WO2012115222A1 - 経皮または経粘膜投与のためのアジュバントおよびこれを含む医薬製剤 - Google Patents
経皮または経粘膜投与のためのアジュバントおよびこれを含む医薬製剤 Download PDFInfo
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- WO2012115222A1 WO2012115222A1 PCT/JP2012/054544 JP2012054544W WO2012115222A1 WO 2012115222 A1 WO2012115222 A1 WO 2012115222A1 JP 2012054544 W JP2012054544 W JP 2012054544W WO 2012115222 A1 WO2012115222 A1 WO 2012115222A1
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- 229920002545 silicone oil Polymers 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229940083538 smallpox vaccine Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229960004599 sodium borate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- MSFGZHUJTJBYFA-UHFFFAOYSA-M sodium dichloroisocyanurate Chemical compound [Na+].ClN1C(=O)[N-]C(=O)N(Cl)C1=O MSFGZHUJTJBYFA-UHFFFAOYSA-M 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 239000012209 synthetic fiber Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000003784 tall oil Substances 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 229940021648 varicella vaccine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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- 229910052726 zirconium Inorganic materials 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
Definitions
- the present invention relates to an adjuvant for enhancing skin immune activity safely and efficiently, a pharmaceutical preparation mainly for transdermal or transmucosal administration, and an immunostimulation method using them.
- the skin is composed of the outermost stratum corneum, epidermis, dermis, and subcutaneous tissue connective tissue, and the stratum corneum, which usually consists of a dead cell layer and a lipid bilayer, exhibits a strong barrier function against many substances.
- stratum corneum which usually consists of a dead cell layer and a lipid bilayer, exhibits a strong barrier function against many substances.
- antigen-presenting cells called Langerhans cells are present and have an immune function.
- the mucous membrane is also the boundary with the external environment that covers the oral cavity, nasal cavity, respiratory organs, digestive organs, and genitals, and has the same structure as the skin except for the absence of the outermost stratum corneum.
- the mucous membrane is in contact with various foreign substances through food intake, breathing, and the like, and is a major route for invading the host body for pathogenic microorganisms, for example. Therefore, the immune defense mechanism in the mucosa is also important as a life barrier.
- Langerhans cells capture protein antigens that have entered the skin, break down inside, and express peptide fragments on MHC molecules.
- the MHC-peptide complex moves from the imported lymphatic vessel to the subcortical layer of the regional lymph node, and contacts through T cells and finger process cells.
- Langerhans cells migrate in this way, so that the antigen is efficiently transmitted from the skin to the TH cells present in the lymph nodes.
- Langerhans cells are rich in MHC class II molecules necessary to present antigens to TH cells.
- Recent vaccines are shifting from live vaccines to inactivated vaccines (whole particles, components, vaccines, etc.) for the purpose of improving safety, reducing the risk of infection, etc., but in order to supplement the immune effect of adjuvants Many require addition.
- An adjuvant is a substance that enhances an immune response to an antigen, and is very useful in vaccination in terms of reducing the dose of vaccine and the number of administrations and speeding up the immune response.
- adjuvants include aluminum salts, immune stimulating complexes (ISCOMs), bacteria-derived substances, and the like.
- ISCOMs immune stimulating complexes
- many of these adjuvants are often administered directly subcutaneously or intramuscularly, which induces tissue damage such as contact hypersensitivity, subcutaneous nodules and granulomas. Therefore, there is a high demand for adjuvants and preparations that can be administered safely and efficiently in immunostimulation such as human vaccination.
- adjuvants Numerous vaccine formulations containing attenuated pathogens or protein subunit antigens have been developed as adjuvants.
- Conventional vaccine preparations often include adjuvants that enhance the immune response.
- adjuvants that form Depot are well known. This adjuvant absorbs / or precipitates the administered antigen and forms a depot at the injection location.
- Typical depot-forming adjuvants include aluminum compounds such as aluminum phosphate, aluminum hydroxide gel, and oil-in-water emulsions.
- the conventional adjuvant often cause severe local tissue damage when administered subcutaneously or intramuscularly. Therefore, transdermal administration was considered to avoid this local tissue damage, but the conventional adjuvant is a macromolecule such as an immune stimulating complex (ISCOM) or a bacterial substance, or an aluminum compound, All of these compounds were unsuitable for transdermal administration.
- ISCOM immune stimulating complex
- Patent Document 1 discloses electroporation as a method for delivering a macromolecular antigen into skin cells, but does not describe an adjuvant.
- Patent Document 2 discloses a skin patch having a microprojection array, a reservoir containing an antigenic agent and an immune response enhancing adjuvant, and a method of using the same for vaccinating animals (eg, humans). Yes.
- the adjuvant described in the same document is only a metal salt or a macromolecule (such as a peptide), and no adjuvant having skin permeability is described.
- Patent Document 3 discloses long-chain aliphatic alcohols, esters thereof with C1-C6 alkanoic acids, or specific esters of long-chain fatty acids with alkanols and polyols as low-molecular adjuvants administered by injection.
- Patent Document 4 describes that an adjuvant which is a hydroxy unsaturated fatty acid or a derivative thereof is orally administered.
- an adjuvant which is a hydroxy unsaturated fatty acid or a derivative thereof is orally administered.
- Patent Document 5 discloses a local administration method comprising a step of administering a mixture of an antigen and a lipophilic solvent and a step of administering a Langerhans cell migration inducer after the administration.
- the substance that promotes the induction of Langerhans cells is limited to divalent unsaturated carboxylic acid esters such as dibutyl phthalate.
- Patent Document 6 discloses a dry preparation containing cholera toxin or related ADP-ribosylating toxin as an adjuvant.
- cholera toxin or related ADP-ribosylating toxin adjuvants are said to cross the skin and induce an immune response.
- adjuvants have the disadvantages that there is little information on safety and that they are polymers, so that they have low permeability to the skin and are expensive.
- Patent Document 7 describes a method of delivering an immunogenic composition to an intradermal compartment and an excipient used in the method.
- polyhydric alcohol as an immunostimulatory adjuvant administered separately from the antigen and an immunostimulatory method using the same.
- Patent Documents 8 and 9 disclose aliphatic adjuvants, free fatty acids and fatty acid derivatives as adjuvants for transdermal or transmucosal administration. However, the adjuvant effect of polyhydric alcohols such as glycerin and their derivatives is not disclosed.
- an object of the present invention is to provide a low-molecular-weight adjuvant and its preparation that can be safely administered without inducing skin irritation or the like by transdermal or transmucosal administration, and efficiently enhance the immunogenicity of the antigen. There is to do.
- the present inventors surprisingly found that certain low molecular weight compounds, particularly polyhydric alcohols such as glycerin and derivatives thereof, are transdermal or transmucosal.
- polyhydric alcohols such as glycerin and derivatives thereof
- the present invention provides the following [1] to [15].
- An adjuvant for transdermal or transmucosal administration comprising one or more selected from the group consisting of glycerin, propylene glycol, polyethylene glycol and triacetin, which are polyhydric alcohols or derivatives thereof.
- a pharmaceutical preparation comprising the adjuvant according to [1].
- the pharmaceutical preparation according to [2] which is used for transdermal or transmucosal administration.
- the pharmaceutical preparation according to [2] or [3] which is an ointment, cream, gel, suppository, poultice, lotion, liquid, impregnation or blister.
- [5] The pharmaceutical preparation according to any one of [2] to [4], wherein the adjuvant is contained in an amount of 75 to 100% by weight.
- the physical or chemical treatment is at least one of laser irradiation, skin polishing, or microneedle, thermal, ultrasonic wave, electric field, magnetic field, pressure, or alkali treatment. .
- the pharmaceutical preparation according to [11] which is applied by at least one of iontophoresis, sonophoresis or electroporation.
- kits comprising the adjuvant according to [1] or the pharmaceutical preparation according to any one of [2] to [13].
- the kit according to [14] comprising an antigen or vaccine and / or a device for antigen administration.
- Glycerin and its derivatives have a track record as pharmaceuticals, and are inexpensive and highly safe, with precedent use as injections.
- an adjuvant effect was obtained only by fatty alcohols and fatty acids having high transdermal absorbability as described in Patent Documents 8 and 9, The inventors have shown that the polyhydric alcohols and derivatives thereof of the present invention also have an adjuvant effect in transdermal or transmucosal administration.
- the adjuvant of the present invention exhibits a further superior immune enhancing effect when applied to the skin or the like at a high concentration. Therefore, the adjuvant of the present invention is particularly excellent as an adjuvant with less skin irritation for transdermal or transmucosal administration.
- the adjuvant of the present invention does not need to be mixed with the antigen and can be administered by a route different from that of the antigen.
- an excellent adjuvant effect can be obtained by administering the adjuvant of the present invention transdermally or transmucosally independently of the antigen or vaccine. Therefore, it is not necessary to consider the dosage of the antigen and other conditions at the time of administration of the adjuvant, and the concentration of the adjuvant itself, the application time, the dosage, etc. can be freely selected. Furthermore, it is possible to avoid swelling at the administration site that occurs during administration of an antigen or the like and pain associated with administration.
- the adjuvant for transdermal or transmucosal absorption according to the present invention has a low melting point and low molecular weight, it exhibits high transdermal or transmucosal absorbability, so that various transdermal absorption preparations such as solutions, patches, and ointments are used.
- the preparation can be applied to agents, gels, impregnations, creams, lotions, etc., and can be provided at low cost.
- FIG. 1 shows the IgG antibody titer increasing effect of the adjuvant of the present invention.
- FIG. 2 shows the adjuvant effect of the adjuvant of the present invention (glycerin).
- FIG. 3 shows the adjuvant effect of the present invention by OVA antigen intradermal injection application and microneedle application.
- FIG. 4 shows the time course of IgG antibody titer by the application of the adjuvant of the present invention by intradermal injection of OVA antigen and microneedle application.
- FIG. 5 shows the adjuvant effect of the adjuvant of the present invention (glycerin and glycerin derivatives).
- the adjuvant of the present invention includes one or more selected from the group consisting of glycerin, propylene glycol, polyethylene glycol and triacetin, which are polyhydric alcohols or derivatives thereof.
- the polyethylene glycol (for example, macrogol 400) used in the adjuvant of the present invention preferably has an average molecular weight of 200 to 4000, more preferably 200 to 1000.
- Polyhydric alcohol derivatives such as oleic acid monoglycerin can also be used.
- the adjuvant of the present invention preferably has a low molecular weight, and particularly preferably has 3 linear carbon atoms such as glycerin and its derivatives.
- R 1 , R 2 , R 3 are each independently selected from H, OH, OCOR 4 ; n is 0, 1 or 2; when n is 2, R 2 may be the same or different; R 4 is a linear or branched alkyl group having 1 to 3 carbon atoms, or a linear or branched alkenyl group or alkynyl group having 2 or 3 carbon atoms, Provided that two or more of R 1 , R 2 and R 3 are not H at the same time, The compound shown by these may be sufficient.
- the adjuvant of the present invention can be used either alone or in combination. In particular, when there is a synergistic effect between adjuvants, these may be used in combination. In other cases, the adjuvant may be used alone, or may be used in combination depending on the purpose.
- the adjuvant of the present invention can enhance the antigen effect simply by transdermal or transmucosal administration, and the adjuvant itself has the effect of enhancing the antigen effect. Therefore, it can be administered in a dosage form different from the antigen or vaccine, or by an independent route.
- the adjuvant of the present invention can be administered at a timing or procedure different from that of the antigen or the like, and the adjuvant of the present invention is administered in the same or different dosage form before, during or after the antigen administration. Can do. Therefore, it can be applied to a suitable site of a subject at a preferred time without selecting a dosage form such as an antigen.
- the adjuvant of the present invention can be used by being contained in a pharmaceutical preparation, and can be used at various concentrations in the preparation.
- the adjuvant of the present invention is preferably used at a high concentration in a pharmaceutical preparation.
- the adjuvant of the present invention can be used at 50 to 100% by weight in the preparation, but it is preferably 75 to 100% by weight, more preferably 85 to 100% by weight, still more preferably 95 to 100% by weight.
- the adjuvant of the present invention exhibits a particularly excellent immunostimulatory effect when the concentration is 75% by weight or more in the pharmaceutical preparation. Therefore, the use of the adjuvant of the present invention at a high concentration makes the difference in effect from other components such as excipients used in the formulation clear.
- a pharmaceutical preparation is preferably a dosage form containing the adjuvant of the present invention and capable of transdermally administering the adjuvant, and is a patch, patch preparation, ointment, cream, liquid, gel. , An impregnating agent, a lotion agent, and the like.
- the patch preparation includes matrix-type, laminated-type tape preparation and reservoir-type preparation. Of these, matrix-type tape preparation and reservoir-type preparation are preferably used, and matrix-type tape preparation is particularly preferred. Preferably used.
- An impregnating agent or an impregnating preparation is a preparation in which a pad part is covered with an adhesive cover material in a state in which a liquid containing an active ingredient is impregnated and held in a pad.
- the composition is not particularly limited, but may include a support, a backing member (film) impermeable to the liquid, an adhesive cover agent, a pad, a liner, and the like.
- the liquid, ointment, or gel impregnated in the pad portion And the like can be stably prepared.
- a preparation that is stored in a state where a liquid agent is held in a blister container or the like and is impregnated into the pad portion when applied is also included.
- the pad shown in the present invention can be a natural fabric member such as gauze or absorbent cotton, a synthetic fiber fabric member such as polyester, polyethylene, or polyvinyl, and pulp. Can be used after processing.
- the adjuvant or pharmaceutical preparation of the present invention can be used as a kit for an immunostimulation method.
- the kit of the present invention only needs to contain the adjuvant or pharmaceutical preparation of the present invention, and may contain an antigen or vaccine, or a device for antigen administration.
- the device for antigen administration can be, for example, an administration device such as a microneedle or a syringe.
- the kit of the present invention comprises the adjuvant or pharmaceutical preparation of the present invention, an antigen or vaccine, or a device for antigen administration.
- a kit comprising a microneedle whose needle portion is coated with an antigen and a patch preparation containing the adjuvant of the present invention can be used.
- an immunostimulation method or immunomodulation method using the adjuvant or pharmaceutical preparation of the present invention is excellent in increasing the immunogenicity of an antigen or vaccine and increasing the antibody titer.
- the adjuvant or pharmaceutical preparation of the present invention is preferably applied in a transdermal or transmucosal dosage form.
- the immunostimulation method or immunomodulation method of the present invention may be administered simultaneously with the antigen or vaccine, or may be administered with a time difference.
- the method of the present invention is preferably administered by another route without mixing the adjuvant of the present invention and the antigen.
- the adjuvant or pharmaceutical formulation of the present invention may be applied in a different dosage form or independent route than the antigen or vaccine.
- the site to which the adjuvant or pharmaceutical preparation of the present invention is applied may be the same as or different from the site or region to which the antigen or the like is applied.
- a preferable combination of administration forms is a method in which an antigen or the like is administered by subcutaneous injection or puncture, and an adjuvant or the like is administered transdermally or transmucosally. Furthermore, when an administration device such as a microneedle is used, the adjuvant of the present invention can be applied while the administration device is applied.
- the matrix-type tape preparation is a tape preparation comprising a pharmacologically active substance dispersed and contained in a base containing an essentially rubbery (glassy) polymer or gel having adhesiveness. It has a pressure-sensitive adhesive layer, and has a support on one side of the pressure-sensitive adhesive layer and a release liner on the other side.
- the multi-layer tape preparation is a tape preparation having a pressure-sensitive adhesive layer in which a pharmacologically active substance is dispersed and contained in a plurality of adhesive bases, and one side of the pressure-sensitive adhesive layer. And a support and a release liner bonded to the other surface.
- the reservoir-type 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 , which includes a drug-permeable pressure-sensitive adhesive layer and a release liner.
- transdermal or transmucosal preparations include, as a base, a solubilizer, a solubilizer, a pH adjuster, an antiseptic, an absorption accelerator, a stabilizer, a filler, a thickener, an adhesive, a wetting agent, and the like. Any of the above components can be produced by a conventional method using a combination of the adjuvant of the present invention.
- pharmaceutical preparations of other dosage forms can be produced by a conventional method.
- the thickener is capable of stably maintaining water at 30 to 80% and having water retention.
- Specific examples include guar gum, locust bean gum, carrageenan, alginic acid, sodium alginate, agar, gum arabic (acacia gum), tragacanth gum, karaya gum, pectin, starch, etc.
- 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, dialdehyde starch, polyvinyl alcohol, polyvinylpyrrolidone, Vinyl-based materials such as polyvinyl methacrylate, acrylic materials such as polyacrylic acid and sodium polyacrylate, other polyethylene oxide, methyl
- water-soluble polymers such as synthetic polymers such as vinyl ether / maleic anhydride copolymer is preferably used.
- sodium polyacrylate is preferable. This is because the gel strength is strong and the water retention is excellent.
- sodium polyacrylate having an average degree of polymerization of 20000 to 70000 is preferred.
- the average degree of polymerization is less than 20000, the thickening effect tends to be poor, and sufficient gel strength tends to be not obtained.
- the average degree of polymerization is greater than 70000, the thickening effect is too strong and workability tends to decrease.
- a polymer complex can be formed with a strong ionic polymer of sodium polyacrylate, and an elastic gel with higher gel strength can be obtained.
- Glycerin, propylene glycol and the like also have an effect as a wetting agent, but if necessary, a polyhydric alcohol such as sorbitol may be used as the wetting agent.
- a polyhydric alcohol such as sorbitol
- kaolin, zinc oxide, talc, titanium, bentonite, aluminum silicate, titanium oxide, zinc oxide, aluminum metasilicate, calcium sulfate, calcium phosphate, or the like may be added as a filler.
- the total amount of the wetting agent and filler is preferably from 0.1 to 30% by weight, more preferably from 0.1 to 20% by weight, based on the total composition of the pressure-sensitive adhesive layer.
- solubilizer or absorption promoter propylene carbonate, crotamiton, l-menthol, mint oil, limonene, diisopropyl adipate, etc.
- methyl salicylate, glycol salicylate, l-menthol, thymol, mint oil, Nonyl acid vanillylamide, pepper extract and the like may be added.
- the surfactant may be any of a nonionic active agent and an ionic active agent (cation, anion, amphoteric).
- a nonionic active agent usually used for a pharmaceutical base is used. desirable. More specifically, sugar alcohol fatty acid esters such as sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid Examples thereof include esters, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil.
- a crosslinking agent In the transdermal administration preparation of the present invention, a crosslinking agent, a polymerization agent, etc. may be added as necessary.
- the plaster can be strengthened and water retention can be imparted.
- This crosslinking agent and polymerization agent are appropriately selected depending on the type of thickener and the like.
- polyacrylic acid or polyacrylate when applied to the thickener, a compound having at least two epoxy groups in the molecule, hydrochloride such as Ca, Mg, Al, sulfate, phosphate, Inorganic acid salts such as carbonate, organic acid salts such as citrate, tartrate, gluconate and stearate, oxides such as zinc oxide and anhydrous silicic acid, hydroxides such as aluminum hydroxide and magnesium hydroxide Multivalent metal compounds such as are preferably used.
- hydrochloride such as Ca, Mg, Al
- sulfate phosphate
- Inorganic acid salts such as carbonate
- organic acid salts such as citrate, tartrate, gluconate and stearate
- oxides such as zinc oxide and anhydrous silicic acid
- hydroxides such as aluminum hydroxide and magnesium hydroxide Multivalent metal compounds such as are preferably used.
- polyvinyl alcohol When polyvinyl alcohol is applied as a thickener, adipic acid, thioglycolic acid, epoxy compound (epichlorohydrin), aldehydes, N-methylol compound, Al, Ti, Zr, Sn, V, Cu, B, Cr Complexes of compounds such as are preferably used.
- polyvinyl pyrrolidone When polyvinyl pyrrolidone is applied 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.
- polyethylene oxide when polyethylene oxide is applied to the thickener, peroxide, polysulfone azide, and the like are preferably used.
- a methyl vinyl ether / maleic anhydride copolymer when applied as a thickener, polyfunctional hydroxy compounds, polyamines, iodine, gelatin, polyvinyl pyrrolidone, iron, mercury, lead salts, and the like are preferably used.
- aldehydes such as formaldehyde, glutaraldehyde, and dialdehyde starch
- diepoxides such as glyoxal and butadiene oxide
- diketones such as divinyl ketone
- diisocyanates are preferably used.
- a polyvalent metal salt such as lithium hydroxide, zinc hydroxide, aluminum hydroxide or sodium borate is preferably added as a crosslinking agent.
- zinc salts and aluminum salts are preferred. This is because the crosslinking reaction is promoted.
- the concentration of the polyvalent metal salt added as a crosslinking agent is preferably 0.5 to 1.5 equivalents relative to 1 equivalent of the thickener (or water-soluble polymer).
- an acrylic polymer or a rubber polymer is preferable.
- the acrylic polymer may be a copolymer containing at least one (meth) acrylic acid derivative represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like. Although it is not particularly limited, it is desirable that it contains 50% or more of 2-ethylhexyl acrylate.
- adhesives include acrylic acid / octyl acrylate copolymer and 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer listed as adhesives in Pharmaceutical Additives Encyclopedia 2000 (edited by Japan Pharmaceutical Additives Association).
- the included adhesives such as acrylic polymer, DURO-TAK acrylic adhesive series (manufactured by Henkel), Eudragit series (Higuchi Shokai) and the like can be used.
- rubber polymers examples 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.
- SIS styrene-isoprene-styrene block copolymer
- PIB polyisobutylene
- SBS styrene-butadiene-styrene block copolymer
- SBR styrene-butadiene rubber
- polysiloxane and the like.
- SIS styrene-isoprene-styrene block copoly
- Two or more of these hydrophobic polymers may be used as a mixture, and the blending amount based on the weight of the entire composition of these polymers takes into consideration the formation of the pressure-sensitive adhesive layer and sufficient permeability to the skin. Thus, it is preferably 5 to 90% by weight, more preferably 10 to 70% by weight.
- a plasticizer may be blended in the adhesive matrix (adhesive layer) of the patch of the present invention.
- Plasticizers that can be used include petroleum oils (eg paraffinic process oils, naphthenic process oils, aromatic process oils), squalane, squalene, vegetable oils (eg olive oil, camellia oil, castor oil, tall Oil, peanut oil), silicone oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber), liquid fatty acid esters (isopropyl myristate, hexyl laurate, sebacine) Diethyl glycol, diisopropyl sebacate), diethylene glycol, polyethylene glycol, glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, crotamiton, etc.
- petroleum oils eg paraffinic process
- liquid paraffin liquid polybutene, isopropyl myristate, diethyl sebacate, and hexyl laurate are preferable, and liquid polybutene, isopropyl myristate, and liquid paraffin are particularly preferable.
- the total amount is 10 to 70% by weight, preferably 10 to 60% by weight, more preferably 10 to 50% by weight.
- a tackifying resin when the adhesive strength is insufficient, and as a tackifying resin that can be used, a rosin derivative (for example, Rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, pentaerythrester ester of rosin), alicyclic saturated hydrocarbon resin (eg Alcon P100, Arakawa Chemical Industries), aliphatic 1 series hydrocarbon Examples thereof include resins (for example, Quinton B170, Nippon Zeon), terpene resins (for example, Clearon P-125 Yasuhara Chemical), maleic resin, and the like.
- a rosin derivative for example, Rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, pentaerythrester ester of rosin
- alicyclic saturated hydrocarbon resin eg Alcon P100, Arakawa Chemical Industries
- glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and terpene resin are preferable.
- a tackifying resin is 5 to 70% by weight, preferably 5 to 60% by weight based on the total composition of the pressure-sensitive adhesive layer in consideration of sufficient adhesive strength as a patch and irritation to the skin at the time of peeling. %, More preferably 10 to 50% by weight.
- the adhesive matrix (adhesive layer) of the patch of the present invention may contain an absorption enhancer, and the absorption enhancer that can be used is a compound that has been conventionally recognized as having an effect of promoting absorption in the skin. Any of these may be used, for example, fatty acids having 6 to 20 carbon chains, fatty alcohols, fatty acid esters, amides, or ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers (above Saturated or unsaturated, and any of cyclic, linear, and branched) may be used.
- lactic acid esters lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpene compounds, and Azone
- Azone derivatives pyrothiodecane, glycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fat
- esters Span
- polysorbates Teween
- polyethylene glycol fatty acid esters polyoxyethylene hydrogenated castor oil (HCO)
- HCO polyoxyethylene hydrogenated castor oil
- sucrose fatty acid esters and vegetable oils.
- Such absorption enhancers may be used singly or in combination of two or more, and have sufficient skin permeability as a patch and irritation to the skin such as redness and edema.
- it is preferably 0.01 to 40% by weight, more preferably 0.05 to 10% by weight, particularly preferably 0.1 to 5% by weight based on the weight of the entire composition of the pressure-sensitive adhesive layer. can do.
- the adjuvant of the present invention is preferably administered separately from the antigen, but can also be administered into the body together with the antigen.
- a transdermal noninvasive preparation containing an adjuvant and the antigen can be obtained.
- a transdermal administration formulation such as a cataplasm, a patch formulation, an ointment, a cream, a liquid, an impregnation agent, a gel, a lotion can be selected as necessary.
- an impregnating agent is preferred.
- the patch preparation includes matrix-type, laminated-type tape preparation, and reservoir-type patch preparation.
- such a transdermal preparation also uses any component such as a solubilizer, a solubilizer, a pH adjuster, an antiseptic, an absorption accelerator, a stabilizer, a filler, a thickener, and an adhesive as a base,
- a solubilizer e.g., a solubilizer, a pH adjuster, an antiseptic, an absorption accelerator, a stabilizer, a filler, a thickener, and an adhesive
- the base can include an adjuvant and / or an agent that enhances the skin permeability of the antigen as the absorption enhancer. Even if such an absorption enhancer is not included, the adjuvant of the present invention does not contain the antigen immunogen. Sexuality can be enhanced.
- the antigen used in combination does not have sufficient transdermal or transmucosal activity, only the adjuvant of the present invention is administered transdermally or transmucosally, and the antigen used in combination is non-transdermal or non-transdermal.
- administration by injection or oral administration may be considered.
- a preferred method of administration of the pharmaceutical preparation of the present invention is a pharmaceutical preparation containing the adjuvant of the present invention (particularly preferably, before, after, or simultaneously with administration of the antigen non-transcutaneously or non-mucosally).
- Patch formulation Particularly preferably, the pharmaceutical formulation of the present invention is applied after the antigen is administered transdermally or non-mucosally. In such a case, the pharmaceutical formulation of the present invention is continued while administering the antigen.
- the pharmaceutical preparation of the present invention may be applied while the antigen is administered with a microneedle or the like.
- the pharmaceutical preparation of the present invention when the pharmaceutical preparation of the present invention is affixed before the antigen is administered transdermally or non-mucosally, the pharmaceutical preparation of the present invention is continued at the time of antigen administration and further after the antigen administration. It may be affixed.
- the compounding amount of the antigen and the adjuvant in the combined preparation of the antigen and the adjuvant can be appropriately determined depending on the combination of the antigen and the adjuvant, and is not limited, but it is preferable to use a high concentration adjuvant.
- the content of the adjuvant in such a preparation is not particularly limited, and may be an amount that can induce a sufficient antigen-immune response by the transdermal route, but a high concentration of adjuvant is preferable.
- an antigen means a substance that binds to an antigen receptor on an immune cell and elicits an immune response.
- examples thereof include, but are not limited to, polynucleotides (DNA vaccines, RNA vaccines). ), Protein-based vaccines and the like.
- proteins, polysaccharides, oligosaccharides, lipoproteins, attenuated or inactivated viruses such as cytomegalovirus, hepatitis B virus, hepatitis C virus, human papilloma virus, rubella virus and varicella zoster
- viruses such as pertussis, tetanus, diphtheria, group A streptococcus, Legionella pneumophila, meningococcus, Pseudomonas aeruginosa, Streptococcus pneumoniae, syphilis treponema and cholera , As well as antigens in the form of mixtures thereof.
- vaccines containing antigenic agents can also be used in the present invention.
- influenza vaccine Lyme disease vaccine, rabies vaccine, measles vaccine, mumps vaccine, varicella vaccine, smallpox vaccine, hepatitis vaccine, pertussis vaccine and diphtheria vaccine, as well as cancer, arteriosclerosis, neurological disease, Also included are antigens used in vaccine therapy such as Alzheimer.
- the antigen may be an allergen substance having antigenicity (sensitization), and a wide variety of metals and chemical substances correspond to it.
- allergen substance having antigenicity 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.
- antigens recognized by inflammatory T cells associated with T cell mediated autoimmune diseases or conditions are also included.
- the administration route of these antigens is not particularly limited, and examples include oral, injection (intramuscular, subcutaneous, intradermal) administration methods, transmucosal administration, and transdermal administration.
- a transdermal administration means is selected according to the skin permeability of the antigen and the required dosage.
- transdermal or transmucosal administration means skin or mucosal Langerhans cells are activated and efficiently transmitted from the skin or mucous membrane to TH cells present in lymph nodes. An immune response is completed. This makes it possible to easily evaluate the antigenicity of external medicines, cosmetics or allergens, prevent or treat with vaccines such as infectious diseases, cancer, and allergies, and treat T cell-mediated autoimmune diseases. .
- a preferred method of administration of the pharmaceutical preparation of the present invention is a method of transdermally or transmucosally administering the adjuvant pharmaceutical preparation of the present invention before or after administration of the antigen, or simultaneously with administration of the antigen, more preferably After administering the antigen, a pharmaceutical preparation containing the adjuvant of the present invention is applied.
- the pharmaceutical preparation of the present invention when the pharmaceutical preparation of the present invention is affixed before administering the antigen, the pharmaceutical preparation of the present invention may be continuously applied at the time of antigen administration and further after the antigen administration.
- the application time of the pharmaceutical preparation of the present invention is such that the adjuvant of the present invention can sufficiently protect the skin or mucous membrane even when the application is performed before or after the antigen administration, or at the same time as the antigen administration.
- it is not particularly limited as long as it can permeate and exhibit its effect sufficiently, it is preferably 0.1 to 96 hours, more preferably 0.5 to 48 hours, and particularly preferably 2 to 24 hours.
- the pharmaceutical preparation containing the adjuvant of the present invention can be applied to intact skin or mucous membrane, but for the purpose of further enhancing percutaneous or transmucosal absorbability, skin polishing treatment or mucosal polishing treatment, It can also be applied to skin or mucous membrane that has been subjected to physical or chemical treatment such as treatment with a needle, laser irradiation, thermal treatment, electric field treatment, magnetic field treatment, pressure treatment, or alkali treatment. Furthermore, by taking a transdermal or transmucosal dosage form with a device equipped with a device such as iontophoresis, electroporation, sonophoresis (ultrasound), microcannula, microneedle, needleless injection, etc. In addition, an immune response to a highly safe antigen can be completed with higher efficiency.
- transdermal or transmucosal administration is particularly preferred by polishing, microneedle, or needleless injection.
- the administration form is not particularly limited, and an optimum administration means can be selected according to the permeability of the antigen to the skin or mucous membrane and the required dose.
- Another preferred method for administering the pharmaceutical preparation of the present invention uses a microneedle in which a part or all of the needle part is coated with the pharmaceutical preparation of the present invention containing the antigen and the adjuvant of the present invention together with a base such as a carrier.
- a base such as a carrier.
- the antigen is administered using a microneedle by coating a part or the entire surface of the needle portion of the microneedle, and the pharmaceutical preparation containing the adjuvant of the present invention is not administered by the microneedle, but is applied to the skin or mucous membrane. It may be applied to or applied to the skin or mucous membrane before or after the antigen administration, or may be applied to the skin or mucous membrane simultaneously with the antigen administration.
- the description of the coating on the needle portion of the microneedle can be found in JP-T-2004-504120, JP-T-2004-528900, WO 2005/016440, and the like.
- One of the preferable methods of immunostimulation using the pharmaceutical preparation of the present invention is to administer the antigen using the microneedle by coating the antigen on a part or the whole of the needle part of the microneedle, and administer the antigen.
- This is a method of transdermally or transmucosally administering a pharmaceutical preparation containing the adjuvant of the present invention before or after or simultaneously with administration of an antigen. More preferably, by coating the antigen on a part or the entire surface of the needle part of the microneedle, the pharmaceutical preparation containing the adjuvant of the present invention is pasted after the antigen is administered using the microneedle.
- the antigen is administered using the microneedle, and the pharmaceutical preparation of the present invention is administered to the skin or mucous membrane simultaneously with the antigen administration or after the antigen administration.
- the antigen administration is performed by puncture administration with a microneedle, and the entire microneedle to be punctured is applied (administered) so that the pharmaceutical preparation of the present invention covers the skin or mucous membrane.
- Example 1 The dorsal part of female 8-week-old hairless rats was shaved and divided into (i) microneedle (OVA) application group, (ii) microneedle (OVA) application + adjuvant candidate application group.
- the microneedle was coated with 20 ⁇ g of OVA antigen at the tip of the needle, and was punctured for 30 minutes (the coating solution was an OVA / pullulan solution, and a polylactic acid microneedle having a needle length of about 500 ⁇ m and 625 / cm 2 was used).
- each adjuvant candidate (glycerin, ethanol, and glycerin / ethanol (1/1) mixed solution) was transdermally administered to the puncture site for 6 hours.
- Each adjuvant candidate application method is a patch test tape for glycerin, ethanol, and glycerin / ethanol (1/1) mixed solution; a small size (Torii Pharmaceutical) pad part impregnated with 120 ⁇ L of each adjuvant candidate stock solution did. All groups were fixed with corban and skinnagate. Antigen and adjuvant administration were performed after 0, 2, 4 weeks, blood collection was performed after 2, 4, 5 weeks, and OVA-specific IgG antibody titers were measured by ELISA (FIG. 1 shows each antibody titer after 5 weeks). .
- Example 2 In the above (ii) microneedle (OVA) application + adjuvant candidate application group, the skin condition 24 hours after each adjuvant peeling was observed, and the degree of skin irritation was evaluated by score (Table 1). As shown in Table 1, in the lauryl alcohol (tape) application group, although no irritation was observed immediately after peeling, there were individuals in which some scales were observed 24 hours after peeling. In addition, significant skin irritation accompanied by necrosis was observed in the ethanol application group, and skin irritation equivalent to that was also observed in the ethanol / glycerin mixed solution application group.
- the tape preparation containing 40% lauryl alcohol is 4.0 g LA (Nippon Oil), 13.3 g (dry weight 6.0 g) DURO-TAK 87-2194 (manufactured by Henkel).
- Acrylic pressure-sensitive adhesive was mixed, spread on a release liner, dried at 80 ° C. for 15 minutes to a thickness of 50 ⁇ m, and then a support was attached to produce.
- Example 3 The dorsal part of female 8-week-old hairless rats was shaved and divided into (i) microneedle (OVA) application group, (ii) microneedle (OVA) application + adjuvant candidate application group.
- the microneedle was coated with 20 ⁇ g of OVA antigen at the tip of the needle, and was punctured for 30 minutes (the coating solution was an OVA / pullulan solution, and a polylactic acid microneedle having a needle length of about 500 ⁇ m and 625 / cm 2 was used).
- FIG. 2 shows each antibody titer after 5 weeks).
- the glycerin used in the present invention is concentrated glycerin (Merck: purity 99.0% or more, Kao: purity 98.0% or more), and the adjuvant effect is not due to the influence of impurities, but is presumed to be possessed by glycerin itself.
- Example 4 Shaved dorsal part of female 8-week-old hairless rat, (i) Intradermal injection (OVA) application group, (ii) Intradermal injection (OVA) application + glycerin application group, (iii) Microneedle (OVA) It was divided into an application group, (iv) microneedle (OVA) application + glycerin application group. In (i) and (ii), OVA 20 ⁇ g / 50 mL (physiological saline) was intradermally administered.
- (Iii) and (iv) were coated with 20 ⁇ g of OVA antigen at the tip of the microneedle needle and administered by puncture for 30 minutes (the coating solution was an OVA / pullulan solution, the needle length was about 500 ⁇ m, and 625 / cm 2 made of polylactic acid) Microneedle was used). Furthermore, in the groups (ii) and (iv), after puncture administration for 30 minutes, a needle for patch test was applied to the puncture site; a pad of small size (Torii Pharmaceutical) impregnated with 120 ⁇ L of glycerin was applied for 6 hours . All groups were fixed with corban and skinnagate.
- FIG. 3 shows the antibody titer after 4 weeks
- FIG. 4 shows the antibody titer). Shows the time course).
- the adjuvant effect of glycerin was more prominent in the microneedle application than in the case of the OVA antigen intradermal injection application.
- IgG antibody was not detected after 2 weeks even in the dermal injection group in the intradermal injection group, but the IgG antibody titer increased after 2 weeks by using glycerol in the microneedle group. Admitted. Therefore, it was shown that the adjuvant effect by glycerin was obtained more prominently by administering the antigen with microneedles, and the rise of the IgG antibody titer was earlier.
- Example 5 The dorsal part of female 8-week-old hairless rats was shaved and divided into (i) microneedle (OVA) application group, (ii) microneedle (OVA) application + adjuvant candidate (glycerin or glycerin derivative) application group.
- the microneedle was coated with 20 ⁇ g of OVA antigen at the tip of the needle, and was punctured for 30 minutes (the coating solution was an OVA / pullulan solution, and a polylactic acid microneedle having a needle length of about 500 ⁇ m and 625 / cm 2 was used).
- the microneedle is glycerin as an adjuvant candidate at the puncture site, glycerin derivative and polyhydric alcohol as propylene glycol (PG), macrogol 400, oleic acid monoglycerin (GMO ) Or triacetin, a patch test tape; a pad of small size (Torii Pharmaceutical) impregnated with 120 ⁇ L of each adjuvant candidate stock solution was affixed for 6 hours. All groups were fixed with corban and skinnagate. Antigen and adjuvant administration were performed at 0, 2, 4 weeks, blood collection was performed at 2, 4, 5 weeks, and OVA-specific IgG antibody titers were measured by ELISA (FIG. 5 shows each antibody titer after 5 weeks). .
- Example 6 The dorsal part of a female 8-week-old hairless rat was shaved, and microneedle (OVA) application + adjuvant (0, 25, 75% glycerin solution) was applied.
- OVA microneedle
- the microneedle was coated with 20 ⁇ g of OVA antigen on the needle tip, and punctured for 30 minutes (the coating solution was OVA / pullulan solution, and a microneedle with a needle length of about 500 ⁇ m and 625 needles / cm 2 was used). Thereafter, a patch test tape; a pad of small size (Torii Pharmaceutical) impregnated with 120 ⁇ L of each adjuvant solution was applied for 6 hours. All groups were fixed with corban and skinnagate. Antigen and adjuvant administration were performed 0, 2 weeks later, blood was collected 2, 4 weeks later, and OVA-specific IgG antibody titers were measured by ELISA (Table 2 shows the antibody titers after 4 weeks).
- Example 7 Shaved dorsal side of female 8-week-old hairless rat, (i) Microneedle (OVA / pullulan / 41% glycerin mixed) application group, (ii) Microneedle (OVA) application + adjuvant (100% glycerin) application Divided into groups.
- the microneedle was coated with 20 ⁇ g of OVA antigen on the needle tip, and punctured for 30 minutes (the coating solution was OVA / pullulan solution, and a microneedle with a needle length of about 500 ⁇ m and 625 needles / cm 2 was used).
- the microneedle was punctured for 30 minutes and allowed to stand for 10 minutes, and then the patch test tape; small size (Torii Pharmaceutical) pad part impregnated with 120 ⁇ L of adjuvant solution 6 Time stuck. All groups were fixed with corban and skinnagate. Antigen and adjuvant administration were performed 0, 2 weeks later, blood was collected 2, 4 weeks later, and OVA-specific IgG antibody titers were measured by ELISA (Table 3 shows the antibody titers after 4 weeks).
- the adjuvant effect was not observed in the group administered with microneedles mixed with OVA and glycerin, whereas an obvious increase in IgG antibody titer was observed in the group impregnated with glycerin after antigen administration. .
- a high IgG antibody titer was obtained even when impregnated and pasted 10 minutes after OVA administration.
- the effect of enhancing immune activity was achieved even when an adjuvant was applied at intervals after the antigen administration.
- the adjuvant effect of glycerin according to the present invention is not only in terms of efficacy and safety but also in terms of administration compared with other existing adjuvants. That is, the adjuvant effect of the present invention is not achieved by mixed administration with an antigen as generally seen in other adjuvants for injections, but is administered separately from the antigen, particularly after the administration of the antigen. It has been shown to be achieved by applying or applying a high concentration adjuvant formulation. Furthermore, it was clearly shown that even when applied at a high concentration in an impregnated state, there is no skin irritation and the antibody titer can be safely increased.
- a low-molecular-weight adjuvant selected from polyhydric alcohols or derivatives thereof for safe and efficient enhancement of skin immune activity and a preparation for transdermal administration are provided. That is, the adjuvant and pharmaceutical preparation of the present invention can be directly administered transdermally, or can be applied after skin polishing, or transdermally administered using iontophoresis, microneedles, etc. Alternatively, it is widely used for evaluation of allergenic substances, infections, cancer, arteriosclerosis, cranial nerve diseases such as Alzheimer's disease, and vaccine treatment for allergies. The present invention is also utilized as an anti-inflammatory immune modulator for therapy for T cell mediated diseases. Therefore, the present invention greatly contributes to the development of the pharmaceutical industry and related industries.
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Abstract
Description
表皮層には、ランゲルハンス細胞と呼ばれる抗原提示細胞が存在し、免疫機能を担っている。粘膜もまた、口腔、鼻腔、呼吸器、消化器、生殖器を被う、外部環境との境界であり、皮膚の最外層の角質層がないことを除いては皮膚と同じ構造である。粘膜は、食物摂取、呼吸などを通して種々の異物と接しており、例えば病原微生物にとっては宿主体内へ侵入する主要な経路となっている。そのために、粘膜における免疫防御機構もまた生命バリアとして重要である。
したがって、本発明の目的は、経皮または経粘膜投与により皮膚刺激などを誘発することなく安全に投与可能であり、抗原の免疫原性を効率よく増強するための低分子アジュバントおよびその製剤を提供することにある。
[1]多価アルコールまたはその誘導体である、グリセリン、プロピレングリコール、ポリエチレングリコールおよびトリアセチンからなる群から選択される1または2以上を含む、経皮または経粘膜投与のためのアジュバント。
[2][1]に記載のアジュバントを含む、医薬製剤。
[3]経皮または経粘膜投与に用いられる、[2]に記載の医薬製剤。
[4]軟膏剤、クリーム剤、ゲル剤、座剤、パップ剤、ローション剤、液剤、含浸剤またはブリスター剤である、[2]または[3]に記載の医薬製剤。
[5]アジュバントが、75~100重量%で含まれる、[2]~[4]のいずれか一項に記載の医薬製剤。
[6]マトリックス型もしくは積層型のテープ製剤、またはリザーバー型の製剤である、[2]~[5]に記載の医薬製剤。
[7]無傷の皮膚もしくは粘膜または物理的もしくは化学的な処理を施された皮膚もしくは粘膜に適用される、[2]~[6]のいずれか一項に記載の医薬製剤。
[8]物理的もしくは化学的な処理が、レーザー照射、皮膚研磨、またはマイクロニードル、サーマル、超音波、電場、磁場、圧力もしくはアルカリ処理の少なくとも1つである、[7]に記載の医薬製剤。
[9]皮膚研磨、マイクロニードルおよび無針注射の少なくとも1つによって適用される、[2]~[8]のいずれか一項に記載の医薬製剤。
[10]マイクロニードルの針部の一部または全面に抗原および/またはアジュバントをコーティングする、[9]に記載の医薬製剤。
[11]角質層のラメラ構造変化、水和、変性、小孔形成、剥離またはバイパス形成の少なくとも1つによって適用される、[2]~[10]のいずれか一項に記載の医薬製剤。
[12]イオントフォレーシス、ソノフォレーシスまたはエレクトロポレーションの少なくとも1つによって適用される、[11]に記載の医薬製剤。
[13]抗原投与前または抗原投与後、あるいは、抗原投与と同時に、皮膚もしくは粘膜に適用される、[2]~[12]のいずれか一項に記載の医薬製剤。
[14][1]に記載のアジュバントまたは[2]~[13]のいずれか一項に記載の医薬製剤を含む、キット。
[15]抗原またはワクチン、および/または抗原投与のための器具を含む、[14]に記載のキット。
また、式I
CH2R1(CHR2)nCH2R3 (I)
式中、R1、R2、R3は、それぞれ相互に独立して、H、OH、OCOR4から選択され、
nは、0、1または2であり、
nが2であるとき、R2は同一でも異なってもよく、
R4は、直鎖または分枝の炭素原子数1~3のアルキル基、または直鎖または分枝の炭素原子数2または3のアルケニル基またはアルキニル基であり、
ただし、2以上のR1、R2およびR3が、同時にHではない、
で示される化合物であってもよい。
なお、本明細書においてパッチ製剤にはマトリックス型、積層型のテープ製剤およびリザーバー型の製剤が包含され、これらのうち、マトリックス型テープ製剤およびリザーバー型製剤が好ましく用いられ、マトリックス型テープ製剤がとくに好ましく用いられる。
また、本発明のアジュバントまたは医薬製剤を適用する部位は、抗原などを適用する部位または領域と同一であっても、異なっていてもよい。
また、かかる経皮または経粘膜投与製剤は、基剤として溶解剤、溶解補助剤、pH調整剤、防腐剤、吸収促進剤、安定化剤、充填剤、増粘剤、粘着剤、湿潤剤などの任意の成分を、本発明のアジュバントとを組み合わせたものを用いることによって、常法により製造することができる。また、本発明の医薬製剤のうち、他の剤型の医薬製剤も、常法により製造することができる。
また、前記水溶性高分子を2種類以上併用することにより、例えば、ポリアクリル酸ナトリウムの強イオン高分子と高分子コンプレックスを形成し、より一層ゲル強度の大きい弾性ゲルを得ることができる。
また、溶解補助剤または吸収促進剤として、炭酸プロピレン、クロタミトン、l-メントール、ハッカ油、リモネン、ジイソプロピルアジペートなどや、薬効補助剤として、サリチル酸メチル、サリチル酸グリコール、l-メントール、チモール、ハッカ油、ノニル酸ワニリルアミド、トウガラシエキスなどを添加してもよい。さらに、必要に応じて、安定化剤や抗酸化剤、乳化剤、界面活性剤などを添加してもよい。
また、増粘剤にポリビニルピロリドンを適用した場合は、メチルビニルエーテル/無水マレイン酸共重合体、ポリアシッド化合物またはそのアルカリ金属塩(ポリアクリル酸やタンニン酸およびその誘導体)などが好適に用いられる。また、増粘剤にポリエチレンオキサイドを適用した場合は、パーオキサイド、ポリスルホンアザイドなどが好適に用いられる。
とくに、亜鉛塩、アルミニウム塩が好ましい。架橋反応が促進されるからである。架橋剤として添加される多価金属塩の濃度は、増粘剤(または水溶性高分子)1当量に対し0.5~1.5当量が好ましい。多価金属塩の濃度を0.5当量以上とすることによって、反応が促進されてゲル強度が高くなり、多価金属塩の濃度を1.5当量以下とすることによって、反応を適度な速度において行わせしめ、ゲル化を均一とし、作業性が向上するからである。
このような疎水性高分子は2種以上混合して使用してもよく、これら高分子の組成全体の重量に基づく配合量は、粘着剤層の形成および充分な皮膚への透過性を考慮して、5~90重量%であることが好ましく、さらに10~70重量%であることが好ましい。
このような粘着付与樹脂は、貼付剤としての充分な粘着力および剥離時の皮膚への刺激性を考慮して、粘着剤層の組成全体に基づき5~70重量%、好ましくは5~60重量%、さらに好ましくは10~50重量%の量で配合することができる。
一方、併用される抗原が十分な経皮もしくは経粘膜活性を有していない場合には、本発明のアジュバントのみを経皮もしくは経粘膜投与し、併用される抗原は非経皮的もしくは非経粘膜的に投与してもよく、例えば、注射による投与、経口による投与が考えられる。
また、かかる製剤中におけるアジュバントの含量もとくに限定されることはなく、経皮経路により十分な抗原免疫応答を誘起せしめる量であればよいが、高濃度のアジュバントであることが好ましい。
また、抗原を、マイクロニードルの針部の一部または全面にコーティングすることにより、マイクロニードルを用いて投与し、本発明のアジュバントを含む医薬製剤は、マイクロニードルによって投与せずに、皮膚もしくは粘膜に塗布または貼付するなどして、抗原投与前もしくは抗原投与後に皮膚もしくは粘膜に適用してもよく、また、抗原投与と同時に皮膚もしくは粘膜に適用することも可能である。
例えば、マイクロニードルの針部へのコーティングの記載は、特表2004-504120号公報、特表2004-528900号公報、WO2005/016440などにある。
雌性8週齢のヘアレスラット背側部を剃毛し、(i)マイクロニードル(OVA)適用群、(ii)マイクロニードル(OVA)適用+アジュバント候補適用群に分けた。マイクロニードルは針先端部にOVA抗原20μgをコーティングし、30分間穿刺投与した(コーティング液はOVA/プルラン溶液とし、針長約500μm、625本/cm2のポリ乳酸製マイクロニードルを使用した)。さらに(ii)の群では、マイクロニードル30分間穿刺投与後、穿刺部位に各アジュバント候補(グリセリン、エタノール、およびグリセリン/エタノール(1/1)混液)を6時間経皮投与した。各アジュバント候補適用方法は、グリセリン、エタノール、およびグリセリン/エタノール(1/1)混液についてはパッチテスト用テープ;スモールサイズ(鳥居薬品)のパット部に各アジュバント候補原液を120μL含浸させたものを貼付した。いずれの群もコーバンおよびスキナゲートで固定した。
抗原およびアジュバント投与は0、2、4週間後、採血は2、4、5週間後に行い、OVA特異的IgG抗体価をELISAにて測定した(図1に5週間後の各抗体価を示す)。
図1に示すとおり、OVAを単独でマイクロニードル投与する群と比較して、アジュバント候補適用群ではいずれも顕著に高いIgG抗体価を示しており、グリセリン、エタノール、およびグリセリン/エタノール:1/1混液のいずれも高いアジュバント効果を有することが確認された。
上記(ii)マイクロニードル(OVA)適用+アジュバント候補適用群において、各アジュバント剥離24時間後の皮膚状態を観察し、皮膚刺激の程度をスコアで評価した(表1)。
表1に示すとおり、ラウリルアルコール(テープ)適用群は剥離直後にはほとんど刺激が認められないものの、剥離24時間後に若干の鱗屑が認められる個体が存在した。また、エタノール適用群では壊死を伴う顕著な皮膚刺激、エタノール/グリセリン混液適用群でもそれに準ずる皮膚刺激が認められた。これに対し、グリセリン適用群では皮膚刺激は認められず、グリセリンは顕著な抗体価上昇効果を有しながら皮膚刺激リスクの少ない、優れたアジュバントであることが認められた。
なお、前記のラウリルアルコール40%配合テープ製剤(マトリックス型テープ製剤)は、4.0gのLA(日油)、13.3g(乾燥重量6.0g)のDURO-TAK 87-2194(Henkel社製アクリル系粘着剤)を混合、剥離ライナー上に展膏し、80℃15分間乾燥させて厚み50μmとした後、支持体を付着させて製造した。
雌性8週齢のヘアレスラット背側部を剃毛し、(i)マイクロニードル(OVA)適用群、(ii)マイクロニードル(OVA)適用+アジュバント候補適用群に分けた。マイクロニードルは針先端部にOVA抗原20μgをコーティングし、30分間穿刺投与した(コーティング液はOVA/プルラン溶液とし、針長約500μm、625本/cm2のポリ乳酸製マイクロニードルを使用した)。さらに(ii)の群では、マイクロニードル30分間穿刺投与後、穿刺部位にアジュバント候補としてグリセリン(Merck)、グリセリン(花王)、スクワレン、コントロールとして精製水を用い、パッチテスト用テープ;スモールサイズ(鳥居薬品)のパット部に各アジュバント候補原液を120μL含浸させたものを6時間貼付した。いずれの群もコーバンおよびスキナゲートで固定した。
図2に示すとおり、グリセリンによるアジュバント効果はメーカーを変更した場合も同様に確認された。本発明に用いたグリセリンは濃グリセリン(Merck:純度99.0%以上, 花王:純度98.0%以上)であり、アジュバント効果は不純物の影響によるものではなく、グリセリン自体が有するものと推測される。
また、グリセリン同様に刺激が認められず、他社でアジュバントとしての使用実績を有するスクワレンはコントロールと同様の低いIgG抗体価を示した。このことより、グリセリンの優れたアジュバント効果が確認された。
雌性8週齢のヘアレスラット背側部を剃毛し、(i)皮内注射(OVA)適用群、(ii)皮内注射(OVA)適用+グリセリン適用群、(iii)マイクロニードル(OVA)適用群、(iv)マイクロニードル(OVA)適用+グリセリン適用群に分けた。(i)および(ii)は皮内にOVA 20μg/50 mL(生理食塩水)を投与した。(iii)および(iv)はマイクロニードル針先端部にOVA抗原20μgをコーティングし、30分間穿刺投与した(コーティング液はOVA/プルラン溶液とし、針長約500μm、625本/cm2のポリ乳酸製マイクロニードルを使用した)。さらに(ii)および(iv)の群では、マイクロニードル30分間穿刺投与後、穿刺部位にパッチテスト用テープ;スモールサイズ(鳥居薬品)のパット部にグリセリンを120μL含浸させたものを6時間貼付した。いずれの群もコーバンおよびスキナゲートで固定した。
図3に示すとおり、OVA抗原皮内注射適用の場合と比較して、マイクロニードル適用ではグリセリンのアジュバント効果がより顕著に示された。また図4に示すように、皮内注射群ではグリセリン併用時も2週間後にIgG抗体が検出されなかったが、マイクロニードル群にグリセリンを併用することにより、2週間後からIgG抗体価の上昇が認められた。
よって、グリセリンによるアジュバント効果はマイクロニードルで抗原投与することによってより顕著に得られ、IgG抗体価の立ち上がりもより早いことが示された。
雌性8週齢のヘアレスラット背側部を剃毛し、(i)マイクロニードル(OVA)適用群、(ii)マイクロニードル(OVA)適用+アジュバント候補(グリセリンまたはグリセリン誘導体)適用群に分けた。マイクロニードルは針先端部にOVA抗原20μgをコーティングし、30分間穿刺投与した(コーティング液はOVA/プルラン溶液とし、針長約500μm、625本/cm2のポリ乳酸製マイクロニードルを使用した)。さらに(ii)の群では、マイクロニードル30分間穿刺投与後、穿刺部位にアジュバント候補としてグリセリンの他に、グリセリン誘導体および多価アルコールとしてプロピレングリコール(PG)、マクロゴール400、オレイン酸モノグリセリン(GMO)またはトリアセチンを用い、パッチテスト用テープ;スモールサイズ(鳥居薬品)のパット部に各アジュバント候補原液を120μL含浸させたものを6時間貼付した。いずれの群もコーバンおよびスキナゲートで固定した。
抗原およびアジュバント投与は0、2、4週間後、採血は2、4、5週間後に行い、OVA特異的IgG抗体価をELISAにて測定した(図5に5週間後の各抗体価を示す)。
また、グリセリンのみならず、これらグリセリン誘導体においても皮膚刺激性は認められず、高いアジュバント効果を有しながら安全性の高いアジュバントとなり得ることが示された。
雌性8週齢のヘアレスラット背側部を剃毛し、マイクロニードル(OVA)適用+アジュバント(0、25、75%グリセリン溶液)適用を行った。マイクロニードルは針先端部にOVA抗原として20μgをコーティングし、30分間穿刺投与した(コーティング液はOVA/プルラン溶液とし、針長約500μm、625本/cm2のマイクロニードルを使用した)。その後、パッチテスト用テープ;スモールサイズ(鳥居薬品)のパット部に各アジュバント溶液120μLを含浸させたものを6時間貼付した。いずれの群もコーバンおよびスキナゲートで固定した。
抗原およびアジュバント投与は0、2週間後、採血は2、4週間後に行い、OVA特異的IgG抗体価をELISAにて測定した(表2に4週間後の各抗体価を示す)。
雌性8週齢のヘアレスラット背側部を剃毛し、(i)マイクロニードル(OVA/プルラン/41%グリセリン混合)適用群、(ii)マイクロニードル(OVA)適用+アジュバント(100%グリセリン)適用群に分けた。マイクロニードルは針先端部にOVA抗原として20μgをコーティングし、30分間穿刺投与した(コーティング液はOVA/プルラン溶液とし、針長約500μm、625本/cm2のマイクロニードルを使用した)。また、(ii)の群では、マイクロニードル30分間穿刺投与後、10分間静置してから、パッチテスト用テープ;スモールサイズ(鳥居薬品)のパット部にアジュバント溶液120μLを含浸させたものを6時間貼付した。いずれの群もコーバンおよびスキナゲートで固定した。
抗原およびアジュバント投与は0、2週間後、採血は2、4週間後に行い、OVA特異的IgG抗体価をELISAにて測定した(表3に4週間後の各抗体価を示す)。
また、抗原投与後、時間間隔をあけてアジュバントを貼付しても、免疫活性増強効果を達成することが示された。
Claims (15)
- 多価アルコールまたはその誘導体である、グリセリン、プロピレングリコール、ポリエチレングリコールおよびトリアセチンからなる群から選択される1または2以上を含む、経皮または経粘膜投与のためのアジュバント。
- 請求項1に記載のアジュバントを含む、医薬製剤。
- 経皮または経粘膜投与に用いられる、請求項2に記載の医薬製剤。
- 軟膏剤、クリーム剤、ゲル剤、座剤、パップ剤、ローション剤、液剤、含浸剤またはブリスター剤である、請求2または3に記載の医薬製剤。
- アジュバントが、75~100重量%で含まれる、請求項2~4のいずれか一項に記載の医薬製剤。
- マトリックス型もしくは積層型のテープ製剤、またはリザーバー型の製剤である、請求項2~5に記載の医薬製剤。
- 無傷の皮膚もしくは粘膜または物理的もしくは化学的な処理を施された皮膚もしくは粘膜に適用される、請求項2~6のいずれか一項に記載の医薬製剤。
- 物理的もしくは化学的な処理が、レーザー照射、皮膚研磨、またはマイクロニードル、サーマル、超音波、電場、磁場、圧力もしくはアルカリ処理の少なくとも1つである、請求項7に記載の医薬製剤。
- 皮膚研磨、マイクロニードルおよび無針注射の少なくとも1つによって適用される、請求項2~8のいずれか一項に記載の医薬製剤。
- マイクロニードルの針部の一部または全面に抗原および/またはアジュバントをコーティングする、請求項9に記載の医薬製剤。
- 角質層のラメラ構造変化、水和、変性、小孔形成、剥離またはバイパス形成の少なくとも1つによって適用される、請求項2~10のいずれか一項に記載の医薬製剤。
- イオントフォレーシス、ソノフォレーシスまたはエレクトロポレーションの少なくとも1つによって適用される、請求項11に記載の医薬製剤。
- 抗原投与前または抗原投与後、あるいは、抗原投与と同時に、皮膚もしくは粘膜に適用される、請求項2~12のいずれか一項に記載の医薬製剤。
- 請求項1に記載のアジュバントまたは請求項2~13のいずれか一項に記載の医薬製剤を含む、キット。
- 抗原またはワクチン、および/または抗原投与のための器具を含む、請求項14に記載のキット。
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WO2015064710A1 (ja) | 2013-10-31 | 2015-05-07 | 久光製薬株式会社 | アジュバント組成物、これを含むアジュバント製剤、及びキット |
WO2016035808A1 (ja) * | 2014-09-03 | 2016-03-10 | 日東電工株式会社 | ビスホスホネート剤を含む細胞性免疫用ワクチン医薬組成物 |
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Also Published As
Publication number | Publication date |
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JP5876468B2 (ja) | 2016-03-02 |
US20140037694A1 (en) | 2014-02-06 |
TWI576111B (zh) | 2017-04-01 |
ES2834200T3 (es) | 2021-06-16 |
EP2679242A4 (en) | 2016-07-20 |
EP2679242B1 (en) | 2020-09-09 |
TW201238597A (en) | 2012-10-01 |
EP2679242A1 (en) | 2014-01-01 |
JPWO2012115222A1 (ja) | 2014-07-07 |
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