、大腸癌、結腸癌、胃癌、直腸癌、肝癌、乳癌、膀胱癌、前立腺癌、子宮頚癌、頭頚部癌、胆管癌、胆嚢癌、口腔癌、脳腫瘍等の固形癌、白血病、悪性リンパ腫等の血液がん等のがん細胞;インフルエンザウイルス、トリインフルエンザウイルス、パラインフルエンザウイルス、アデノウイルス、SARSウイルス、AIDSウイルス、サイトメガロウイルス、肝炎ウイルス、日本脳炎ウイルス、麻疹ウイルス、風疹ウイルス、水痘・帯状疱疹ウイルス、ポリオウイルス、パピローマウイルス、ヘルペスウイルス、ムンプスウイルス、ロタウイルス、コレラウイルス、狂犬病ウイルス、HIV等の病原性ウイルス;ジフテリア、破傷風、結核菌、肺炎球菌、髄膜炎菌、ブドウ球菌、緑膿菌、百日咳菌、炭疽菌、サルモネラ等の細菌等の病原性細菌;マラリア原虫、ダニ等の病原性生物;スギ花粉、ヒノキ花粉、シラカバ花粉等の花粉等が挙げられる。これらの抗原の由来の中でも、好ましくはがん細胞、インフルエンザウイルス、及び花粉が挙げられる。
The origin of the antigen is not particularly limited, but examples thereof include cancer cells, pathogenic viruses, pathogenic bacteria, pathogenic organisms, pollen, and the like. As the origin of the antigen, specifically, melanoma, pancreatic cancer, lung cancer, osteosarcoma, colon cancer, colon cancer, gastric cancer, rectal cancer, liver cancer, breast cancer, bladder cancer, prostate cancer, cervical cancer, head and neck cancer, bile duct cancer. , Cancer cells such as solid cancers such as gallbladder cancer, oral cancer, brain tumors, and blood cancers such as leukemia and malignant lymphoma; influenza virus, avian influenza virus, parainfluenza virus, adenovirus, SARS virus, AIDS virus, cytomegalo Viral, hepatitis virus, Japanese encephalitis virus, measles virus, rubella virus, varicella-zoster virus, polio virus, papilloma virus, herpes virus, mumps virus, rotavirus, cholera virus, rabies virus, HIV and other pathogenic viruses; diphtheria , Tetanus, tubercle bacillus, pneumococcus, meningococcus, staphylococcus, aeruginosa, pertussis, anthrax, salmonella and other pathogenic bacteria; malaria parasites, mites and other pathogenic organisms; cedar pollen, Examples include pollen such as cypress pollen and birch pollen. Among these antigens, cancer cells, influenza virus, and pollen are preferable.
本発明のワクチン製剤において、水相(溶解液)中の抗原の含有量としては、例えば、0.001~60重量%、好ましくは0.001~50重量%、より好ましく0.001~40重量%、更に好ましくは0.1~25重量%、特に好ましくは0.1~5重量%が挙げられる。
In the vaccine preparation of the present invention, the content of the antigen in the aqueous phase (dissolution) is, for example, 0.001 to 60% by weight, preferably 0.001 to 50% by weight, more preferably 0.001 to 40% by weight. %, more preferably 0.1 to 25% by weight, particularly preferably 0.1 to 5% by weight.
本発明のワクチン製剤における抗原の含有量は、抗原の種類、患者の状態、投与量等に応じて適宜設定すればよいが、例えば0.0001~5重量%、好ましくは0.0001~3.5重量%、より好ましく0.0001~2.5重量%、特に好ましくは0.01~2重量%が挙げられる。
The content of the antigen in the vaccine preparation of the present invention may be appropriately set according to the type of the antigen, the condition of the patient, the dose, etc., but is, for example, 0.0001 to 5% by weight, preferably 0.0001 to 3. 5% by weight, more preferably 0.0001 to 2.5% by weight, particularly preferably 0.01 to 2% by weight.
・水相基剤
水相には、抗原を溶解させるための水相基剤が含まれる。水相基剤の種類については、抗原を溶解可能であることを限度として特に制限されないが、例えば、水、1価低級アルコール、及びこれらの混合液が挙げられる。 -Aqueous phase base The aqueous phase contains an aqueous phase base for dissolving the antigen. The type of aqueous phase base is not particularly limited as long as it can dissolve the antigen, and examples thereof include water, a monohydric lower alcohol, and a mixed solution thereof.
水相には、抗原を溶解させるための水相基剤が含まれる。水相基剤の種類については、抗原を溶解可能であることを限度として特に制限されないが、例えば、水、1価低級アルコール、及びこれらの混合液が挙げられる。 -Aqueous phase base The aqueous phase contains an aqueous phase base for dissolving the antigen. The type of aqueous phase base is not particularly limited as long as it can dissolve the antigen, and examples thereof include water, a monohydric lower alcohol, and a mixed solution thereof.
水相基剤として使用される水は、精製水、超純水等の水の他、緩衝液、生理食塩水等の状態であってもよい。
The water used as the aqueous phase base may be purified water, ultrapure water, or the like, as well as a buffer solution, physiological saline, or the like.
また、水相基剤として使用される1価低級アルコールとしては、例えば、炭素数2~5の1価アルコールが挙げられる。1価低級アルコールとして、より具体的には、
エタノール、n-プロパノール、イソプロパノール、n-ブタノール、sec-ブタノール、tert-ブタノール、n-アミルアルコール、sec-アミルアルコール、イソアミルアルコール、tert-アミルアルコール、ネオペンチルアルコール等が挙げられる。これらの1価低級アルコールは、1種単独で含まれていてもよく、2種以上が組み合わされて含まれていてもよい。 Examples of monohydric lower alcohols used as the aqueous phase base include monohydric alcohols having 2 to 5 carbon atoms. As the monohydric lower alcohol, more specifically,
Examples thereof include ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-amyl alcohol, sec-amyl alcohol, isoamyl alcohol, tert-amyl alcohol and neopentyl alcohol. These monohydric lower alcohols may be contained alone or in combination of two or more.
エタノール、n-プロパノール、イソプロパノール、n-ブタノール、sec-ブタノール、tert-ブタノール、n-アミルアルコール、sec-アミルアルコール、イソアミルアルコール、tert-アミルアルコール、ネオペンチルアルコール等が挙げられる。これらの1価低級アルコールは、1種単独で含まれていてもよく、2種以上が組み合わされて含まれていてもよい。 Examples of monohydric lower alcohols used as the aqueous phase base include monohydric alcohols having 2 to 5 carbon atoms. As the monohydric lower alcohol, more specifically,
Examples thereof include ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-amyl alcohol, sec-amyl alcohol, isoamyl alcohol, tert-amyl alcohol and neopentyl alcohol. These monohydric lower alcohols may be contained alone or in combination of two or more.
水相基剤の好適な一態様としては、水と1価低級アルコールの混合液、より好ましくは水とイソプロパノールとの混合液が挙げられる。また、水相基剤の他の好適な一態様としては、1価の低級アルコールを含まない水又は水溶液(緩衝液、生理食塩水等)が挙げられる。
A preferable embodiment of the aqueous phase base is a mixed solution of water and a monohydric lower alcohol, more preferably a mixed solution of water and isopropanol. In addition, another preferable embodiment of the aqueous phase base is water or an aqueous solution (buffer solution, physiological saline, etc.) containing no monohydric lower alcohol.
水相基剤として、水と1価低級アルコールの混合液を使用する場合、これらの混合比については、特に制限されないが、例えば、水1重量部当たり、1価低級アルコールが1~50重量部、好ましくは1~45重量部、より好ましくは1~40重量部、特に好ましくは1~20重量部となる比率が挙げられる。
When a mixed liquid of water and a monohydric lower alcohol is used as the aqueous phase base, the mixing ratio of these is not particularly limited, but for example, 1 to 50 parts by weight of the monohydric lower alcohol per 1 part by weight of water. The ratio is preferably 1 to 45 parts by weight, more preferably 1 to 40 parts by weight, and particularly preferably 1 to 20 parts by weight.
水相中の水相基剤の含有量については、例えば、40~99.999重量%が挙げられる。より一層優れた経皮免疫を誘導させるという観点から、水相中の水相基剤の含有量の下限として、好ましくは50重量%以上、より好ましくは60重量%以上、更に好ましくは95重量%以上が挙げられる。より一層優れた経皮免疫を誘導させるという観点から、水相中の水相基剤の含有量の上限として、好ましくは99.9重量%以下、より好ましくは99重量%以下が挙げられる。水相中の水相基剤の含有量として、より具体的には、好ましくは50~99.999重量%、より好ましくは60~99.999重量%、更に好ましくは75~99.9重量%、特に好ましくは95~99.9重量%が挙げられる。
The content of the aqueous phase base in the aqueous phase is, for example, 40 to 99.999% by weight. From the viewpoint of inducing even more excellent transdermal immunity, the lower limit of the content of the aqueous phase base in the aqueous phase is preferably 50% by weight or more, more preferably 60% by weight or more, and further preferably 95% by weight. The above is mentioned. From the viewpoint of inducing even more excellent transdermal immunity, the upper limit of the content of the aqueous phase base in the aqueous phase is preferably 99.9% by weight or less, more preferably 99% by weight or less. More specifically, the content of the aqueous phase base in the aqueous phase is preferably 50 to 99.999% by weight, more preferably 60 to 99.999% by weight, and further preferably 75 to 99.9% by weight. , Particularly preferably 95 to 99.9% by weight.
また、本発明のワクチン製剤における水相基剤の含有量としては、例えば0.1~50重量%が挙げられる。より一層優れた経皮免疫を誘導させるという観点から、発明のワクチン製剤における水相基剤の含有量として、好ましくは0.1~40重量%、より好ましく0.1~30重量%、更に好ましくは0.5~30重量%、特に好ましくは5~20重量%が挙げられる。
The content of the aqueous phase base in the vaccine preparation of the present invention is, for example, 0.1 to 50% by weight. From the viewpoint of inducing even more excellent transdermal immunity, the content of the aqueous phase base in the vaccine preparation of the present invention is preferably 0.1 to 40% by weight, more preferably 0.1 to 30% by weight, and further preferably Is 0.5 to 30% by weight, particularly preferably 5 to 20% by weight.
[グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル]
本発明のワクチン製剤では、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルは、一部又は全部が水相と会合して、水相を油相に分散させて乳化させる役割を果たすと共に、経皮投与によって優れた免疫誘導を可能にする役割を果たす。 [Glycerin fatty acid ester and/or polyglycerin fatty acid ester]
In the vaccine preparation of the present invention, the glycerin fatty acid ester and/or the polyglycerin fatty acid ester plays a part or all in association with the aqueous phase, plays a role of dispersing the aqueous phase in the oil phase and emulsifying, and transdermal administration. Plays a role in enabling superior immunity induction.
本発明のワクチン製剤では、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルは、一部又は全部が水相と会合して、水相を油相に分散させて乳化させる役割を果たすと共に、経皮投与によって優れた免疫誘導を可能にする役割を果たす。 [Glycerin fatty acid ester and/or polyglycerin fatty acid ester]
In the vaccine preparation of the present invention, the glycerin fatty acid ester and/or the polyglycerin fatty acid ester plays a part or all in association with the aqueous phase, plays a role of dispersing the aqueous phase in the oil phase and emulsifying, and transdermal administration. Plays a role in enabling superior immunity induction.
グリセリン脂肪酸エステルとは、脂肪酸とグリセリンとのモノエステル、ジエステル、又はトリエステルである。グリセリン脂肪酸エステルを構成する脂肪酸の炭素数としては、例えば、6~24、好ましくは8~22、更に好ましくは12~18が挙げられる。グリセリン脂肪酸エステルとして、具体的には、モノミリスチン酸グリセリル、モノステアリン酸グリセリル、モノイソステアリン酸グリセリル、モノオレイン酸グリセリル、ジオレイン酸グリセリル、トリオレイン酸グリセリル、ジステアリン酸グリセリル等が挙げられる。これらのグリセリン脂肪酸エステルの中でも、好ましくは、脂肪酸とグリセリンとのモノエステル、より好ましくはモノオレイン酸グリセリルが挙げられる。
Glycerin fatty acid ester is a monoester, diester, or triester of fatty acid and glycerin. The number of carbon atoms of the fatty acid constituting the glycerin fatty acid ester is, for example, 6 to 24, preferably 8 to 22 and more preferably 12 to 18. Specific examples of the glycerin fatty acid ester include glyceryl monomyristate, glyceryl monostearate, glyceryl monoisostearate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, and glyceryl distearate. Among these glycerin fatty acid esters, monoesters of fatty acids and glycerin are preferable, and glyceryl monooleate is more preferable.
ポリグリセリン脂肪酸エステルとは、脂肪酸とポリグリセリンとのエステルである。ポリグリセリン脂肪酸エステルにおいて、エステル結合の数(ポリグリセリン1分子当たり、結合している脂肪酸の数)としては、例えば1~10、好ましくは1~6、更に好ましくは1~3が挙げられる。ポリグリセリン脂肪酸エステルを構成する脂肪酸の炭素数としては、例えば、6~24、好ましくは8~22、更に好ましくは12~18が挙げられる。また、ポリグリセリン脂肪酸エステルを構成するポリグリセリンの重合度は、例えば、2~30、好ましくは2~10が挙げられる。具体的には、ポリグリセリン脂肪酸エステルとして、ステアリン酸ポリグリセリル-2(モノステアリン酸ジグリセリル)、オレイン酸ポリグリセリル-2(モノオレイン酸ジグリセリル)、オレイン酸ポリグリセリル-4(モノオレイン酸テトラグリセリル)、オレイン酸ポリグリセリル-10(モノオレイン酸デカグリセリル)、トリオレイン酸ポリグリセリル-5(トリオレイン酸ペンタグリセリル)、トリオレイン酸ポリグリセリル-10(トリオレイン酸デカグリセリル)、パルミチン酸ポリグリセリル-10(モノパルミチン酸デカグリセリル)、イソステアリン酸ポリグリセリル-2、トリイソステアリン酸ポリグリセリル-2、ステアリン酸ポリグリセリル-4、トリステアリン酸ポリグリセリル-6、ペンタステアリン酸ポリグリセリル-10、ペンタヒドロキシステアリン酸ポリグリセリル-10、ペンタイソステアリン酸ポリグリセリル-10、ペンタオレイン酸ポリグリセリル-10、ポリリシノレイン酸ポリグリセリル-6、ポリリシノレイン酸ポリグリセリル-10等が挙げられる。これらのポリグリセリン脂肪酸エステルの中でも、好ましくは、トリオレイン酸ポリグリセリル、イソステアリン酸ポリグリセリル-2が挙げられる。
“Polyglycerin fatty acid ester” is an ester of fatty acid and polyglycerin. In the polyglycerin fatty acid ester, the number of ester bonds (the number of fatty acids bound to one molecule of polyglycerin) is, for example, 1 to 10, preferably 1 to 6, and more preferably 1 to 3. The carbon number of the fatty acid constituting the polyglycerin fatty acid ester is, for example, 6 to 24, preferably 8 to 22, and more preferably 12 to 18. The degree of polymerization of polyglycerin that constitutes the polyglycerin fatty acid ester is, for example, 2 to 30, and preferably 2 to 10. Specifically, as the polyglycerin fatty acid ester, polyglyceryl-2 stearate (diglyceryl monostearate), polyglyceryl-2 oleate (diglyceryl monooleate), polyglyceryl-4 oleate (tetraglyceryl monooleate), Polyglyceryl oleate-10 (decaglyceryl monooleate), polyglyceryl-5 trioleate (pentaglyceryl trioleate), polyglyceryl-10 trioleate (decaglyceryl trioleate), polyglyceryl-10 palmitate (monopalmitic acid) Decaglyceryl), polyglyceryl-2 isostearate, polyglyceryl-2 triisostearate, polyglyceryl-4 stearate, polyglyceryl tristearate-6, polyglyceryl pentastearate-10, polyglyceryl pentahydroxystearate-10, polyglyceryl pentaisostearate- 10, polyglyceryl-10 pentaoleate, polyglyceryl-6 polyricinoleate, polyglyceryl-10 polyricinoleate, and the like. Among these polyglycerin fatty acid esters, polyglyceryl trioleate and polyglyceryl isostearate-2 are preferable.
本発明において、グリセリン脂肪酸エステル及びポリグリセリン脂肪酸エステルの中から1種の成分を単独で使用してもよく、また2種以上を組み合わせて使用してもよい。
In the present invention, one of the glycerin fatty acid ester and the polyglycerin fatty acid ester may be used alone, or two or more thereof may be used in combination.
グリセリン脂肪酸エステル及びポリグリセリン脂肪酸エステルの中でも、より一層優れた経皮免疫を誘導させるという観点から、好ましくはグリセリン脂肪酸エステル、より好ましくは脂肪酸とグリセリンとのモノエステル、更に好ましくはモノオレイン酸グリセリルが挙げられる。
Among glycerin fatty acid ester and polyglycerin fatty acid ester, from the viewpoint of inducing even more excellent transdermal immunity, preferably glycerin fatty acid ester, more preferably monoester of fatty acid and glycerin, more preferably glyceryl monooleate. Can be mentioned.
本発明のワクチン製剤において水相(溶解液)とグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルとの比率としては、例えば、水相1重量部当たり、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルが総量で0.5~200重量部、好ましくは0.5~75重量部、より好ましくは0.5~50重量部、更に好ましくは0.5~40重量部、特に好ましくは0.5~3重量部が挙げられる。
In the vaccine preparation of the present invention, the ratio of the aqueous phase (dissolved liquid) to the glycerin fatty acid ester and/or polyglycerin fatty acid ester is, for example, the total amount of glycerin fatty acid ester and/or polyglycerin fatty acid ester per 1 part by weight of the aqueous phase. At 0.5 to 200 parts by weight, preferably 0.5 to 75 parts by weight, more preferably 0.5 to 50 parts by weight, further preferably 0.5 to 40 parts by weight, particularly preferably 0.5 to 3 parts by weight. Parts.
また、本発明のワクチン製剤におけるグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルの含有量としては、例えば0.1~30重量%、好ましくは0.25~27.5重量%、より好ましく0.5~25重量%が挙げられる。
The content of glycerin fatty acid ester and/or polyglycerin fatty acid ester in the vaccine preparation of the present invention is, for example, 0.1 to 30% by weight, preferably 0.25 to 27.5% by weight, more preferably 0.5. Up to 25% by weight.
[油相]
本発明のワクチン製剤において、油相は、前記水相の分散媒としての役割を果たし、液状油、固形油、高級アルコール等の油相基剤で形成される。 [Oil phase]
In the vaccine preparation of the present invention, the oil phase serves as a dispersion medium for the aqueous phase, and is formed of an oil phase base such as liquid oil, solid oil and higher alcohol.
本発明のワクチン製剤において、油相は、前記水相の分散媒としての役割を果たし、液状油、固形油、高級アルコール等の油相基剤で形成される。 [Oil phase]
In the vaccine preparation of the present invention, the oil phase serves as a dispersion medium for the aqueous phase, and is formed of an oil phase base such as liquid oil, solid oil and higher alcohol.
液状油とは、25℃において液状の形態を保つ油である。本発明で使用される液状油としては、化粧料や外用医薬品等に通常用いられるものであればよく、例えば、アボガド油、ツバキ油、マカデミアナツツ油、オリーブ油、アルモンド油、ダイズ油、ホホバ油、綿実油、ナタネ油、ゴマ油、シソ油、ケイヒ油、コーン油、ラッカセイ油、サンフラワー油、カカオ油、ハッカ油、ベルガモット油、ウイキョウ油等の植物油;オレイン酸、イソステアリン酸等の脂肪酸;エチルヘキサン酸セチル、パルミチン酸エチルヘキシル、ミリスチン酸オクチルドデシル、ジエチルヘキサン酸ネオペンチルグリコール、トリ2-エチルへキサン酸グリセリル、オレイン酸オクチルドデシル、ミリスチン酸イソプロピル、トリイソステアリン酸グリセリル、ジパラメトキシケイヒ酸-モノエチルへキサン酸グリセリル等のエステル油;ジメチルポリシロキサン、メチルハイドロジエンポリシロキサン、メチルフェニルポリシロキサン、オクタメチルシクロテトラシロキサン等のシリコン油;流動パラフィン、スクワレン、スクワラン等の液状炭化水素油等が挙げられる。これらの液状油は、1種単独で使用してもよく、また2種以上を組み合わせて使用してもよい。これらの液状油の中でも、好ましくはエステル油、より好ましくはミリスチン酸イソプロピルが挙げられる。
-Liquid oil is an oil that maintains a liquid form at 25°C. The liquid oil used in the present invention may be one normally used in cosmetics and external medicines, for example, avocado oil, camellia oil, macadamia atsutu oil, olive oil, almond oil, soybean oil, jojoba oil, Vegetable oils such as cottonseed oil, rapeseed oil, sesame oil, perilla oil, cinnamon oil, corn oil, peanut oil, sunflower oil, cacao oil, mint oil, bergamot oil, fennel oil, etc.; fatty acids such as oleic acid, isostearic acid; ethylhexanoic acid Cetyl, ethylhexyl palmitate, octyldodecyl myristate, neopentyl glycol diethylhexanoate, glyceryl tri-2-ethylhexanoate, octyldodecyl oleate, isopropyl myristate, glyceryl triisostearate, diparamethoxycinnamate-monoethylhexane Ester oils such as glyceryl acid; silicone oils such as dimethylpolysiloxane, methylhydrogenpolysiloxane, methylphenylpolysiloxane and octamethylcyclotetrasiloxane; liquid hydrocarbon oils such as liquid paraffin, squalene and squalane. These liquid oils may be used alone or in combination of two or more. Among these liquid oils, ester oil is preferable, and isopropyl myristate is more preferable.
固形油とは、25℃において固形の形態を保つ油である。本発明で使用される固形油としては、通常化粧料や外用医薬品等に用いられるものであればよく、例えば、キャンデリラロウ、コメヌカロウ、ミツロウ、綿ロウ、カルナウバロウ、ラノリン、セラックロウ、オゾケライト、セレシン、ポリエチレンワックス、マイクロクリスタリンワックス、パラフィン、ワセリン、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、ベヘニン酸、12-ヒドロキシステアリン酸、ウンデシレン酸、ミリスチン酸ミリスチル、ミリスチン酸セチル、ステアリン酸ステアリル、ステアリン酸セチル、パルミチン酸セチル、ステアリン酸コレステリル、オレイン酸コレステリル、パルミチン酸デキストリン、ステアリン酸イヌリン、水素添加ホホバ油、セレシンワックス、固形パラフィンワックス、ポリエチレンワックス、シリコーンワックス等の固形油が挙げられる。これらの固形油は、1種単独で使用してもよく、また2種以上を組み合わせて使用してもよい。
Solid oil is an oil that maintains a solid form at 25°C. The solid oil used in the present invention may be one normally used for cosmetics and external medicines, for example, candelilla wax, rice bran wax, beeswax, cotton wax, carnauba wax, lanolin, shellac wax, ozokerite, ceresin, Polyethylene wax, microcrystalline wax, paraffin, petrolatum, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, 12-hydroxystearic acid, undecylenic acid, myristyl myristate, cetyl myristate, stearyl stearate, cetyl stearate. , Solid oils such as cetyl palmitate, cholesteryl stearate, cholesteryl oleate, dextrin palmitate, inulin stearate, hydrogenated jojoba oil, ceresin wax, solid paraffin wax, polyethylene wax and silicone wax. These solid oils may be used alone or in combination of two or more.
高級アルコールとは、1分子中の炭素原子数が6個以上の1価アルコールである。本発明で使用される高級アルコールにおける1分子中の炭素原子数について、6以上であればよいが、好ましくは6~34、更に好ましくは14~22が挙げられる。
Higher alcohol is a monohydric alcohol having 6 or more carbon atoms in one molecule. The number of carbon atoms in one molecule in the higher alcohol used in the present invention may be 6 or more, preferably 6 to 34, more preferably 14 to 22.
本発明で使用される高級アルコールとしては、通常化粧料や外用医薬品等に用いられるものであればよく、例えば、ラウリルアルコール、セチルアルコール、ステアリルアルコール、ベヘニルアルコール、ミリスチルアルコール、セトステアリルアルコール、セタノール、オレイルアルコール等の直鎖状高級アルコール;ノステアリルグリセリンエーテル(バチルアルコール)、等の分枝鎖状高級アルコールが挙げられる。これらの高級アルコールは、1種単独で使用してもよく、また2種以上を組み合わせて使用してもよい。
The higher alcohol used in the present invention may be one normally used in cosmetics and external medicines, for example, lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, cetostearyl alcohol, cetanol, oleyl. Examples thereof include linear higher alcohols such as alcohols; branched higher alcohols such as nostearyl glycerin ether (batyl alcohol). These higher alcohols may be used alone or in combination of two or more.
これらの油相基剤の中でも、好ましくは液状油が挙げられる。
Among these oil phase bases, liquid oil is preferable.
本発明のワクチン製剤において、水相と油相の比率としては、例えば、水相1重量部当たり、油相が1~1000重量部、好ましくは1.5~1000重量部、より好ましくは2~1000重量部、更に好ましくは2.5~200重量部、特に好ましくは2.5~10重量部が挙げられる。
In the vaccine preparation of the present invention, the ratio of the water phase and the oil phase is, for example, 1 to 1000 parts by weight, preferably 1.5 to 1000 parts by weight, and more preferably 2 to 1 part by weight of the oil phase. The amount is 1000 parts by weight, more preferably 2.5 to 200 parts by weight, and particularly preferably 2.5 to 10 parts by weight.
本発明のワクチン製剤における油相の含有量については、特に制限されず、使用する油相基剤の種類等に応じて適宜設定すればよいが、例えば、40~99.8重量%、好ましくは50~99.7重量%、より好ましくは55~99.4重量%が挙げられる。
The content of the oil phase in the vaccine preparation of the present invention is not particularly limited and may be appropriately set according to the type of the oil phase base used, for example, 40 to 99.8% by weight, preferably 50 to 99.7% by weight, more preferably 55 to 99.4% by weight.
[その他の成分]
本発明のワクチン製剤には、経皮免疫の誘導をより一層向上させるために、アジュバントが含まれていてもよい。アジュバントとしては、例えば、CpGオリゴデオキシヌクレオチド、フロイント、水酸化アルミニウム(Alum)、ミョウバン等が挙げられる。 [Other ingredients]
The vaccine preparation of the present invention may contain an adjuvant in order to further improve the induction of transdermal immunity. Examples of the adjuvant include CpG oligodeoxynucleotide, Freund, aluminum hydroxide (Alum), alum and the like.
本発明のワクチン製剤には、経皮免疫の誘導をより一層向上させるために、アジュバントが含まれていてもよい。アジュバントとしては、例えば、CpGオリゴデオキシヌクレオチド、フロイント、水酸化アルミニウム(Alum)、ミョウバン等が挙げられる。 [Other ingredients]
The vaccine preparation of the present invention may contain an adjuvant in order to further improve the induction of transdermal immunity. Examples of the adjuvant include CpG oligodeoxynucleotide, Freund, aluminum hydroxide (Alum), alum and the like.
また、本発明のワクチン製剤は、必要に応じて、前述した成分以外に、製剤化等に必要とされる他の基剤や添加剤が含まれていてもよい。このような添加剤については、薬学的又は香粧学的に許容されることを限度として特に制限されないが、例えば、防腐剤(メチルパラベン、プロピルパラベン、安息香酸、安息香酸ナトリウム、ソルビン酸等)、着香剤(シトラール、1,8-シオネール、シトロネラール、ファルネソール等)、着色剤(タール色素(褐色201号、青色201号、黄色4号、黄色403号等)、カカオ色素、クロロフィル、酸化アルミニウム等)、粘稠剤(カルボキシビニルポリマー、ヒプロメロース、ポリビニルピロリドン、アルギン酸ナトリウム、エチルセルロース、カルボキシメチルセルロースナトリウム、キサンタンガム、カラギーナン等)、pH調整剤(リン酸、塩酸、クエン酸、クエン酸ナトリウム、コハク酸、酒石酸、水酸化ナトリウム、水酸化カリウム、トリエタノールアミン、トリイソプロパノールアミン等)、湿潤剤(dl-ピロリドンカルボン酸ナトリウム液、D-ソルビトール液、マクロゴール等)、安定化剤(ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エデト酸ナトリウム、メタリン酸ナトリウム、L-アルギニン、L-アスパラギン酸、DL-アラニン、グリシン、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム、二酸化硫黄、クロロゲン酸、カテキン、ローズマリー抽出物等)、多価アルコール(グリセリン、プロピレングリコール、ジプロピレングリコール、ブチレングリコール、ポリエチレングリコール等)、酸化防止剤、紫外線吸収剤、キレート剤、粘着剤、緩衝剤、溶解補助剤、保存剤等の添加剤が挙げられる。
Further, the vaccine preparation of the present invention may contain other bases and additives required for formulation and the like, in addition to the above-mentioned components, if necessary. Such additives are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, for example, preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), Flavoring agents (citral, 1,8-cionele, citronellal, farnesol, etc.), colorants (tar pigments (brown 201, blue 201, yellow 4, yellow 403, etc.), cacao pigments, chlorophyll, aluminum oxide, etc. ), thickeners (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, etc.), pH adjusters (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid) , Sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agent (sodium dl-pyrrolidonecarboxylate solution, D-sorbitol solution, macrogol, etc.), stabilizer (dibutylhydroxytoluene, butylhydroxy) Anisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.) , Polyhydric alcohols (glycerin, propylene glycol, dipropylene glycol, butylene glycol, polyethylene glycol, etc.), antioxidants, UV absorbers, chelating agents, adhesives, buffers, solubilizers, preservatives and other additives Can be mentioned.
本発明のワクチン製剤にアジュバントや添加剤を含有させる場合、水溶性成分は水溶性画分に配合し、親油性成分は油相に配合すればよく、その含有量については、使用する成分の種類に応じて適宜設定すればよい。
When the vaccine preparation of the present invention contains an adjuvant or an additive, the water-soluble component may be added to the water-soluble fraction, and the lipophilic component may be added to the oil phase. It may be set appropriately according to
[製剤形態]
本発明のワクチン製剤は、水相が油相に分散した状態の油中水型(W/O型)の乳化形態である。また、本発明のワクチン製剤は、更に常法に従って水相に分散することによって、W/O/W型製剤としてもよい。 [Formulation form]
The vaccine preparation of the present invention is a water-in-oil type (W/O type) emulsified form in which an aqueous phase is dispersed in an oil phase. The vaccine preparation of the present invention may be further dispersed in an aqueous phase according to a conventional method to give a W/O/W type preparation.
本発明のワクチン製剤は、水相が油相に分散した状態の油中水型(W/O型)の乳化形態である。また、本発明のワクチン製剤は、更に常法に従って水相に分散することによって、W/O/W型製剤としてもよい。 [Formulation form]
The vaccine preparation of the present invention is a water-in-oil type (W/O type) emulsified form in which an aqueous phase is dispersed in an oil phase. The vaccine preparation of the present invention may be further dispersed in an aqueous phase according to a conventional method to give a W/O/W type preparation.
本発明のワクチン製剤の剤型についは、経皮適用可能であることを限度として特に制限されないが、例えば、クリーム剤、軟膏剤、ゲル剤、パップ剤、ローション剤、リニメント剤、エアゾール剤等が挙げられる。これらの中でも、好ましくは、クリーム剤、軟膏剤、乳液剤、ローション剤が挙げられる。
The dosage form of the vaccine preparation of the present invention is not particularly limited as long as it can be applied transdermally, and examples thereof include creams, ointments, gels, poultices, lotions, liniments, and aerosols. Can be mentioned. Of these, creams, ointments, emulsions and lotions are preferable.
[製造方法]
本発明のワクチン製剤は、公知の乳化製剤の製剤化手法に従って製造することができる。例えば、本発明のワクチン製剤の製造方法としては、含有させる成分を水溶性成分と油性成分に分けて、水溶性成分を含む溶解液(水相成分)と、油性成分とグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルとを含む混合液(油相成分とグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル)を調製し、これらを公知の手法に従って乳化させる方法が挙げられる。具体的には、抗原が水相基剤に溶解した溶解液と、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルと油相基剤を含む混合液とを調製し、当該溶解液と混合液とを混合して乳化させることにより、本発明のワクチン製剤を製造することができる。 [Production method]
The vaccine preparation of the present invention can be produced according to a known formulation method for emulsified preparations. For example, as a method for producing the vaccine preparation of the present invention, the components to be contained are divided into a water-soluble component and an oil component, a solution containing the water-soluble component (aqueous phase component), an oil component and a glycerin fatty acid ester and/or Examples include a method of preparing a mixed solution containing a polyglycerin fatty acid ester (oil phase component and glycerin fatty acid ester and/or polyglycerin fatty acid ester), and emulsifying them according to a known method. Specifically, a solution in which an antigen is dissolved in an aqueous phase base, and a mixed solution containing glycerin fatty acid ester and/or polyglycerin fatty acid ester and an oil phase base are prepared, and the solution and the mixed solution are mixed. The vaccine formulation of the present invention can be produced by mixing and emulsifying.
本発明のワクチン製剤は、公知の乳化製剤の製剤化手法に従って製造することができる。例えば、本発明のワクチン製剤の製造方法としては、含有させる成分を水溶性成分と油性成分に分けて、水溶性成分を含む溶解液(水相成分)と、油性成分とグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルとを含む混合液(油相成分とグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル)を調製し、これらを公知の手法に従って乳化させる方法が挙げられる。具体的には、抗原が水相基剤に溶解した溶解液と、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルと油相基剤を含む混合液とを調製し、当該溶解液と混合液とを混合して乳化させることにより、本発明のワクチン製剤を製造することができる。 [Production method]
The vaccine preparation of the present invention can be produced according to a known formulation method for emulsified preparations. For example, as a method for producing the vaccine preparation of the present invention, the components to be contained are divided into a water-soluble component and an oil component, a solution containing the water-soluble component (aqueous phase component), an oil component and a glycerin fatty acid ester and/or Examples include a method of preparing a mixed solution containing a polyglycerin fatty acid ester (oil phase component and glycerin fatty acid ester and/or polyglycerin fatty acid ester), and emulsifying them according to a known method. Specifically, a solution in which an antigen is dissolved in an aqueous phase base, and a mixed solution containing glycerin fatty acid ester and/or polyglycerin fatty acid ester and an oil phase base are prepared, and the solution and the mixed solution are mixed. The vaccine formulation of the present invention can be produced by mixing and emulsifying.
[用量・用法]
本発明のワクチン製剤は、経皮投与され、免疫を誘導するために使用される。従来の一般的な経皮投与用ワクチン製剤は、抗原の利用率が低く、免疫を十分に誘導できないという欠点があったが、本発明のワクチン製剤は経皮投与によって、注射投与を凌ぐ免疫誘導効果を奏することが可能になっている。 [Dose/Usage]
The vaccine formulation of the present invention is transdermally administered and used to induce immunity. The conventional vaccine preparation for general transdermal administration has a drawback that the antigen utilization rate is low and immunity cannot be sufficiently induced, but the vaccine preparation of the present invention induces immunity superior to injection administration by transdermal administration. It is possible to produce an effect.
本発明のワクチン製剤は、経皮投与され、免疫を誘導するために使用される。従来の一般的な経皮投与用ワクチン製剤は、抗原の利用率が低く、免疫を十分に誘導できないという欠点があったが、本発明のワクチン製剤は経皮投与によって、注射投与を凌ぐ免疫誘導効果を奏することが可能になっている。 [Dose/Usage]
The vaccine formulation of the present invention is transdermally administered and used to induce immunity. The conventional vaccine preparation for general transdermal administration has a drawback that the antigen utilization rate is low and immunity cannot be sufficiently induced, but the vaccine preparation of the present invention induces immunity superior to injection administration by transdermal administration. It is possible to produce an effect.
本発明のワクチン製剤は、含有する抗原の種類に応じて、がん免疫療法、感染症予防、花粉症等のアレルギーに対するアレルゲン免疫療法等に使用されるが、がん免疫療法に好適に使用できる。
The vaccine preparation of the present invention is used for cancer immunotherapy, infectious disease prevention, allergen immunotherapy for allergies such as hay fever, etc., depending on the type of antigen contained, but it can be suitably used for cancer immunotherapy. ..
本発明のワクチン製剤の投与対象については、前記免疫誘導が求められる動物である限り、特に制限されず、例えば、ヒト、サル、マウス、ラット、イヌ、ウサギ、ネコ、ウシ、ウマ、ヤギ等の哺乳動物;ニワトリ、ダチョウ等の鳥類が挙げられる。
The subject of administration of the vaccine preparation of the present invention is not particularly limited as long as it is an animal for which the immunity induction is required, and examples thereof include humans, monkeys, mice, rats, dogs, rabbits, cats, cows, horses, goats and the like. Mammals: Birds such as chickens and ostriches are mentioned.
本発明のワクチン製剤の投与量については、使用する抗原の種類、投与対象の症状、年齢、体重等に応じて適宜設定されるが、投与対象動物がヒトである場合、通常、1日1回~数回、好ましくは1日1回、3~12mg/kgに相当する量の抗原を経皮投与すればよい(初回免疫)。また、本発明のワクチン製剤は、初回免疫から通常1~2週間後に初回免疫と同様条件で再投与してもよい(追加免疫)。
The dose of the vaccine preparation of the present invention is appropriately set according to the type of antigen used, symptoms of the subject to be administered, age, body weight, etc., but when the subject animal is a human, it is usually administered once a day. The antigen may be transdermally administered in an amount equivalent to 3 to 12 mg/kg once to several times, preferably once a day (primary immunization). In addition, the vaccine preparation of the present invention may be re-administered usually 1 to 2 weeks after the initial immunization under the same conditions as the initial immunization (boost).
本発明のワクチン製剤が投与される皮膚部位については、特に制限されないが、例えば、ヒトの場合であれば、上腕部、胸部、背部等が挙げられ、非ヒト動物の場合であれば背部、耳介部等が挙げられる。
The skin site to which the vaccine preparation of the present invention is administered is not particularly limited, but, for example, in the case of humans, the upper arm, chest, back, etc. may be mentioned, and in the case of non-human animals, the back, ear. An intermediary part and the like can be mentioned.
以下、実施例を挙げて本発明を説明する。但し、本発明は、以下の実施例に限定されて解釈されるものではない。
The present invention will be described below with reference to examples. However, the present invention is not construed as being limited to the following examples.
試験例1
1.製剤の調製
表1に示す組成の各製剤を以下の手法で調製した。
Test example 1
1. Preparation of formulation Each formulation having the composition shown in Table 1 was prepared by the following method.
1.製剤の調製
表1に示す組成の各製剤を以下の手法で調製した。
1. Preparation of formulation Each formulation having the composition shown in Table 1 was prepared by the following method.
[実施例1及び比較例1]
水相基剤(精製水及びイソプロパノール)に、所定量のメラノーマ抗原ペプチド(K-TRP-2、アミノ酸配列:KKKGSVYDFFVWL、チロシナーゼ関連タンパク質2の180~188位のアミノ酸からなるペチチドのN末端側に1個のグリシン残基と3個のリジン残基を付加したペプチド)を溶解させた溶解液を調製した。別途、所定量の界面活性剤(モノオレイン酸グリセリル又はポリオキシエチレンソルビタンモノオレエート(Tween80))を液状油(ミリスチン酸イソプロピル)に添加し、70℃で10分間加熱し、完全に溶解させた。これに、前記溶解液の所定量を撹拌しながら、少しずつ滴下した。これを常温になるまで撹拌することにより、メラノーマ抗原ペプチドを含む油中水型乳化形態(逆ミセルによって水相が油相に分散して乳化している形態)のワクチン製剤を得た。 [Example 1 and Comparative Example 1]
A predetermined amount of melanoma antigen peptide (K-TRP-2, amino acid sequence: KKKGSVYDFFVWL, tyrosinase-relatedprotein 2 at the N-terminal side of the peptide consisting of amino acids 180 to 188) was added to an aqueous phase base (purified water and isopropanol). A lysate was prepared by dissolving a glycine residue and a peptide to which three lysine residues were added. Separately, a predetermined amount of a surfactant (glyceryl monooleate or polyoxyethylene sorbitan monooleate (Tween 80)) was added to liquid oil (isopropyl myristate) and heated at 70° C. for 10 minutes to completely dissolve it. . While stirring a predetermined amount of the solution, the solution was dropped little by little. By stirring this until it reached room temperature, a vaccine formulation in a water-in-oil emulsified form containing melanoma antigen peptide (a form in which the water phase was dispersed in the oil phase and emulsified by the reverse micelle) was obtained.
水相基剤(精製水及びイソプロパノール)に、所定量のメラノーマ抗原ペプチド(K-TRP-2、アミノ酸配列:KKKGSVYDFFVWL、チロシナーゼ関連タンパク質2の180~188位のアミノ酸からなるペチチドのN末端側に1個のグリシン残基と3個のリジン残基を付加したペプチド)を溶解させた溶解液を調製した。別途、所定量の界面活性剤(モノオレイン酸グリセリル又はポリオキシエチレンソルビタンモノオレエート(Tween80))を液状油(ミリスチン酸イソプロピル)に添加し、70℃で10分間加熱し、完全に溶解させた。これに、前記溶解液の所定量を撹拌しながら、少しずつ滴下した。これを常温になるまで撹拌することにより、メラノーマ抗原ペプチドを含む油中水型乳化形態(逆ミセルによって水相が油相に分散して乳化している形態)のワクチン製剤を得た。 [Example 1 and Comparative Example 1]
A predetermined amount of melanoma antigen peptide (K-TRP-2, amino acid sequence: KKKGSVYDFFVWL, tyrosinase-related
[比較例2及び参考例1]
リン酸緩衝剤(PBS)に所定量の所定量のメラノーマ抗原ペプチド(K-TRP-2)を添加して溶解させることにより、水溶液状のワクチン製剤を得た。 [Comparative Example 2 and Reference Example 1]
An aqueous vaccine preparation was obtained by adding a predetermined amount of a predetermined amount of melanoma antigen peptide (K-TRP-2) to a phosphate buffer (PBS) and dissolving it.
リン酸緩衝剤(PBS)に所定量の所定量のメラノーマ抗原ペプチド(K-TRP-2)を添加して溶解させることにより、水溶液状のワクチン製剤を得た。 [Comparative Example 2 and Reference Example 1]
An aqueous vaccine preparation was obtained by adding a predetermined amount of a predetermined amount of melanoma antigen peptide (K-TRP-2) to a phosphate buffer (PBS) and dissolving it.
2.免疫誘導実験
6週齢のマウス(C57BL/6N、雌)を表2に示す4つの試験群に分けて(1群当たり、6匹)、表2に示す条件で初日(Day-14)に初回免疫、1週間後(Day -7)に追加免疫を行った。なお、初回免疫及び追加免疫のそれぞれにおいて、投与された各成分量は表1に示す通りである。
2. Immune induction experiment 6-week-old mice (C57BL/6N, female) were divided into four test groups shown in Table 2 (6 mice per group), and the first day (Day-14) under the conditions shown in Table 2 Immunization, one week later (Day -7), booster immunization was performed. The amount of each component administered in each of the primary immunization and the booster immunization is as shown in Table 1.
6週齢のマウス(C57BL/6N、雌)を表2に示す4つの試験群に分けて(1群当たり、6匹)、表2に示す条件で初日(Day-14)に初回免疫、1週間後(Day -7)に追加免疫を行った。なお、初回免疫及び追加免疫のそれぞれにおいて、投与された各成分量は表1に示す通りである。
追加免疫から7日後の各マウスに、HBSS(-)培地に1.0×106cells/mlとなるように懸濁したマウスメラノーマ細胞(B16F10)の細胞懸濁液100μlを皮下注射により移植した(Day 0)。マウスメラノーマ細胞の移植5日後から2日おきに腫瘍の長径と短径を測定し、下記式に基づいて、腫瘍体積を算出した。
Seven days after the booster immunization, 100 μl of a cell suspension of mouse melanoma cells (B16F10) suspended in HBSS(−) medium at 1.0×10 6 cells/ml was transplanted subcutaneously to each mouse. (Day 0). The major axis and minor axis of the tumor were measured every 2 days from 5 days after the transplantation of mouse melanoma cells, and the tumor volume was calculated based on the following formula.
また、実施例1経皮投与群及び参考例1注射投与群については、マウスメラノーマ細胞の移植14日後に、皮下から腫瘍を取り出して、腫瘍を20μm厚に裁断し、スライドガラスに載せて、アロフィコシアニン(APC)標識抗CD8抗体とDAPI(4’,6-diamidino-2-phenylindole)にて染色した(Day 14)。
For the transdermal administration group of Example 1 and the injection administration group of Reference Example 14, 14 days after the transplantation of mouse melanoma cells, the tumor was taken out from the skin, the tumor was cut to a thickness of 20 μm, and placed on a slide glass. It was stained with a phycocyanin (APC)-labeled anti-CD8 antibody and DAPI (4′,6-diamidino-2-phenylindole) (Day 14).
図1に実験スケジュール、図2に腫瘍体積を経時的に測定した結果、及び図3に移植14日後取り出した腫瘍をAPC標識抗CD8抗体とDAPIで染色した結果を示す。図2から分かるように、比較例1皮下投与群及び比較例2皮下投与群では、参考例1注射投与群に比べて、腫瘍体積が大きく、がん免疫の誘導が不十分になっていた。これに対して、実施例1経皮投与群では、参考例1注射投与群よりも腫瘍体積が小さく、がん免疫を効果的に誘導できていた。更に、図3から分かるように、参考例1注射投与群では、腫瘍中にAPCの蛍光が認められず、細胞障害性T細胞は腫瘍中に遊走していなかったが、実施例1経皮投与群では、腫瘍中にAPCの蛍光が観察され、腫瘍中に細胞障害性T細胞が遊走していることが確認された。
Fig. 1 shows the experimental schedule, Fig. 2 shows the results of measuring the tumor volume over time, and Fig. 3 shows the results of staining the tumors taken out 14 days after transplantation with the APC-labeled anti-CD8 antibody and DAPI. As can be seen from FIG. 2, in the subcutaneous administration group of Comparative Example 1 and the subcutaneous administration group of Comparative Example 2, the tumor volume was large and the induction of cancer immunity was insufficient as compared with the injection administration group of Reference Example 1. On the other hand, in the transdermal administration group of Example 1, the tumor volume was smaller than that in the injection administration group of Reference Example 1, and cancer immunity could be effectively induced. Furthermore, as can be seen from FIG. 3, in the injection administration group of Reference Example 1, fluorescence of APC was not observed in the tumor, and cytotoxic T cells were not migrated into the tumor. In the group, fluorescence of APC was observed in the tumor, and it was confirmed that cytotoxic T cells migrated in the tumor.
また、実施例1の経皮投与用のワクチン製剤において、モノオレイン酸グリセリルに代えて、トリオレイン酸ポリグリセリル-10、又はイソステアリン酸ポリグリセリル-2を使用した経皮投与用のワクチン製剤を調製し、前記と同様の免疫誘導実験を行ったところ、トリオレイン酸ポリグリセリル-10又はイソステアリン酸ポリグリセリル-2を使用した経皮投与用のワクチン製剤でも、優れたがん免疫の誘導が確認された。更に、実施例1の経皮投与用のワクチン製剤において、水相基剤をリン酸緩衝液とイソプロパノールの混合液からリン酸緩衝液単独に代えて経皮投与用のワクチン製剤を調製し、前記と同様の免疫誘導実験を行ったところ、優れたがん免疫の誘導が確認された。
Further, in the vaccine preparation for transdermal administration of Example 1, in place of glyceryl monooleate, polyglyceryl-10 trioleate or polyglyceryl isostearate-2 was used to prepare a vaccine preparation for transdermal administration, When the same immunity induction experiment as described above was carried out, excellent induction of cancer immunity was confirmed even with a vaccine preparation for transdermal administration using polyglyceryl-10 trioleate or polyglyceryl isostearate-2. Furthermore, in the vaccine preparation for transdermal administration of Example 1, a vaccine preparation for transdermal administration is prepared by replacing the aqueous phase base from a mixed solution of a phosphate buffer and isopropanol with a phosphate buffer alone. When an immunity induction experiment similar to that was conducted, excellent induction of cancer immunity was confirmed.
以上の結果から、抗原が水に溶解した溶解液とグリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルとを含む水溶性画分を、油相に分散させたワクチン製剤は、経皮投与によって免疫を効果的に誘導できることが確認された。
From the above results, a vaccine preparation in which a water-soluble fraction containing a solution in which an antigen is dissolved in water and a glycerin fatty acid ester and/or a polyglycerin fatty acid ester are dispersed in an oil phase is effective for immunity by transdermal administration. It was confirmed that it can be induced.
試験例2
1.製剤の調製
表3に示す組成の各製剤を以下の手法で調製した。
Test example 2
1. Preparation of formulation Each formulation having the composition shown in Table 3 was prepared by the following method.
1.製剤の調製
表3に示す組成の各製剤を以下の手法で調製した。
1. Preparation of formulation Each formulation having the composition shown in Table 3 was prepared by the following method.
[実施例2]
水相基剤(精製水及びイソプロパノール)に、所定量の花粉抗原ペプチド(pepA、アミノ酸配列:SMKVTVAFNQFGP)を溶解させた溶解液を調製した。別途、所定量の界面活性剤(モノオレイン酸グリセリル)を液状油(ミリスチン酸イソプロピル)に添加し、70℃で10分間加熱し、完全に溶解させた。これに、前記溶解液の所定量を撹拌しながら、少しずつ滴下した。これを常温になるまで撹拌することにより、花粉抗原ペプチドを含む油中水型乳化形態(逆ミセルによって水相が油相に分散して乳化している形態)のワクチン製剤を得た。 [Example 2]
A solution was prepared by dissolving a predetermined amount of pollen antigen peptide (pepA, amino acid sequence: SMKVTVAFNQFGP) in an aqueous phase base (purified water and isopropanol). Separately, a predetermined amount of a surfactant (glyceryl monooleate) was added to a liquid oil (isopropyl myristate) and heated at 70° C. for 10 minutes to completely dissolve it. While stirring a predetermined amount of the solution, the solution was dropped little by little. By stirring this to room temperature, a vaccine formulation in a water-in-oil emulsified form (form in which the water phase was dispersed in the oil phase by the reverse micelle and emulsified) containing the pollen antigen peptide was obtained.
水相基剤(精製水及びイソプロパノール)に、所定量の花粉抗原ペプチド(pepA、アミノ酸配列:SMKVTVAFNQFGP)を溶解させた溶解液を調製した。別途、所定量の界面活性剤(モノオレイン酸グリセリル)を液状油(ミリスチン酸イソプロピル)に添加し、70℃で10分間加熱し、完全に溶解させた。これに、前記溶解液の所定量を撹拌しながら、少しずつ滴下した。これを常温になるまで撹拌することにより、花粉抗原ペプチドを含む油中水型乳化形態(逆ミセルによって水相が油相に分散して乳化している形態)のワクチン製剤を得た。 [Example 2]
A solution was prepared by dissolving a predetermined amount of pollen antigen peptide (pepA, amino acid sequence: SMKVTVAFNQFGP) in an aqueous phase base (purified water and isopropanol). Separately, a predetermined amount of a surfactant (glyceryl monooleate) was added to a liquid oil (isopropyl myristate) and heated at 70° C. for 10 minutes to completely dissolve it. While stirring a predetermined amount of the solution, the solution was dropped little by little. By stirring this to room temperature, a vaccine formulation in a water-in-oil emulsified form (form in which the water phase was dispersed in the oil phase by the reverse micelle and emulsified) containing the pollen antigen peptide was obtained.
[比較例3]
リン酸緩衝剤(PBS)に所定量の所定量の花粉抗原ペプチド(pepA)を添加して溶解させることにより、水溶液状のワクチン製剤を得た。 [Comparative Example 3]
An aqueous vaccine preparation was obtained by adding a predetermined amount of a predetermined amount of pollen antigen peptide (pepA) to a phosphate buffer (PBS) and dissolving it.
リン酸緩衝剤(PBS)に所定量の所定量の花粉抗原ペプチド(pepA)を添加して溶解させることにより、水溶液状のワクチン製剤を得た。 [Comparative Example 3]
An aqueous vaccine preparation was obtained by adding a predetermined amount of a predetermined amount of pollen antigen peptide (pepA) to a phosphate buffer (PBS) and dissolving it.
2.免疫誘導実験
6週齢のマウス(B10.S、雌)40匹を水と餌を自由摂取できる環境で1週間飼育して馴化させた後に、花粉抗原抽出物10μg及びInject? Alum Adjuvant(Thermo Fisher Scientific社製)4mgを含むリン酸緩衝液(PBS)200μlを両足の付け根に1週間に1回の頻度で合計3回皮下投与し、花粉症モデルマウスを作製した。3回目の皮下投与から6日後にヒスタミン(20ng/head)を経鼻投与し、その翌日から、花粉暴露を1日回の頻度で5日間行った。花粉暴露は、スギ花粉抽出物(商品名「スギ花粉抽出物-Cj」、株式会社エル・エス・エル製)を0.1mg/mLとなるようにPBS溶液に溶解させた花粉溶液を両鼻腔に10μLずつ経鼻曝露することにより行った。花粉暴露終了から1週間後に、マウスの尾から採血し、ELISAにより血中のIgE抗体価を測定した。IgE抗体価が高い順で5番目~34番目の花粉症モデルマウスから、12匹を選定し、各群のIgE抗体価の平均値が同じになるように、表4に示す2群(1群当たり、6匹)に分け、通常の環境で8日間飼育した後に、表4に示す条件で初回免疫及び追加免疫を行った。
2. Immunity induction experiment 40 6-week-old mice (B10.S, female) were bred for 1 week in an environment where they could freely ingest water and food, and then acclimatized, and then 10 μg of pollen antigen extract and Inject? 200 μl of a phosphate buffer solution (PBS) containing 4 mg of Alum Adjuvant (Thermo Fisher Scientific) was subcutaneously administered to the roots of both legs once a week for a total of 3 times to prepare a pollinosis model mouse. Histamine (20 ng/head) was intranasally administered 6 days after the third subcutaneous administration, and from the next day, pollen exposure was performed once a day for 5 days. For pollen exposure, the pollen solution was prepared by dissolving a cedar pollen extract (trade name "Cedar pollen extract-Cj", manufactured by LSS Co., Ltd.) in a PBS solution to a concentration of 0.1 mg/mL in both nostrils. By nasal exposure of 10 μL each. One week after the end of the pollen exposure, blood was collected from the tail of the mouse, and the IgE antibody titer in the blood was measured by ELISA. Twelve mice were selected from the 5th to 34th pollinosis model mice in descending order of IgE antibody titers, and the two groups (1 group) shown in Table 4 were selected so that the average IgE antibody titers in each group were the same. 6 animals) and were bred for 8 days in a normal environment, and then subjected to the initial immunization and booster immunization under the conditions shown in Table 4.
6週齢のマウス(B10.S、雌)40匹を水と餌を自由摂取できる環境で1週間飼育して馴化させた後に、花粉抗原抽出物10μg及びInject? Alum Adjuvant(Thermo Fisher Scientific社製)4mgを含むリン酸緩衝液(PBS)200μlを両足の付け根に1週間に1回の頻度で合計3回皮下投与し、花粉症モデルマウスを作製した。3回目の皮下投与から6日後にヒスタミン(20ng/head)を経鼻投与し、その翌日から、花粉暴露を1日回の頻度で5日間行った。花粉暴露は、スギ花粉抽出物(商品名「スギ花粉抽出物-Cj」、株式会社エル・エス・エル製)を0.1mg/mLとなるようにPBS溶液に溶解させた花粉溶液を両鼻腔に10μLずつ経鼻曝露することにより行った。花粉暴露終了から1週間後に、マウスの尾から採血し、ELISAにより血中のIgE抗体価を測定した。IgE抗体価が高い順で5番目~34番目の花粉症モデルマウスから、12匹を選定し、各群のIgE抗体価の平均値が同じになるように、表4に示す2群(1群当たり、6匹)に分け、通常の環境で8日間飼育した後に、表4に示す条件で初回免疫及び追加免疫を行った。
2回目の追加免疫終了(合計3回の免疫終了)から6日後にヒスタミン(20ng/head)を経鼻投与し、その翌日から、花粉暴露を1日回の頻度で5日間行った。花粉暴露は、スギ花粉抽出物(商品名「スギ花粉抽出物-Cj」、株式会社エル・エス・エル製)を0.1mg/mLとなるようにPBS溶液に溶解させた花粉溶液を両鼻腔に10μLずつ経鼻曝露することにより行った。花粉暴露終了から1週間後に、マウスの尾から採血し、更に脾臓を摘出した。
Histamine (20 ng/head) was intranasally administered 6 days after the completion of the second booster immunization (completion of a total of 3 immunizations), and from the next day, pollen exposure was performed once a day for 5 days. For pollen exposure, a pollen solution prepared by dissolving a cedar pollen extract (trade name “Sugi pollen extract-Cj”, manufactured by ELS Co., Ltd.) in a PBS solution to a concentration of 0.1 mg/mL was applied to both nostrils. By nasal exposure of 10 μL each. One week after the end of pollen exposure, blood was collected from the tail of the mouse, and the spleen was extracted.
得られた血液から血清を調製し、ELISAによりCrij1特異的IgE抗体、及びIgG1抗体の血清中濃度を測定した。
Serum was prepared from the obtained blood, and serum concentrations of Crij1-specific IgE antibody and IgG1 antibody were measured by ELISA.
また、得られた脾臓は、すりつぶして溶血処理を行った後に、70μmのセルストレーナーで不純物を除去することにより細胞を回収した。得られた細胞を10%非働化済みFBS(牛胎児血清)、50μMの2-メルカプトエタノール、及び1% 抗生物質/抗真菌剤混合溶液を含むPRMI1640培地にて37℃で3日間培養した後に、培養液(脾臓細胞培養液)を回収した。得られた培養液中のサイトカイン(IL-4、及びIL-5)濃度をELISAにより測定した。
Also, the obtained spleen was ground and subjected to hemolytic treatment, and then cells were collected by removing impurities with a 70 μm cell strainer. After culturing the obtained cells in a PRMI1640 medium containing 10% inactivated FBS (fetal bovine serum), 50 μM 2-mercaptoethanol, and 1% antibiotic/antimycotic mixed solution at 37° C. for 3 days, The culture medium (spleen cell culture medium) was collected. The cytokine (IL-4 and IL-5) concentration in the obtained culture solution was measured by ELISA.
図4に実験スケジュール、並びに図5にCrij1特異的IgE抗体、及びIgG1抗体の血清中濃度、並びに脾臓細胞培養液中のサイトカイン(IL-4、及びIL-5)濃度の測定結果を示す。この結果、実施例2経皮投与群では、比較例3経皮投与群に比べて、血清中の抗体濃度が低下しており、更にアレルギー反応に関与するサイトカインの産生量を抑制できることが確認された。
FIG. 4 shows the experimental schedule, and FIG. 5 shows the results of measuring the serum concentrations of Crij1-specific IgE antibody and IgG1 antibody and the cytokine (IL-4 and IL-5) concentrations in the spleen cell culture medium. As a result, in the transdermal administration group of Example 2, the antibody concentration in the serum was lower than that in the transdermal administration group of Comparative Example 3, and it was confirmed that the production amount of cytokines involved in allergic reaction can be suppressed. It was
試験例3
1.製剤の調製
表5に示す組成の各製剤を以下の手法で調製した。
Test example 3
1. Preparation of formulation Each formulation having the composition shown in Table 5 was prepared by the following method.
1.製剤の調製
表5に示す組成の各製剤を以下の手法で調製した。
1. Preparation of formulation Each formulation having the composition shown in Table 5 was prepared by the following method.
[実施例3]
水相基剤(精製水及びイソプロパノール)に、所定量のインフルエンザウイルス抗原タンパク質(Influenza A H3N2(A/Aichi/1968)Hemagglutinin/HA Protein(His tag)、Sino Biological)を溶解させた溶解液を調製した。別途、所定量の界面活性剤(モノオレイン酸グリセリル)を液状油(ミリスチン酸イソプロピル)に添加し、70℃で10分間加熱し、完全に溶解させた。これに、前記溶解液の所定量を撹拌しながら、少しずつ滴下した。これを常温になるまで撹拌することにより、花粉抗原ペプチドを含む油中水型乳化形態(逆ミセルによって水相が油相に分散して乳化している形態)のワクチン製剤を得た。 [Example 3]
A solution was prepared by dissolving a predetermined amount of influenza virus antigen protein (Influenza A H3N2 (A/Aichi/1968) Hemagglutinin/HA Protein (His tag), Sino Biological) in an aqueous phase base (purified water and isopropanol). did. Separately, a predetermined amount of a surfactant (glyceryl monooleate) was added to a liquid oil (isopropyl myristate) and heated at 70° C. for 10 minutes to completely dissolve it. While stirring a predetermined amount of the solution, the solution was dropped little by little. By stirring this to room temperature, a vaccine formulation in a water-in-oil emulsified form (form in which the water phase was dispersed in the oil phase by the reverse micelle and emulsified) containing the pollen antigen peptide was obtained.
水相基剤(精製水及びイソプロパノール)に、所定量のインフルエンザウイルス抗原タンパク質(Influenza A H3N2(A/Aichi/1968)Hemagglutinin/HA Protein(His tag)、Sino Biological)を溶解させた溶解液を調製した。別途、所定量の界面活性剤(モノオレイン酸グリセリル)を液状油(ミリスチン酸イソプロピル)に添加し、70℃で10分間加熱し、完全に溶解させた。これに、前記溶解液の所定量を撹拌しながら、少しずつ滴下した。これを常温になるまで撹拌することにより、花粉抗原ペプチドを含む油中水型乳化形態(逆ミセルによって水相が油相に分散して乳化している形態)のワクチン製剤を得た。 [Example 3]
A solution was prepared by dissolving a predetermined amount of influenza virus antigen protein (Influenza A H3N2 (A/Aichi/1968) Hemagglutinin/HA Protein (His tag), Sino Biological) in an aqueous phase base (purified water and isopropanol). did. Separately, a predetermined amount of a surfactant (glyceryl monooleate) was added to a liquid oil (isopropyl myristate) and heated at 70° C. for 10 minutes to completely dissolve it. While stirring a predetermined amount of the solution, the solution was dropped little by little. By stirring this to room temperature, a vaccine formulation in a water-in-oil emulsified form (form in which the water phase was dispersed in the oil phase by the reverse micelle and emulsified) containing the pollen antigen peptide was obtained.
[コントロール]
インフルエンザウイルス抗原タンパク質を含まないこと以外は、前記実施例3と同様の方法で、油中水型乳化形態(逆ミセルによって水相が油相に分散して乳化している形態)のワクチン製剤を得た。 [Control]
A vaccine preparation in a water-in-oil emulsified form (form in which an aqueous phase is dispersed in an oil phase by reverse micelles and emulsified) is prepared in the same manner as in Example 3 except that the influenza virus antigen protein is not included. Obtained.
インフルエンザウイルス抗原タンパク質を含まないこと以外は、前記実施例3と同様の方法で、油中水型乳化形態(逆ミセルによって水相が油相に分散して乳化している形態)のワクチン製剤を得た。 [Control]
A vaccine preparation in a water-in-oil emulsified form (form in which an aqueous phase is dispersed in an oil phase by reverse micelles and emulsified) is prepared in the same manner as in Example 3 except that the influenza virus antigen protein is not included. Obtained.
2.免疫誘導実験
6週齢のマウス(BALB/c、雌)を水と餌を自由摂取できる環境で1週間飼育して馴化させた後に、表6に示す2つの試験群に分けて(1群当たり、6匹)、表6に示す条件で初回免疫及び追加免疫を行った。
2. Immunity induction experiment Six-week-old mice (BALB/c, female) were bred for 1 week in an environment where they could freely ingest water and food and acclimated, and then divided into two test groups shown in Table 6 (per group). , 6), and the initial immunization and booster immunization were performed under the conditions shown in Table 6.
6週齢のマウス(BALB/c、雌)を水と餌を自由摂取できる環境で1週間飼育して馴化させた後に、表6に示す2つの試験群に分けて(1群当たり、6匹)、表6に示す条件で初回免疫及び追加免疫を行った。
2回目の追加免疫後、通常の環境で3週間飼育した。初回免疫行った日から1週間に1回の頻度で、マウスの尾から採血した。得られた血液から血清を調製し、ELISAにより抗インフルエンザA(H3N2)抗体の血清中濃度を測定した。
After the second booster immunization, the animals were raised in a normal environment for 3 weeks. Blood was collected from the tail of the mouse once a week from the day of the first immunization. Serum was prepared from the obtained blood and the serum concentration of anti-influenza A(H3N2) antibody was measured by ELISA.
図6に実験スケジュール、並びに図7に抗インフルエンザA(H3N2)抗体の血清中濃度の測定結果を示す。この結果、実施例3経皮投与群では、hyou
初回免疫から3週間後には、抗インフルエンザA(H3N2)抗体の産生が認められ、経時的に当該抗体濃度が上昇することが確認された。 FIG. 6 shows the experimental schedule, and FIG. 7 shows the measurement results of the serum concentration of anti-influenza A(H3N2) antibody. As a result, in the transdermal administration group of Example 3, hyou
Three weeks after the initial immunization, production of anti-influenza A(H3N2) antibody was observed, and it was confirmed that the antibody concentration increased with time.
初回免疫から3週間後には、抗インフルエンザA(H3N2)抗体の産生が認められ、経時的に当該抗体濃度が上昇することが確認された。 FIG. 6 shows the experimental schedule, and FIG. 7 shows the measurement results of the serum concentration of anti-influenza A(H3N2) antibody. As a result, in the transdermal administration group of Example 3, hyou
Three weeks after the initial immunization, production of anti-influenza A(H3N2) antibody was observed, and it was confirmed that the antibody concentration increased with time.
Claims (7)
- 抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散している、経皮投与用ワクチン製剤。 A vaccine preparation for transdermal administration, which comprises an aqueous phase in which an antigen is dissolved, a glycerin fatty acid ester and/or a polyglycerin fatty acid ester, and an oil phase, and the aqueous phase is dispersed in the oil phase.
- 前記抗原の由来が、がん細胞、病原性ウイルス、病原性細菌、病原性生物、又は花粉である、請求項1に記載の経皮投与用ワクチン製剤。 The vaccine preparation for transdermal administration according to claim 1, wherein the origin of the antigen is a cancer cell, a pathogenic virus, a pathogenic bacterium, a pathogenic organism, or pollen.
- 前記抗原が抗原ペプチドである、請求項1又は2に記載の経皮投与用ワクチン製剤。 The vaccine preparation for transdermal administration according to claim 1 or 2, wherein the antigen is an antigen peptide.
- 前記グリセリン脂肪酸エステルが、モノオレイン酸グリセリルである、請求項1~3のいずれかに記載の経皮投与用ワクチン製剤。 The vaccine preparation for transdermal administration according to any one of claims 1 to 3, wherein the glycerin fatty acid ester is glyceryl monooleate.
- 前記グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステルの含有量が0.1~30重量%である、請求項1~4のいずれかに記載の経皮投与用ワクチン製剤。 The vaccine preparation for transdermal administration according to any one of claims 1 to 4, wherein the content of the glycerin fatty acid ester and/or the polyglycerin fatty acid ester is 0.1 to 30% by weight.
- 抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散している組成物の、経皮投与用ワクチン製剤の製造のための使用。 For the production of a vaccine preparation for transdermal administration of a composition comprising an aqueous phase in which an antigen is dissolved, glycerin fatty acid ester and/or polyglycerin fatty acid ester, and an oil phase, wherein the aqueous phase is dispersed in the oil phase Use of.
- 抗原が溶解した水相、グリセリン脂肪酸エステル及び/又はポリグリセリン脂肪酸エステル、並びに油相を含み、前記水相が前記油相に分散している組成物の免疫誘導に有効な量を、免疫誘導が求められている動物に対して経皮投与する工程を含む、免疫誘導方法。 An immune-inducing effective amount of a composition containing an aqueous phase in which an antigen is dissolved, glycerin fatty acid ester and/or polyglycerin fatty acid ester, and an oil phase, the aqueous phase being dispersed in the oil phase, A method for inducing immunity, comprising the step of transdermal administration to an animal in need.
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JP2008179561A (en) * | 2007-01-24 | 2008-08-07 | Aspion Kk | S/o type transcutaneous immunizing agent |
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WO2018124043A1 (en) * | 2016-12-28 | 2018-07-05 | 小林製薬株式会社 | Composition for external application |
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