JP6352718B2 - Adjuvant composition and adjuvant formulation - Google Patents

Description

  The present invention relates to an adjuvant composition and an adjuvant formulation.

  An adjuvant is a substance that enhances immunogenicity, and when administered with an antigen, an immune response to the antigen is enhanced. For example, in vaccination, it is possible to reduce the dose and frequency of administration of vaccine by using an adjuvant.

  There are various types of adjuvants, and in recent years, an adjuvant composition containing a therapeutic drug for dyslipidemia has been proposed (Patent Document 1).

JP 2014-40396 A

  The object of the present invention is to provide a new adjuvant composition.

  As a result of intensive studies, the present inventors have found that captopril and amlodipine have an enhancing effect on immune responses. Captopril is known as an angiotensin modifying enzyme (ACE) inhibitor and is used for the treatment of hypertension. Amlodipine is also known as a calcium channel antagonist and is used for the treatment of hypertension and angina. However, captopril and amlodipine are not considered to be involved in the immune response in view of their mechanism of action, and the findings obtained by the present inventors were surprising. Based on this finding, the present inventors have completed the present invention.

  That is, the present invention provides an adjuvant composition containing a drug selected from the group consisting of captopril and amlodipine or a salt thereof. The present invention also provides an adjuvant formulation containing such an adjuvant composition. Such adjuvant formulations may be transdermal or transmucosal formulations.

  According to the present invention, a new adjuvant composition is provided.

  Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

  The adjuvant composition according to the present embodiment is characterized by containing a drug selected from the group consisting of captopril and amlodipine or a salt thereof.

  The adjuvant composition having the above-described configuration can exert an excellent immune response enhancing action (immunostimulatory effect).

  In addition, since the adjuvant composition according to the present embodiment can exert an immune response enhancing action by itself, it is not necessary to administer the adjuvant composition in combination with the antigen, and it can be administered separately from the antigen. The timing of administration of the adjuvant composition may be before the antigen administration, at the time of antigen administration, or after the antigen administration. It is preferably performed before or after antigen administration. Furthermore, the dosage form of the adjuvant composition can also be administered in a dosage form different from the antigen, and may be administered by a route independent of the antigen. Therefore, when administering the adjuvant composition, it is not necessary to consider conditions such as the dosage of the antigen, and the dosage, administration time, dosage form, etc. of the adjuvant composition itself can be selected. Since the adjuvant composition according to this embodiment can be administered separately from the antigen, the adjuvant composition can be administered while avoiding swelling and pain at the administration site that occurs during administration of the antigen.

  The content of captopril or a salt thereof is preferably 1 to 10% by mass and more preferably 1 to 5% by mass based on the total mass of the adjuvant composition. By setting it within the above range, it is possible to sufficiently obtain the immune response enhancing action of the adjuvant composition and to sufficiently suppress the skin irritation of the adjuvant composition.

  The content of amlodipine or a salt thereof is preferably 0.01 to 0.1% by mass, and more preferably 0.01 to 0.05% by mass based on the total mass of the adjuvant composition. By setting it within the above range, it is possible to sufficiently obtain the immune response enhancing action of the adjuvant composition and to sufficiently suppress the skin irritation of the adjuvant composition. Examples of amlodipine salts include amlodipine besylate.

  The adjuvant composition may contain a pharmaceutically acceptable carrier. Examples of the pharmaceutically acceptable carrier include water, physiological saline, buffer solution and the like.

  The above adjuvant composition can be used as an adjuvant preparation containing the same.

  The content of the adjuvant composition in the adjuvant preparation can be adjusted according to the purpose of use and the like, but it is preferable to contain the adjuvant composition at a high concentration. The content of the adjuvant composition can be 50 to 100% by mass based on the total mass of the adjuvant preparation, but is preferably 75 to 100% by mass, more preferably 85 to 100% by mass, More preferably, it is 95-100 mass%. By setting the content of the adjuvant composition to 50% by mass or more, the enhancing action of the immune response of the adjuvant preparation can be further improved.

  The adjuvant preparation can contain other components depending on the purpose of use, the form of the preparation, and the like. Other ingredients include thickeners, wetting agents, fillers, solubilizers, solubilizers, absorption enhancers, medicinal aids, stabilizers, antioxidants, emulsifiers, surfactants, crosslinkers, and polymerizers. , Adhesives, plasticizers, pH adjusters, preservatives, excipients and the like.

  It is preferable that the thickener is capable of stably holding water at 30 to 80% and having water retention. Thickeners include, for example, guar gum, locust bean gum, carrageenan, alginic acid, sodium alginate, agar, gum arabic (acacia gum), tragacanth gum, karaya gum, pectin, starch and other microbial systems such as xanthan gum, gelatin, collagen Natural polymers such as animal systems, cellulose systems such as methylcellulose, ethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, starch-based semisynthetic polymers such as soluble starch, carboxymethyl starch, and dialdehyde starch, polyvinyl alcohol, polyvinylpyrrolidone , Vinyls such as polyvinyl methacrylate, acrylics such as polyacrylic acid and sodium polyacrylate, polyethylene oxide, methyl vinyl ether / A water-soluble polymer such as a synthetic polymer water maleate copolymer, and the like. Of these thickeners, sodium polyacrylate is preferred. Sodium polyacrylate has high gel strength and excellent water retention. Sodium polyacrylate having an average degree of polymerization of 20000 to 70000 is more preferred. When the average degree of polymerization is larger than 20000, the thickening effect becomes more sufficient and the gel strength tends to be improved. Moreover, when the average degree of polymerization is less than 70000, it is possible to suppress a decrease in workability due to an excessively thickening effect. Further, by using two or more kinds of the above thickeners in combination, for example, sodium polyacrylate forms a polymer complex with a strong ionic polymer, and an elastic gel with even higher gel strength can be obtained.

  As the wetting agent, a polyhydric alcohol such as sorbitol can be used. As the filler, kaolin, zinc oxide, talc, titanium, bentonite, aluminum silicate, titanium oxide, zinc oxide, aluminum metasilicate, calcium sulfate, calcium phosphate and the like can be used. The total amount of the wetting agent and the filler is preferably 0.1 to 30% by mass, more preferably 0.1 to 20% by mass based on the total mass of the adjuvant preparation.

  As a solubilizer or absorption promoter, propylene carbonate, crotamiton, l-menthol, peppermint oil, limonene, diisopropyl adipate, and the like can be used.

  As medicinal aids, use methyl salicylate, glycol salicylate, l-menthol, thymol, mint oil, nonyl acid vanillylamide, red pepper extract, aluminum hydroxide, aluminum phosphate, aluminum chloride, aluminum hydroxyphosphite sulfate, etc. Can do.

  As the surfactant, any of a nonionic active agent and an ionic active agent (cation, anion, amphoteric) can be used. From the viewpoint of safety, it is desirable to use a nonionic active agent usually used for a pharmaceutical base. Examples of such surfactants include sugar alcohol fatty acid esters such as sucrose fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene Examples include glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil.

  The adjuvant preparation may contain a crosslinking agent, a polymerization agent and the like. By containing such components, the plaster can be strengthened and water retention can be imparted. A crosslinking agent and a polymerization agent are suitably selected according to kinds, such as a thickener.

  For example, when polyacrylic acid or polyacrylate is used as the thickener, in addition to a compound having at least two epoxy groups in the molecule, for example, hydrochlorides such as Ca, Mg, Al, sulfates, Inorganic acid salts such as phosphate and carbonate, organic acid salts such as citrate, tartrate, gluconate and stearate, oxides such as zinc oxide and anhydrous silicic acid, aluminum hydroxide, magnesium hydroxide, etc. A polyvalent metal compound such as a hydroxide is preferably used.

  When polyvinyl alcohol is used as the thickener, adipic acid, thioglycolic acid, epoxy compound (epichlorohydrin), aldehydes, N-methylol compound, Al, Ti, Zr, Sn, V, Cu, B, Cr Etc. are preferably used.

  When polyvinylpyrrolidone is used as the thickener, methyl vinyl ether / maleic anhydride copolymer, polyacid compound or alkali metal salt thereof (polyacrylic acid, tannic acid and derivatives thereof) and the like are preferably used.

  In addition, when polyethylene oxide is used as the thickener, peroxide, polysulfone azide and the like are preferably used.

  Further, when a methyl vinyl ether / maleic anhydride copolymer is used as the thickener, polyfunctional hydroxy compounds, polyamines, iodine, gelatin, polyvinyl pyrrolidone, iron, mercury, lead salts, and the like are preferably used.

  When gelatin is used as the thickener, aldehydes such as formaldehyde, glutaraldehyde, and dialdehyde starch, diepoxides such as glyoxal and butadiene oxide, diketones such as divinyl ketone, and diisocyanates are preferably used. .

  When sodium polyacrylate is used as the thickener, a polyvalent metal salt such as lithium hydroxide, zinc hydroxide, aluminum hydroxide, sodium borate is preferably used as the crosslinking agent. In particular, zinc salts and aluminum salts are preferred. This is because the crosslinking reaction is promoted.

  The concentration of the polyvalent metal salt added as the crosslinking agent is preferably 0.5 to 1.5 equivalents per 1 equivalent of the thickener (or water-soluble polymer). By setting the concentration of the polyvalent metal salt to 0.5 equivalents or more, the reaction is promoted and the gel strength is increased. In this case, the gelation can be made uniform and workability can be improved.

  As the adhesive, an acrylic polymer or a rubber polymer is preferable.

  The acrylic polymer may be a copolymer containing at least one (meth) acrylic acid derivative typified by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like. Although it will not specifically limit, Preferably what contains 50% or more of 2-ethylhexyl acrylate is preferable. Specific examples of adhesives include acrylic acid / acrylic acid octyl ester copolymers, 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer, which are listed as adhesives in Pharmaceutical Additives Encyclopedia 2000 (edited by Japan Pharmaceutical Additives Association). Combined solution, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin alkanolamine liquid The included adhesives such as acrylic polymers, DURO-TAK acrylic adhesive series (manufactured by Henkel), Eudragit series (Higuchi Shokai) and the like can be used. Examples of rubber polymers include styrene-isoprene-styrene block copolymer (hereinafter abbreviated as SIS), isoprene rubber, polyisobutylene (hereinafter abbreviated as PIB), styrene-butadiene-styrene block copolymer ( Hereinafter, abbreviated as SBS), styrene-butadiene rubber (hereinafter abbreviated as SBR), polysiloxane, and the like. Of these rubber polymers, SIS, PIB and polysiloxane are preferred, and SIS and PIB are more preferred. These pressure-sensitive adhesives may be used alone or in combination of two or more.

  The compounding amount of the adhesive is preferably 5 to 90% by mass, more preferably 10 to 70% by mass, based on the total mass of the adjuvant preparation. When the blending amount of the pressure-sensitive adhesive is within such a range, it is preferable from the viewpoint of permeability of the adjuvant preparation to the skin or mucous membrane, and when forming a patch, it is preferable from the viewpoint of forming the pressure-sensitive adhesive layer.

  When the adhesive strength is insufficient, it is desirable to add a tackifying resin separately. Examples of the tackifier resin include rosin derivatives (eg, rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, pentaerythrester ester of rosin), alicyclic saturated hydrocarbon resins (eg, Alcon P100, Arakawa Chemical Industries), aliphatic hydrocarbon resins (for example, Quinton B170, Nippon Zeon), terpene resins (for example, Clearon P-125 Yasuhara Chemical), resin maleate and the like. In particular, glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and terpene resin are preferable.

  The blending amount of the tackifying resin is preferably 5 to 70% by mass based on the total mass of the adjuvant preparation in consideration of sufficient adhesive strength as a patch and irritation to the skin at the time of peeling. More preferably, it is -60 mass%, and it is further more preferable that it is 10-50 mass%.

  Plasticizers include petroleum oils (eg liquid paraffin, paraffinic process oil, naphthenic process oil, aromatic process oil, etc.), squalane, squalene, vegetable oils (eg olive oil, camellia oil, castor oil, tall Oil, peanut oil, etc.), silicon oil, dibasic acid esters (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, liquid polybutene, liquid isoprene rubber, etc.), liquid fatty acid esters (isopropyl myristate, lauric acid) Hexyl, diethyl sebacate, diisopropyl sebacate), diethylene glycol, polyethylene glycol, glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, crotamiton Etc., and the like. Among these plasticizers, liquid paraffin, liquid polybutene, isopropyl myristate, hexyl laurate, and diethyl sebacate are preferable, and liquid paraffin, liquid polybutene, and isopropyl myristate are more preferable. These plasticizers may be used individually by 1 type, or may be used in combination of 2 or more type.

  The compounding amount of the plasticizer is preferably 10 to 70% by mass, more preferably 10 to 60% by mass, and further preferably 10 to 50% by mass based on the total mass of the adjuvant preparation. When the blending amount of the plasticizer is within such a range, it is preferable from the viewpoint of permeability of the adjuvant preparation to the skin or mucous membrane, and when forming a patch, it is preferable because sufficient cohesive force can be maintained.

  As the absorption enhancer, any compound can be used as long as it is a compound that has been conventionally recognized to absorb absorption in the skin. The absorption promoter is, for example, a fatty acid having 6 to 20 carbon atoms, a fatty alcohol, a fatty acid ester, an amide, an ether, an aromatic organic acid, an aromatic alcohol, an aromatic organic acid ester or an ether (above saturated, Any of unsaturated, cyclic, linear or branched), lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpene compounds, Azone, Azone ) Derivatives, pyrothiodecane, glycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters (Span), polysorbate (Tween), polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil (HCO), Polyoxyethylene alkyl ethers, ® sugar fatty acid esters, vegetable oils, and the like. Such absorption promoters may be used alone or in combination of two or more.

  The blending amount of the absorption enhancer is 0.01 to 40% by mass based on the total mass of the adjuvant preparation in consideration of sufficient skin permeability and skin irritation such as redness and edema. Preferably, it is 0.05 to 10% by mass, and more preferably 0.1 to 5% by mass.

  Adjuvant formulations can also be used in various dosage forms and can be the same dosage forms as conventionally used transdermal or transmucosal formulations. The dosage form of such an adjuvant preparation is preferably such that the adjuvant composition can be administered transcutaneously or transmucosally, and is an ointment, cream, gel, suppository, cataplasm, patch preparation, A dosage form such as a lotion, liquid, impregnation or blister is preferred, and a patch or impregnation is more preferred. In the case of such a dosage form, non-invasive administration in the body is possible as an external preparation adjuvant preparation.

  Examples of the patch preparation include a matrix type tape preparation, a laminated type tape preparation, and a reservoir type patch preparation. Of these, use as a matrix-type tape formulation and a reservoir-type patch formulation is preferred, and use as a reservoir-type patch formulation is more preferred.

  The matrix type tape preparation means a tape preparation having an adhesive layer in which a pharmacologically active substance is dispersed and contained in a base having adhesiveness. The matrix-type tape preparation includes a support on one side of the pressure-sensitive adhesive layer and a release liner on the other side. The base essentially comprises a rubbery (glassy) polymer or gel.

  Laminated tape formulation has a plurality of adhesive layers in which a pharmacologically active substance is dispersed and contained in an adhesive base of the tape formulation, and is supported on one side of the adhesive layer The body and the other surface are bonded with a release liner.

  A reservoir type patch preparation has a reservoir for storing a pharmacologically active substance, and has a backing member (support) impermeable to the drug on one side of the reservoir, and a release liner on the other side. Or what has a drug-permeable pressure-sensitive adhesive layer and a release liner.

  In general, the impregnating agent is a preparation in which the pad portion is covered with an adhesive cover material in a state where the liquid agent containing the active ingredient is impregnated and held in the pad. Although the structure is not particularly limited, a support, an impervious backing member (film) for a liquid agent, an adhesive cover agent, a pad, a liner, and the like can be provided. By using the impregnating agent, the liquid agent, ointment or gel impregnated in the pad portion can be stably held. Alternatively, the liquid agent or the like may be stored in a blister container or the like and impregnated into the pad part at the time of administration to prepare the impregnating agent.

  As the pad, for example, natural members such as pulp, natural fabric members such as gauze and absorbent cotton, synthetic fiber fabric members such as polyester, polyethylene, and polyvinyl can be used. These members can be combined and processed into a woven fabric or a non-woven fabric.

  The adjuvant preparation may be applied to the skin or mucous membrane as the above-mentioned dosage form, but can also be administered to the skin or mucous membrane by microneedle puncture, needleless injection, skin polishing or mucosal polishing.

  As an administration method of the adjuvant preparation, a method in which at least a part of the microneedle is coated with the adjuvant preparation and administered by puncture may be used. About the coating to a microneedle, it can carry out by the method as described in Japanese translations of PCT publication No. 2004-504120 gazette, Japanese translations of PCT publication No. 2004-528900 gazette, and international publication 2005/016440, for example. In addition, the administration method of the adjuvant preparation may be a method of administration by iontophoresis, sonophoresis or electroporation.

  An antigen is a substance that binds to an antigen receptor on an immune cell and induces an immune response, and the antigen is not particularly limited. For example, polynucleotides (DNA vaccines, RNA vaccines), protein-based vaccines and the like can be used. Such antigens include, for example, cytomegalovirus, hepatitis B virus, hepatitis C virus, human papilloma virus, rubella virus, varicella zoster, etc., attenuated or inactivated viruses such as pertussis, tetanus , Diphtheria, group A streptococcus, Legionella pneumophila, meningococcus, Pseudomonas aeruginosa, Streptococcus pneumoniae, syphilis treponema, cholera, etc., attenuated or inactivated bacteria, proteins, polysaccharides , Oligosaccharides, lipoproteins, and mixtures thereof.

  Commercially available vaccines containing antigenic agents can also be used. Examples of such vaccines include influenza vaccine, Lyme disease vaccine, rabies vaccine, measles vaccine, epidemic parotitis vaccine, varicella vaccine, smallpox vaccine, hepatitis vaccine, pertussis vaccine, diphtheria vaccine and the like. Furthermore, antigens used in vaccine therapy for cancer, arteriosclerosis, neurological disease, Alzheimer and the like can also be used.

  Further, an allergen substance having antigenicity (sensitization) may be used as an antigen. Examples of such allergen materials include a wide variety of metals and chemical substances. For example, in the case of allergy tests and treatments that reveal antigens of atopic dermatitis, dust, house dust such as inactivated mites, various pollen, etc. may be used. Also included are antigens recognized by inflammatory T cells associated with T cell mediated autoimmune diseases or conditions.

  The method for administering the antigen is not particularly limited, and oral, injection (intramuscular, subcutaneous, intradermal), administration methods such as microneedle puncture, transdermal or transmucosal administration methods, and the like can be used. In the case of transdermal administration, a transdermal administration means is selected according to the skin permeability of the antigen and the required dosage. If the antigen can be administered transdermally, a transdermal non-invasive preparation containing the adjuvant composition and the antigen can be formed. If the antigen does not have sufficient transdermal or transmucosal activity, it may be administered non-transdermally or non-mucosally, for example, administration by injection or oral administration is conceivable. In the case of administration by injection, the adjuvant composition and the antigen may be administered simultaneously.

  The administration method of the adjuvant preparation is to administer an adjuvant preparation (particularly preferably an impregnation agent or a patch preparation) before, after, or simultaneously with the administration of the antigen non-transcutaneously or non-mucosally. preferable. More preferably, the adjuvant formulation is administered after the antigen is administered transdermally or non-mucosally. In such a case, administration of the adjuvant preparation (preferably administration by sticking) can be continued while administering the antigen. For example, an adjuvant preparation can be separately administered by sticking or the like while the antigen is administered by microneedle puncture or the like.

  When the administration method of the adjuvant preparation is sticking, the sticking time is not particularly limited as long as the adjuvant preparation can sufficiently permeate the skin or mucous membrane and exert its effect, but it is 0.1 to 96 hours. Preferably, it is 0.5 to 48 hours, more preferably 2 to 24 hours.

  When the antigen is mixed with an adjuvant composition or an adjuvant preparation, the mixing ratio can be appropriately determined depending on the combination of the antigen and the adjuvant. It is preferable to use it in a formulation that results in a high concentration of adjuvant.

Test Example 1: Evaluation of enhancement of immune response of various drugs A physiological saline solution in which a drug and 0.1 μg of ovalbumin (OVA) are dissolved once a week in male 7-week-old BALB / C mice 50 μL was administered intradermally twice. The serum IgG antibody titer from the first administration to 3 weeks later was measured by ELISA. The experiment was performed with n = 5. OVA alone was administered as a negative control, and 1% by weight alum (aluminum hydroxide) and OVA were administered as positive controls. When the IgG antibody titer after 3 weeks was more than twice that of the negative control, it was judged that there was an effect of enhancing the immune response. The results are shown in Table 1.

  As is clear from the results shown in Table 1, amlodipine and captopril showed an immune response enhancing action, while other drugs did not show such an action. More specifically, in the case of 0.01 w / v% amlodipine, the IgG antibody titer was 3.3 times, and in the case of 1 w / v% captopril, the IgG antibody titer was 5.6 times, 1 w / v In the case of% alum, the IgG antibody titer was 7.0 times.

Claims (3)

  An adjuvant composition comprising a drug selected from the group consisting of captopril and amlodipine or a salt thereof.   An adjuvant preparation containing the adjuvant composition according to claim 1.   The adjuvant preparation according to claim 2, which is a transdermal or transmucosal preparation.