WO2017135313A1 - 免疫誘導促進用組成物及びワクチン医薬組成物 - Google Patents
免疫誘導促進用組成物及びワクチン医薬組成物 Download PDFInfo
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Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
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- 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
Definitions
- the present invention relates to a composition for promoting immunity induction and a vaccine pharmaceutical composition, and more particularly to a composition for promoting immunity induction and a vaccine pharmaceutical composition containing an agent that acts on an ion channel or an ion pump to control intracellular ion concentration.
- a widely used vaccine is one that attenuates or nullifies the toxicity of a pathogen such as a microorganism or virus, or a part thereof, and induces immunity by being administered to a living body.
- Most of the dosage forms of vaccine preparations that are currently commercialized are injections.
- injection such as subcutaneous or intradermal injection or intramuscular injection is generally used.
- the vaccine needs to be invasively administered into the body.
- adjuvants generally used in immunity induction by injection aluminum hydroxide, aluminum phosphate, aluminum salts such as aluminum chloride, and emulsions containing squalene such as MF59 and AS03 have been put to practical use.
- flagellar components, nucleic acids, cytokines, cationic polymers, polypeptides and the like have been widely studied.
- Toxins such as heat-resistant toxins can be mentioned, but they have not been put into practical use. Furthermore, there are few reports on effective immunostimulating agents that can be used in induction of humoral immunity by transdermal administration of an antigen, and sufficient humoral immunity induction effects are often not obtained compared to injection.
- immunity induction promoters those that contribute to the sustained release of antigen, those that contribute to uptake into dendritic cells, those that contribute to the innate immune system such as Toll-like receptor ligand and NOD-like receptor ligand.
- the immunostimulants that have been used so far are effective due to the sustained release of antigens such as fragments derived from microorganisms and viruses such as Toll-like receptor ligands, toxins such as cholera toxin and E. coli heat-labile toxin, and antigens.
- antigens such as fragments derived from microorganisms and viruses such as Toll-like receptor ligands
- toxins such as cholera toxin and E. coli heat-labile toxin
- antigens such as cholera toxin and E. coli heat-labile toxin
- Th2 cell differentiation inhibitor see, for example, Patent Document 4
- its principle is a prostaglandin that promotes a Th2 reaction.
- Th1 cells that activate cellular immunity are relatively activated.
- Patent Document 4 describes only evaluation for inducing cellular immunity, and the technology for effectively promoting humoral immunity that induces antibody production has not been known.
- the present invention is universally usable for induction of cellular immunity and / or humoral immunity against various antigens, and promotes immunity induction capable of exerting a high cellular immunity and / or humoral immunity induction effect. It aims at providing the composition for vaccines and a vaccine pharmaceutical composition.
- the present inventors have controlled cellular immunity characterized by the production of cytotoxic T cells (CTL cells) by controlling the intracellular ion concentration of immunocompetent cells and Attention was focused on the ability to effectively induce humoral immunity characterized by antibody production.
- CTL cells cytotoxic T cells
- Dendritic cells a type of immunocompetent cell that has phagocytosed foreign substances such as viruses and microorganisms, migrate to the lymph nodes, give information on foreign substances to naive T cells (Th0 cells), and induce differentiation of helper T cells .
- Th0 cells differentiate into type 1 helper T cells (Th1 cells) responsible for cellular immunity and type 2 helper T cells (Th2 cells) responsible for humoral immunity by exchanging various information with dendritic cells. It is known that the direction of differentiation of helper T cells can be controlled by biological signal molecules such as cytokines, and is widely used in in vitro test systems.
- Dendritic cells are activated upon stimulation by cytokines and the like, and are considered to determine the direction of T cell differentiation in the course of complex signal transduction. That is, T cell differentiation is determined by the “state” of dendritic cells, and cellular immunity and humoral immunity are induced. The former is called Th1 reaction because Th1 cells are the center of the reaction, and the latter is also called Th2 reaction.
- the present inventors paid attention to the above viewpoint and found that intracellular ion concentration is used as a signal transduction system when these immunocompetent cells phagocytose antigens.
- intracellular ion concentration agonist that controls intracellular ion concentration together with an antigen.
- antigen-specific cellular immunity and / or humoral immunity can be effectively induced by administering an intracellular ion concentration agonist that controls intracellular ion concentration directly to a living body together with an antigen.
- Intracellular ion-concentration agonists are already widely used as drugs, ensuring safety for humans, and excellent in terms of convenience.
- the present inventors have found that cellular immunity and / or humoral immunity can be further promoted by using a Toll-like receptor (TLR) ligand in combination.
- TLR Toll-like receptor
- the present invention is a composition for promoting immunity induction comprising a first immunity induction promoter that is an intracellular ion concentration agonist acting on an ion channel or ion pump.
- the intracellular ion concentration agonist is at least one selected from the group consisting of a sodium channel agonist, a calcium channel agonist, a potassium channel agonist, a chlorine channel agonist, and a sodium-potassium pump agonist. Is preferred.
- the present invention is also a vaccine pharmaceutical composition comprising an antigen for immunity induction and the immunity induction promoting composition.
- the vaccine pharmaceutical composition may further comprise a second immunity induction promoter that is at least one immunostimulatory agent selected from Toll-like receptor (TLR) ligand, cyclic dinucleotide, and helper peptide. preferable.
- TLR Toll-like receptor
- the vaccine pharmaceutical composition is preferably administered on the body surface.
- the vaccine pharmaceutical composition is preferably administered by intradermal injection, subcutaneous injection or intramuscular injection.
- the composition for promoting immunity induction and the vaccine pharmaceutical composition of the present invention are used for humoral immunity and / or cellular immunity induction.
- a method for quantitatively measuring the humoral immunity induction effect is not particularly limited, and various methods have been developed.
- immunity induction experiments using an animal model for immunity evaluation and ELISA method antigen-specific IgG antibody
- examples of the sample for measuring humoral immunity include blood of a model animal for immunity evaluation.
- a method for quantitatively measuring the cellular immunity induction effect is not particularly limited, and various methods have been developed.
- immunity induction experiments using an animal model for immunity evaluation and ELISPOT method (number of antigen-specific CTLs) examples of the sample for measuring cellular immunity include spleen cells collected from a model animal for immunity evaluation.
- the composition for promoting immunity induction of the present invention includes a first immunity induction promoter (hereinafter, also simply referred to as a first immunity induction promoter) that is an intracellular ion concentration agonist acting on an ion channel or ion pump.
- a first immunity induction promoter that is an intracellular ion concentration agonist acting on an ion channel or ion pump.
- intracellular ionic concentration agonist acts on the ion channel or ion pump of an immunocompetent cell to induce cellular and / or humoral immunity of the co-administered antigen.
- the intracellular ion concentration agonist acting on the ion channel is preferably at least one selected from the group consisting of sodium channel agonists, calcium channel agonists, potassium channel agonists, and chlorine channel agonists.
- sodium channel agonist means a substance that acts on a sodium channel to change the concentration of ions in the cell.
- Sodium channel agonists are roughly classified into voltage-dependent sodium channel agonists and epithelial sodium channel agonists according to the mechanism of action.
- Examples of the voltage-gated sodium channel agonist include lidocaine, mepivacaine, bupivacaine, levobupivacaine, ropivacaine, procaine, tetracaine, benzocaine, dibucaine, prilocaine, cocaine, mexiletine, flecainide, quinidine, carbamazepine, zonisamide, bromotrigine, And derivatives thereof, and pharmacologically acceptable salts thereof.
- epithelial sodium channel agonist examples include amiloride, triamterene, suramin, and derivatives thereof, and pharmacologically acceptable salts thereof.
- the sodium channel agonist is preferably amiloride, suramin or triamterene.
- calcium channel agonist means a substance that acts on a calcium channel and changes the concentration of ions in the cell. Calcium channel agonists are roughly classified into voltage-dependent calcium channel agonists and ion channel-containing receptor calcium channel agonists according to the mechanism of action.
- Examples of the voltage-gated calcium channel agonist include cilnidipine, ziconotide, dronedarone, amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, rasidipine, nilvadipine, manidipine, varnidipine, benidipine, clevidilomil, verapamil, Diltiazem, fendiline, bepridil, perhexiline, topiramate, alanidipine, azelnidipine, dalodipine, efonidipine, kilenidipine, mibefradil, ethosuccimide, valproic acid, zonisamide, penfluridol, flunarizine, alanidipine, efonodipinevirgapinega gapentagagaga , Lidofurazine, metal Tar
- Examples of the ion channel-containing receptor calcium channel agonist include topiramate, kainic acid, thezan panel, peran panel, farampeter, thezan panel, taran panel, zonan panel, besonprodil, traxoprodil, ifenprodil, ketamine, esketamine, ethomidone, flupirtine, memantine, Methadone, acamprosate, dextromethorphan, aptiganel, delcemin, dextrorphan, dizocilpine, gavestinel, levomethadone, lycostine, latrepyridine, neramexane, peudinfotel, phencyclidine, remacymide, selfotel, tiletamine, and derivatives thereof, and Examples thereof include pharmacologically acceptable salts.
- the calcium channel agonist is preferably amlodipine or manidipine.
- potassium channel agonist means a substance that acts on a potassium channel to change intracellular ion concentration. Potassium channel agonists are roughly classified into voltage-dependent potassium channel agonists, calcium-dependent potassium channel agonists, inward rectifier potassium channel agonists, and in-line pore domain potassium channel agonists, depending on the mechanism of action.
- Examples of the voltage-gated potassium channel agonist include pilsicainide, verapamil, propafenone, bepridil, clofylium, flecainide, amiodarone, tedisamil, dronedarone, nifekalant, linopirudine, azimilide, linopirudine, ezogabine, bretylide tosylate, aprindine, dofetilide, Tedisamil, sotalol, cocaine, azimilide, clofilium, dexsotalol, nifekalant, sematilide, tericalicant, tetraethylammonium, 4-aminopyridine, dendrotoxin, capsaicin, zcapsaicin, mabatrep, nonivamid, menthol and their derivatives, and their drugs Examples include salts that are physically acceptable.
- the calcium-dependent potassium channel agonists include topiramate, kainic acid, thezan panel, peran panel, faran peter, thezan panel, taran panel, zonan panel, besonprodil, troxoprodil, ifenprodil, ketamine, esketamine, ethobemidone, flupirtine, memantine, methadone, acan Prosert, dextromethorphan, aptiganel, delcemin, dextrorphan, dizocilpine, gavestinel, levomethadone, ricostinel, latrepyridine, neramexane, peudinfotel, phencyclidine, remasemide, serfotel, tiretamine, and derivatives thereof, and their drugs Examples include salts that are physically acceptable.
- Examples of the inward rectifier potassium channel agonist include glibenclamide, tolbutamide, diazoxide, pinacidil, amiodarone, dronedarone, bepridil, edisamil, nifekalant, tericarant, nicorandil, minoxidil, lebuchroma potassium, and derivatives thereof, and their drugs Examples include salts that are physically acceptable.
- Examples of the tandem pore domain potassium channel agonist include halothane, derivatives thereof, and pharmacologically acceptable salts thereof.
- the potassium channel agonist is preferably dofetilide or glibenclamide.
- chlorine channel agonist means a substance that acts on a chloride channel and changes the concentration of ions in the cell. Chlorine channel agonists are broadly classified into CIC chloride channel agonists, calcium-dependent chloride channel agonists, cell volume sensitive chloride channel agonists, and CFTR chloride channel agonists, depending on the mechanism of action. Examples of the CIC chloride channel agonist include rubiprostone and derivatives thereof, and pharmacologically acceptable salts thereof. Examples of the calcium-dependent chloride channel agonist include niflumic acid, derivatives thereof, and pharmacologically acceptable salts thereof. The chlorine channel agonist is preferably niflumic acid.
- the intracellular ion concentration agonists acting on the ion pump are roughly classified into sodium-potassium pump agonists, proton-potassium pump agonists, calcium pump agonists, proton pump agonists, and copper ion pump agonists.
- sodium-potassium pump agonist means a substance that acts on Na + / K + -ATPase, which is a sodium-potassium pump, to change the intracellular ion concentration.
- sodium-potassium pump agonist examples include digitoxin, digoxin, lanatoside C, deslanoside, methyl digoxin, acetyl digoxin, acetyl digitoxin, gitoformate, prossilaridin, G-strophanthin, and their derivatives, and their Examples thereof include pharmacologically acceptable salts.
- the sodium-potassium pump agonist is preferably digitoxin or digoxin.
- proton-potassium pump agonist means a substance that acts on the proton-potassium pump H + / K + -ATPase to change the intracellular ion concentration.
- Examples of the proton-potassium pump agonist include omeprazole, pantoprazole, rabeprazole, esomeprazole, dexlansoprazole, lansoprazole, leminoprazole, picoprazole, tenatoprazole, timoprazole, and derivatives thereof, and their pharmacology And salts that are acceptable.
- salt may be any organic or inorganic acid, but is preferably a pharmaceutically acceptable salt.
- pharmaceutically acceptable salt means a salt that does not adversely affect the subject of administration and does not eliminate the pharmacological activity of the ingredients in the vaccine pharmaceutical composition.
- inorganic acid salts for example, hydrochloride, phosphate
- organic acid salts for example, acetate, phthalate, TFA salt
- metal salts for example, alkali metal salts (for example, sodium salt, potassium) Salt
- alkaline earth metal salt eg calcium salt, magnesium salt
- aluminum salt eg triethylamine salt, benzylamine salt, diethanolamine salt, t-butylamine salt, dicyclohexylamine salt, arginine salt, dimethyl
- Ammonium salt ammonium salt
- the content of the first immunity induction promoting agent is not particularly limited, but is preferably 0.0001 to 100% by mass based on the total mass of the immunity induction promoting composition. More preferably, the content is 0.001 to 80% by mass, and still more preferably 0.01 to 50% by mass.
- the content of the first immunity induction promoter is less than 0.0001% by mass, the immunity induction effect may not be sufficiently obtained, and the content of the first immunity induction promoter is 100. When it exceeds mass%, safety may be a problem.
- the composition for promoting immunity induction of the present invention may contain an additive as necessary.
- the additives include isotonic agents, antiseptics / bactericides, antioxidants, solubilizers, solubilizers, suspending agents, fillers, pH regulators, stabilizers, absorption enhancers, and release agents. Examples thereof include a speed control agent, a colorant, a plasticizer, a cross-linking agent, and an adhesive. These additives can be used alone or in combination of two or more.
- the vaccine pharmaceutical composition of the present invention comprises an antigen and the composition for promoting immunity induction.
- the vaccine pharmaceutical composition of the present invention can effectively induce antigen-specific cellular immunity and / or humoral immunity.
- the term “antigen” means any substance capable of inducing an immune response.
- the antigen is not particularly limited, and examples thereof include proteins and peptides.
- an antigen having a low molecular weight for example, a peptide consisting of about 8 to 12 amino acids can be used.
- the antigen is not particularly limited, and examples thereof include cancer antigen peptides, infectious pathogen-derived antigens, human endogenous-derived proteins, and the like.
- cancer means abnormal expression of an oncogene.
- examples of the cancer include cancers with overexpression such as hematopoietic tumors and solid cancers.
- abnormal expression of a gene means that the expression level of the gene in a cell is, for example, 2 times or more, 4 times or more, etc., compared to other cells of the same tissue. It means that the magnification is significantly increased or decreased.
- overexpression means that abnormal expression is an increase in expression levels. The expression level of a gene can be easily measured using any method known in the art.
- oncogene examples include survivin gene, GPC3 gene, HER2 / neu gene, MAGE3 gene, MAGE A1 gene, MAGE A3 / A6 gene, MAGE A4 gene, MAGE12 gene, proteinase-3 gene, AFP gene, CA-125 Gene, CD44 gene, CEA gene, c-Kit gene, c-met gene, c-myc gene, L-myc gene, COX2 gene, CyclinD1 gene, Cytokeratin-7 gene, Cytokeratin-19 gene, Cytokeratin-20 gene, E2F1 Gene, E2F3 gene, EGFR gene, Gli1 gene, hCG ⁇ gene, HIF-1 ⁇ gene, HnRNP A2 / B1 gene, hTERT gene, MDM gene, MD -1 gene, MMP-2 gene, MMP-9 gene, Muc-1 gene, Muc-4 gene, Muc-7 gene, NSE gene, ProGRP gene, PSA gene, RCAS1 gene, SCC gene, thyl
- Cancers with abnormal expression of the survivin gene include, but are not limited to, malignant lymphoma, bladder cancer, lung cancer, colon cancer and the like.
- Cancers with abnormal expression of the GPC3 gene include, but are not limited to, liver cancer, bile duct cancer, gastric cancer and the like.
- Cancers with abnormal expression of the HER2 / neu gene include, but are not limited to, breast cancer, stomach cancer, ovarian cancer, uterine cancer, bladder cancer, non-small cell lung cancer, prostate cancer and the like.
- Cancers with abnormal expression of the MAGE3 gene include, but are not limited to, melanoma, lung cancer, head and neck cancer, bladder cancer, gastric cancer, esophageal cancer, liver cancer and the like.
- Cancers with abnormal expression of the proteinase-3 gene include, but are not limited to, acute myeloid leukemia and pancreatic cancer.
- cancer antigen means a substance such as a protein, peptide, or the like that can be expressed specifically in tumor cells or cancer cells and induce a cellular immune response.
- cancer antigen peptide refers to a partial peptide derived from a cancer antigen protein that can induce a cellular immune response.
- cancer antigen peptides are produced by degradation of cancer antigen proteins, which are products of oncogenes, in cancer cells, and are presented on the surface of cancer cells by MHC class I molecules.
- the cancer antigen peptide may be an endogenous cancer antigen peptide isolated and purified from cancer cells, or a synthetic peptide having the same amino acid sequence as the endogenous cancer antigen peptide.
- Specific examples of the cancer antigen peptides include survivin 2B peptide, GPC3 peptide, HER2 / neu_A24 peptide, MAGE3_A24 peptide, IPEP87 peptide, PR1 peptide, HER2 / neu_A02 peptide, MAGE3_A02 peptide, HBVenv peptide, HER2 / neu_E75 peptide, MUC1 peptide Or their modified peptides are preferred.
- survivin 2B peptide refers to a peptide derived from the oncogene product survivin consisting of the sequence Ala Tyr Ala Cys Asn Thr Ser Thr Leu (SEQ ID NO: 1).
- GPC3 peptide means a peptide derived from the oncogene product GPC3 consisting of the sequence Glu Tyr Ile Leu Ser Leu Glu Glu Leu (SEQ ID NO: 2).
- HER2 / neu_A24 peptide refers to an oncogene product HER2 / neu-derived HLA-A24-restricted peptide consisting of the sequence Thr Tyr Leu Pro Thr Asn Ala Ser Leu (SEQ ID NO: 3). means.
- MAGE3_A24 peptide means an HLA-A24-restricted peptide derived from the oncogene product MAGE3, which consists of the sequence Ile Met Pro Lys Ala Gly Leu Leu Ile (SEQ ID NO: 4).
- IPEP87 peptide means a peptide derived from the hepatitis C virus (HCV) protein consisting of the sequence Asp Leu Met Gly Tyr Ile Pro Ala Val (SEQ ID NO: 5).
- PR1 peptide means a peptide derived from the oncogene product proteinase-3 consisting of the sequence Val Leu Gln Glu Leu Asn Val Thr Val (SEQ ID NO: 6).
- HER2 / neu_A02 peptide refers to the HLA-A02 restricted peptide derived from the oncogene product HER2 / neu, consisting of the sequence Lys Val Phe Gly Ser Leu Ala Phe Val (SEQ ID NO: 7). means.
- MAGE3_A02 peptide means an HLA-A02-restricted peptide derived from the oncogene product MAGE3, which consists of the sequence Lys Val Ala Glu Ile Val His Phe Leu (SEQ ID NO: 8).
- HBVenv peptide refers to a peptide derived from the hepatitis B virus (HBV) protein consisting of the sequence Trp Leu Ser Leu Leu Val Pro Phe Val (SEQ ID NO: 9).
- HER2 / neu_E75 peptide is a peptide derived from the product of the oncogene HER2 / neu (HER2 protein) consisting of the sequence Lys Ile Phe Gly Ser Leu Ala Phe Leu (SEQ ID NO: 10). Means.
- MUC1 peptide consists of the sequence Ser Thr Ala Pro Pro Val His Asn Val (SEQ ID NO: 11) and is derived from MUC1 protein, a glycoprotein that is highly expressed on many cancer cells. Means a peptide.
- modified XX peptide means a peptide in which all or some of the amino acids of the XX peptide have been modified by substitution or modification.
- Modified XX peptides include, for example, (A) a peptide consisting of an amino acid sequence in which one to several, for example 1, 2, 3, 4, or 5 amino acids are substituted, deleted or added in the amino acid sequence of the XX peptide; and (B) In the amino acid sequence of the XX peptide, all or part of amino acids, for example, one or more, for example, 1, 2, 3, 4, 5, 6, 7, 8 , Peptides comprising an amino acid sequence modified with 9 or 10 amino acids.
- Modifications of amino acids that the modified XX peptide may have include, but are not limited to, for example, alkylation such as acetylation, methylation, glycosylation, hydroxylation, carboxylation, aldehyde formation, phosphorylation, sulfonylation , Fatty acid addition modification such as formylation, myristoylation, palmitoylation and stearoylation, octanoylation, esterification, amidation, deamidation, disulfide bond modification such as cystine modification, glutathione modification and thioglycolic acid modification Saccharification, ubiquitination, succinimide formation, glutamylation, prenylation and the like.
- alkylation such as acetylation, methylation, glycosylation, hydroxylation, carboxylation, aldehyde formation, phosphorylation, sulfonylation , Fatty acid addition modification such as formylation, myristoylation, palmitoylation
- the modified XX peptide may comprise a combination of one or more amino acid substitutions, deletions or additions and one or more amino acid modifications.
- the peptides listed above may be in free form or in any pharmacologically acceptable salt form, such as acid salts (acetate, TFA salt, hydrochloride, sulfate, phosphate, lactate, tartrate, maleate Acid salt, fumarate, oxalate, hydrobromide, succinate, nitrate, malate, citrate, oleate, palmitate, propionate, formate, benzoate, Picrate, benzenesulfonate, dodecylsulfate, methanesulfonate, p-toluenesulfonate, glutarate, various amino acid salts, etc.), metal salts (alkali metal salts (for example, sodium salts, potassium salts, etc.) ), Alkaline earth metal salts (eg calcium salts, magnesium salts), aluminum salt
- an “infectious disease pathogen-derived antigen” is an infectious disease pathogen or a component thereof or a substance derived therefrom, and an immune response (eg, maturation of immunocompetent cells, increased production of cytokines, It means any substance that can induce the promotion of antibody production.
- An infectious disease can be treated or prevented by administering the antigen derived from an infectious disease pathogen to a subject.
- infectious pathogens examples include infectious pathogens, infectious pathogen-derived proteins, human endogenous origin proteins, and the like.
- the disease caused by the infectious pathogen is not particularly limited.
- adenovirus for example, human adenovirus
- herpes virus for example, herpes simplex virus, varicella-zoster virus, cytomegalovirus, human herpes virus or Kaposi Sarcoma-associated herpes virus
- picornavirus eg poliovirus, cold virus or hepatitis A virus
- poxvirus eg variola virus, vaccinia virus or infectious molluscum virus
- picornavirus eg rhinovirus
- enterovirus orthomyxovirus
- paramyxovirus eg parainfluenza virus, mumps virus, measles virus, respiratory syncytial virus (RSV) or Newcastle disease virus
- parvovirus eg adeno-associated virus
- hepatitis E virus eg, hepatitis E virus
- papilloma virus for example, human papilloma virus), calicivirus (eg norovirus), rhabdovirus (eg rabies virus or vesicular stomatitis virus), filovirus (eg ebola hemorrhagic fever virus), arena virus (eg Lassa virus or hepatitis D virus), bunya virus (eg California encephalitis virus or Rift Valley fever virus), reovirus (eg rotavirus) or retrovirus (eg human immunodeficiency virus (HIV) or adult T cell leukemia virus) )
- Viral diseases such as diseases caused by infection, Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Prot
- the human endogenous protein that can be used in the present specification is not particularly limited, and examples thereof include survivin 2B, GPC3, HER2 / neu, MAGE3, IPEP87, PR1, HER2 / neu E75, MUC1, and the like.
- the content of the antigen is not particularly limited, but is preferably 0.000001 to 50% by mass, more preferably 0.00001 to 20% by mass, based on the total mass of the vaccine pharmaceutical composition. It is. If the content of the antigen is less than 0.000001% by mass based on the total mass of the vaccine pharmaceutical composition, the function as a preventive or therapeutic agent for infectious diseases may be insufficient, and 50% by mass Beyond that, it can be a safety issue.
- the content of the first immunity induction promoter is not particularly limited, but is preferably 0.001 to 10000 parts by mass, more preferably 1 part by mass of the antigen. 0.01 to 10000 parts by mass.
- the content of the first immunity induction promoter is less than 0.001 parts by mass with respect to 1 part by mass of the antigen, the immunity induction effect may not be sufficiently obtained.
- the content of the accelerator exceeds 10,000 parts by mass with respect to 1 part by mass of the antigen, safety may be a problem.
- the vaccine pharmaceutical composition of the present invention further comprises a second immunity induction promoter (hereinafter referred to as “toll-like receptor (TLR) ligand, cyclic dinucleotide, and at least one immunostimulatory agent selected from helper peptides)”. And simply referred to as a second immunity induction promoter).
- TLR toll-like receptor
- TLR Toll-like receptor
- NF- ⁇ B nuclear factor ⁇ B
- MAP kinase mitogen-activated protein kinase
- TLR3, 7, 8, and 9 contain a subfamily of TLRs that are present in the endosomal or lysosomal compartment of immune cells (such as dendritic cells and monocytes).
- TLR3 is expressed by a wide range of cells, such as dendritic cells and fibroblasts
- TLR7 is expressed by plasmacytoid dendritic cells and to a lesser extent by monocytes
- TLR8 is Expressed by monocytes and monocyte-derived dendritic cells and myeloid dendritic cells
- TLR9 is expressed by plasmacytoid dendritic cells.
- This subfamily mediates recognition of microbial nucleic acids (single stranded RNA, double stranded RNA, single stranded DNA, etc.).
- TLR3, TLR7 and / or TLR8, TLR9 agonists stimulate the production of various inflammatory cytokines including, for example, interleukin-6, interleukin-12, TNF- ⁇ , and interferon- ⁇ . Such agonists also promote increased expression of costimulatory molecules (eg, CD40, CD80, and CD86, etc.), major histocompatibility complex molecules, and chemokine receptors. Type I interferons (IFN ⁇ and IFN ⁇ ) are also produced by cells upon activation with TLR7 and / or TLR8 agonists.
- IFN ⁇ and IFN ⁇ Type I interferons
- the cyclic dinucleotide is preferably a cyclic dipurine nucleotide, and may be a derivative or salt thereof as long as it has the characteristics.
- c-di-GMP which is a cyclic bisguanosine monophosphate
- c-di-AMP which is a cyclic bisadenosine monophosphate
- conductor or salt thereof is preferably used.
- helper peptide is used as the second immunity induction promoter, it is more preferable to use it as an immune part activator for inducing cellular immunity.
- helper peptide means any peptide that activates helper T cells.
- the second cellular immunity induction promoter that is the above-mentioned helper peptide include, for example, tuberculosis-derived helper peptide, measles virus-derived helper peptide, hepatitis B virus-derived helper peptide, hepatitis C virus-derived helper peptide, trachoma chlamydia Helper peptide, tropical malaria parasite sporozoide-derived helper peptide, keyhole limpet haemocyanin-derived helper peptide, tetanus toxin-derived helper peptide, pertussis toxin-derived helper peptide, diphtheria toxin-derived helper peptide, cancer cell-derived helper peptide (eg, IMA-MMP-001) Helper peptide, CEA-006 helper peptide, MMP-001
- PADRE means a 13 amino acid peptide consisting of the sequence D-Ala Lys cyclohexyl-Ala Val Ala Ala Trp Thr Leu Ala Ala Ala D-Ala (SEQ ID NO: 12).
- the content of the second immunity induction promoter in the composition for promoting immunity induction and vaccine pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.001 to 500 parts by mass with respect to 1 part by mass of the antigen. More preferably, the amount is 0.005 to 200 parts by mass, and still more preferably 0.01 to 100 parts by mass. If the content is less than the lower limit, the immune induction effect may not be sufficiently obtained. When the content exceeds the upper limit, safety may be a problem.
- the vaccine pharmaceutical composition of the present invention may be administered intradermally, subcutaneously or intramuscularly, but is preferably administered on the body surface, and more preferably transdermally or transmucosally. That is, the vaccine pharmaceutical composition of the present invention may be a vaccine pharmaceutical composition for intradermal, subcutaneous or intramuscular administration, but is preferably a vaccine pharmaceutical composition for transdermal administration or transmucosal administration.
- the vaccine pharmaceutical composition of the present invention By administering the vaccine pharmaceutical composition of the present invention to a subject by transdermal administration or transmucosal administration, specific cellular immunity and / or humoral immunity of the antigen can be effectively induced.
- the term “subject” means any animal that can be administered a vaccine pharmaceutical composition in a practical stage to induce an immune response.
- the subject is typically a mammal including a human (eg, mouse, rat, dog, cat, rabbit, horse, cow, sheep, pig, goat, monkey, chimpanzee).
- a particularly preferred subject is a human.
- the vaccine pharmaceutical composition for transmucosal administration of the present invention exhibits a high humoral immunity induction effect in transmucosal administration of various antigens in a subject.
- Examples of the transmucosal administration include administration to the tongue (eg, sublingual, behind the tongue), nasal administration, buccal administration, rectal administration, and vaginal administration.
- Examples of the dosage form of the above vaccine composition for transmucosal administration include semi-solid preparations such as gels (jelly preparations), creams, ointments, plasters, liquids, powders, fine granules, granules, films.
- compositions may be a solid preparation such as a tablet or an orally disintegrating tablet, a mucosal spray such as an aerosol, a suction agent, or the like.
- a solid preparation such as a tablet or an orally disintegrating tablet
- a mucosal spray such as an aerosol, a suction agent, or the like.
- the classification, definition, properties, production method, and the like of these compositions are well known in the art, and refer to, for example, the Japanese Pharmacopoeia 16th edition.
- liquid agent examples include appropriate amounts of water, ethanol, glycerin, propylene glycol and the like.
- a liquid agent can be adjusted by dispersing or dissolving the above-described blending components in these solvents.
- Bases used in the gel include carboxyvinyl polymer, gel base, fat-free ointment, polyvinylpyrrolidone, polyvinyl alcohol, sodium polyacrylate, carboxymethylcellulose, starch, xanthan gum, karaya gum, sodium alginate, methylcellulose.
- a fluid gel agent or a moldable gel agent By dissolving these base materials in a solvent and blending the above-mentioned blending components, a fluid gel agent or a moldable gel agent can be prepared.
- the solvent is preferably water, but glycerin, propylene glycol and the like can also be used.
- Bases used in the above creams include water / oil type bases such as hydrophilic ointments and vanishing creams; oils such as hydrophilic petrolatum, purified lanolin, aquahole, euthelin, neothelin, hydrolanolin, cold cream, hydrophilic plastibase, etc.
- oils such as hydrophilic petrolatum, purified lanolin, aquahole, euthelin, neothelin, hydrolanolin, cold cream, hydrophilic plastibase, etc.
- water bases can be prepared by putting these base materials in an oil-based solvent or water, stirring at high speed with a homogenizer or the like, and blending the above-described blending components.
- Bases used in the above film agents include polyvinylpyrrolidone, polyvinyl alcohol, sodium polyacrylate, carboxymethylcellulose, starch, xanthan gum, karaya gum, sodium alginate, methylcellulose, carboxyvinyl polymer, agar, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), carboxymethyl ethyl cellulose (CMEC), ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymer, tragacanth, gum arabic, locust bean gum, guar gum, carrageenan, dextrin, dextran, amylose Carboxymethyl cellulo Potassium, sodium carboxymethylcellulose, calcium carboxymethylcellulose, pullulan, chitosan, sodium carboxymethyl starch, plantago seed coat, galactomannan, aminoalkyl methacrylate copoly
- Additives used in the above powders, fine granules, granules, tablets and the like include excipients such as lactose, corn starch and crystalline cellulose, binders such as hydroxypropylcellulose and gum arabic. These additives are added to an appropriate amount of a solvent such as water or ethanol, the above ingredients are blended, mixed and stirred, and then combined with the steps of granulation, drying, tableting, etc. , Granules, tablets and the like can be prepared. If necessary, a lubricant such as magnesium stearate and a coating agent such as hydroxypropylcellulose and sucrose may be added.
- Examples of the base material used in the orally disintegrating tablet include polysaccharides such as gelatin and pullulan.
- a molding material such as mannitol, trehalose, sorbitol, glycine may be used.
- An orally disintegrating tablet can be prepared by dissolving these base materials and molding material in water, blending the above-mentioned blending components, and lyophilizing after dispensing.
- the aerosol agent examples include fine powders such as a liquid agent, a gel agent having a high fluidity, a cream agent, and a powder. These contents can be efficiently administered to the administration site such as the oral mucosa and the nasal mucosa by dispersing solid or liquid fine particles in the gas using a spray device.
- the vaccine pharmaceutical composition for transmucosal administration of the present invention is preferably a film agent or an orally disintegrating tablet.
- the vaccine pharmaceutical composition for intradermal, subcutaneous or intramuscular administration of the present invention exhibits a high cellular immunity inducing effect upon intradermal, subcutaneous or intramuscular administration of various antigens in a subject.
- the dosage form of the above-mentioned vaccine pharmaceutical composition for intradermal, subcutaneous or intramuscular administration is, for example, a liquid dosage form, a water-soluble or hydrophobic suspension, a dosage form having a certain fluidity that can be administered by injection. I just need it.
- the classification, definition, properties, production method, and the like of these compositions are well known in the art, and refer to, for example, the Japanese Pharmacopoeia 16th edition.
- liquid agent examples include an appropriate amount of water or physiological saline, ethanol, glycerin, propylene glycol and the like.
- a liquid preparation can be prepared by dispersing or dissolving the above-described blending components in these solvents.
- Bases used in the above water-soluble suspension include carboxyvinyl polymer, gel base, fat-free ointment, polyvinylpyrrolidone, polyvinyl alcohol, sodium polyacrylate, carboxymethylcellulose, starch, xanthan gum, karaya gum, sodium alginate, methylcellulose, Hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), carboxymethylethylcellulose (CMEC), ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, tragacanth, gum arabic, tara gum, tamarind seed gum , Psyllium seed gum, agar, gellan gum, glucomannan, ro Cast bean gum, guar gum, carrageenan, dextrin, dextran, amylose, carboxymethylcellulose potassium, carboxymethylcellulose sodium, carboxymethylcellulose calcium, pullulan, chito
- Base materials used for the hydrophobic suspension include water / oil type bases such as hydrophilic ointments and vanishing creams; hydrophilic petrolatum, purified lanolin, aquahole, euselin, neoserin, hydrolanolin, cold cream, hydrophilic plastibase, etc. And an oil / water base.
- a hydrophobic suspending agent can be prepared by putting these base materials in an oil-based solvent or water, stirring at high speed with a homogenizer or the like, and blending the above blending components.
- the dosage form of the above-mentioned vaccine pharmaceutical composition for transdermal administration includes, for example, external liquids such as liniments and lotions, external sprays such as aerosols, patches such as gels, tapes and poultices, ointments, It may be a plaster or a cream.
- the classification, definition, properties, production method and the like of these compositions are well known in the art, and refer to, for example, the Japanese Pharmacopoeia 16th edition.
- the contents of the antigen and the intracellular ion concentration agonist in the vaccine pharmaceutical composition for transdermal administration are not particularly limited, but the content of the antigen is preferably 0.01 to 40% by mass, preferably 0.1 to 30 mass% is more preferable.
- the content of the intracellular ion concentration agonist is preferably 0.001 to 30% by mass, and more preferably 0.01 to 20% by mass.
- Bases used in the liniment include water, ethanol, fatty oil, hard paraffin, soft paraffin, liquid paraffin, glycerin, paraffin oil, beeswax, metal soap; mucilage, natural oil (for example, almond oil, Corn oil, peanut oil, castor oil, olive oil or derivatives thereof (for example, polyoxyl castor oil)), sheep fat or derivatives thereof, fatty acids and / or esters thereof (for example, stearic acid, oleic acid, isopropyl myristate), etc. Is mentioned.
- the lotion is a preparation in which the compounding ingredients (that is, the antigen and the intracellular ionic concentration agonist) are finely and uniformly dispersed in an aqueous liquid.
- the suspension lotion and the emulsion lotion are mixed with each other.
- the suspending agent include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, bentonine and the like.
- the emulsifier include sodium lauryl sulfate and sorbitan fatty acid ester.
- a base material used for the said ointment what is generally used as a hydrophobic base material, such as fats and oils, a wax, a hydrocarbon compound, is mentioned.
- specific examples include mineral bases such as yellow petrolatum, white petrolatum, paraffin, liquid paraffin, plastibase, and silicone, and animal and plant bases such as beeswax and animal and vegetable fats and oils.
- Bases used in the cream include water / oil type bases such as hydrophilic ointments and vanishing creams, oils such as hydrophilic petrolatum, purified lanolin, aquahole, euselin, neoserin, hydrolyzed lanolin, cold cream, and hydrophilic plastibase.
- oils such as hydrophilic petrolatum, purified lanolin, aquahole, euselin, neoserin, hydrolyzed lanolin, cold cream, and hydrophilic plastibase.
- examples include water bases.
- Bases used in the above gels include carboxyvinyl polymer, gel base, fat-free ointment, polyvinylpyrrolidone, polyvinyl alcohol, sodium polyacrylate, carboxymethylcellulose, starch, xanthan gum, karaya gum, sodium alginate, methylcellulose, hydroxypropylcellulose.
- HPMCP Hydroxypropylmethylcellulose phthalate
- CAP cellulose acetate phthalate
- CMEM carboxymethylethylcellulose
- ethylcellulose ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose
- carboxyvinyl polymer tragacanth, gum arabic, tara gum, tamarind seed gum, psyllium seed Gum, agar, gellan gum, glucomannan, locus Bean gum, guar gum, carrageenan, dextrin, dextran, amylose, potassium carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, pullulan, chitosan, sodium carboxymethyl starch, plantago seed coat, galactomannan, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS , Methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copoly
- Examples of the base used in the cataplasm include gelatin, sodium carboxymethyl cellulose, methyl cellulose, sodium polyacrylate, kaolin, polyvinyl alcohol, polyvinyl pyrrolidone, glycerin, propylene glycol, water and the like.
- the tape preparation has an adhesive layer formed of the vaccine pharmaceutical composition containing a compounding component (that is, the antigen, the intracellular ion concentration agonist, etc.), and a support for supporting the adhesive layer. It is preferable. You may further have the release liner which can peel easily from the said adhesive layer at the time of use, without exposing the said adhesive layer before use.
- a compounding component that is, the antigen, the intracellular ion concentration agonist, etc.
- the pressure-sensitive adhesive forming the pressure-sensitive adhesive layer is not particularly limited.
- an acrylic pressure-sensitive adhesive containing an acrylic polymer synthetic isoprene rubber, polyisobutylene (PIB), butyl rubber, polybutadiene, styrene-butadiene rubber, styrene- Rubber adhesives containing rubber elastomers such as isoprene-styrene (SIS) rubber; styrene-diene-styrene block copolymers such as styrene-isoprene-styrene block copolymers and styrene-butadiene-styrene block copolymers Silicone-based adhesives such as silicone rubber, dimethylsiloxane base and diphenylsiloxane base; vinyl ether-based adhesives such as polyvinyl methyl ether, polyvinyl ethyl ether and polyvinyl isobutyl ether; vinyl ether
- the content of the pressure-sensitive adhesive in the pressure-sensitive adhesive layer is not particularly limited, but the solid content is preferably 10 to 90% by mass, more preferably 20 to 80% by mass, based on the total weight of the pressure-sensitive adhesive layer.
- the content of the antigen and the intracellular ion concentration agonist in the adhesive layer is not particularly limited, but the content of the antigen is preferably 0.01 to 40% by mass, and 0.1 to 30% by mass. Is more preferable.
- the content of the intracellular ion concentration agonist is preferably 0.001 to 30% by mass, and more preferably 0.01 to 20% by mass.
- the acrylic pressure-sensitive adhesive preferably contains a polymer containing (meth) acrylic acid C2-18 alkyl ester as the first monomer as a main component.
- the first monomer include linear, branched or cyclic alkyl groups having 1 to 18 carbon atoms (for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclohexyl, (Meth) acrylic acid alkyl esters having ptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl and the like.
- a linear, branched or cyclic alkyl group having 4 to 18 carbon atoms in the alkyl group for example, butyl, pentyl, hexyl, cyclohexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, (Meth) acrylic acid alkyl esters having dodecyl, tridecyl, etc.
- alkyl group having 4 to 18 carbon atoms in the alkyl group for example, butyl, pentyl, hexyl, cyclohexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, (Meth) acrylic acid alkyl esters having dodecyl, tridecyl, etc.
- the first monomer examples include butyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, cyclohexyl acrylate, and cyclohexyl methacrylate.
- the acid 2-ethylhexyl is particularly preferred.
- These 1st monomers can be used individually or in combination of 2 or more types.
- the first monomer may be copolymerized with the second monomer, and such a second monomer has a functional group that can serve as a crosslinking point when a crosslinking agent is used. And monomers.
- the functional group that can participate in the crosslinking reaction include a hydroxyl group, a carboxyl group, and a vinyl group, and a hydroxyl group and a carboxyl group are preferable.
- the second monomer include (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester, N-hydroxyalkyl (meth) acrylamide, (meth) acrylic acid, itaconic acid, malein.
- Examples include acid, maleic anhydride, mesaconic acid, citraconic acid, and glutaconic acid.
- acrylic acid, methacrylic acid and hydroxyethyl acrylate (particularly 2-hydroxyethyl acrylate) are preferred, and acrylic acid is particularly preferred from the viewpoint of availability.
- These second monomers can be used alone or in combination of two or more.
- the first monomer and the second monomer may be further copolymerized with a third monomer.
- the third monomer include vinyl esters such as vinyl acetate and vinyl propionate; vinyl ethers such as methyl vinyl ether and ethyl vinyl ether; vinyl amides such as N-vinyl-2-pyrrolidone and N-vinylcaprolactam. ; (Meth) acrylic acid methoxyethyl ester, (meth) acrylic acid ethoxyethyl ester, (meth) acrylic acid tetrahydrofurfuryl ester, etc.
- (meth) acrylic acid alkoxy ester hydroxypropyl (meth) acrylate, ⁇ -hydroxymethyl acrylate Hydroxyl group-containing monomer such as (not used as a crosslinking point because it is used as a third monomer); (meth) acrylamide, dimethyl (meth) acrylamide, N-butyl (meth) acrylamide, N-methylol (meth) acrylamid (Meth) acrylic acid derivatives having an amide group such as (meth) acrylic acid such as (meth) acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic acid t-butylaminoethyl ester Aminoalkyl ester; (meth) acrylic acid methoxyethylene glycol ester, (meth) acrylic acid methoxydiethylene glycol ester, (meth) acrylic acid methoxypolyethylene glycol ester, (meth) acrylic acid methoxypolypropylene
- Alkylene glycol ester (meth) acrylonitrile; styrenesulfonic acid, allylsulfonic acid, sulfopropyl (meth) acrylate, (meth) acryloyloxynaphthalenesulfonic acid, acrylic Monomers having a sulfonic acid such as chloramidomethyl sulfonic acid; vinyl group-containing monomers such as vinyl piperidone, vinyl pyrimidine, vinyl piperazine, vinyl pyrrole, vinyl imidazole, vinyl oxazole and vinyl morpholine. Of these, vinyl esters and vinyl amides are preferable. Vinyl esters are preferably vinyl acetate, and vinyl amides are preferably N-vinyl-2-pyrrolidone. These 3rd monomers can be used individually or in combination of 2 or more types.
- the (meth) The weight ratio between the alkyl acrylate and the vinyl monomer having a functional group capable of participating in the crosslinking reaction is preferably 99 to 85: 1 to 15, more preferably 99 to 90: 1 to 10.
- the weight ratio of the above (meth) acrylic acid alkyl ester, the vinyl monomer having a functional group that can participate in the crosslinking reaction, and other monomers other than these is: 40 to 94: 1 to 15: 5 to 50 are preferable, and 50 to 89: 1 to 10:10 to 40 are more preferable.
- the polymerization reaction is not particularly limited and may be performed by a conventionally known method.
- a polymerization initiator for example, benzoyl peroxide, azobisisobutyronitrile, etc.
- a solvent for example, ethyl acetate, etc.
- a method of reacting the above-mentioned monomer at 50 to 70 ° C. for 5 to 48 hours may be mentioned.
- the acrylic pressure-sensitive adhesive is a copolymer of 2-ethylhexyl acrylate / acrylic acid / N-vinyl-2-pyrrolidone, 2-ethylhexyl acrylate / N- (2-hydroxyethyl) acrylamide / N-vinyl-2-pyrrolidone copolymer, acrylic acid 2-ethylhexyl ester / acrylic acid 2-hydroxyethyl ester / vinyl acetate copolymer, acrylic acid 2-ethylhexyl ester / acrylic acid copolymer It is more preferable to contain a polymer, and it is particularly preferable to contain a copolymer of 2-ethylhexyl acrylate / acrylic acid / N-vinyl-2-pyrrolidone.
- the acrylic pressure-sensitive adhesive may be subjected to physical cross-linking treatment by irradiation with radiation such as ultraviolet irradiation or electron beam irradiation.
- Isocyanate compounds such as trifunctional isocyanate, organic peroxides, organic metal salts, metal alcoholates
- Chemical cross-linking treatment using a cross-linking agent such as a metal chelate compound or a polyfunctional compound (for example, a polyfunctional external cross-linking agent or a polyfunctional internal cross-linking monomer such as di (meth) acrylate) may be performed. .
- Examples of the rubber-based elastomer forming the rubber-based pressure-sensitive adhesive include, for example, polyisobutylene-polybutene, styrene-diene-styrene block copolymer, styrene-butadiene, nitrile, chloroprene, vinylpyridine, and polyisobutylene. Butyl, isoprene-isobutylene and the like.
- polyisobutylene PIB
- styrene-diene-styrene block copolymer for example, styrene-butadiene-styrene block copolymer (SBS), styrene- Isoprene-styrene block copolymer (SIS)
- SBS styrene-butadiene-styrene block copolymer
- SIS styrene- Isoprene-styrene block copolymer
- the rubber-based adhesive can be used by mixing rubber-based elastomers having different average molecular weights with the same component or different components.
- a mixture of a high molecular weight polyisobutylene having an average molecular weight of 150,000 to 5.5 million and a medium molecular weight polyisobutylene having an average molecular weight of 10,000 to 150,000 and / or a low molecular weight polyisobutylene having an average molecular weight of 500 to 4,000 is preferable.
- the blending amount of the high molecular weight polyisobutylene is 10 to 80% by mass, preferably 20 to 70% by mass with respect to the total amount of polyisobutylene.
- the blending amount of the medium molecular weight polyisobutylene is 0 to 90% by mass, preferably 10 to 80% by mass, based on the total amount of polyisobutylene.
- the blending amount of the low molecular weight polyisobutylene is 0 to 80% by mass, preferably 10 to 60% by mass, based on the total amount of polyisobutylene.
- average molecular weight refers to the viscosity average molecular weight calculated from the Flory viscosity equation, and the Staudinger index (J0) at 20 ° C. of the capillary 1 of the Ubbelohde viscometer. It is calculated from the flow time by the Schulz-Blaschke equation, and is obtained by the following equation using this J0 value.
- tackifier such as a resin may be blended. These tackifiers can be used alone or in combination of two or more.
- the content of the pressure-sensitive adhesive imparting agent is preferably 50% by mass or less, more preferably 5 to 40% by mass based on the total weight of the rubber-based pressure-sensitive adhesive.
- silicone pressure-sensitive adhesive examples include silicone pressure-sensitive adhesives composed of polyorganosiloxane, polydimethylsiloxane, polydimethyldiphenyl-siloxane, and the like. Among these, commercially available silicone adhesives such as BIO PSA manufactured by Dow Corning Corporation are preferably used.
- the pressure-sensitive adhesive layer may further contain a skin permeability enhancer.
- skin permeability enhancer means any substance that can improve the efficiency with which a transdermally administered antigen penetrates the skin.
- the skin permeability enhancer is preferably liquid (that is, has fluidity) at room temperature (25 ° C.). When two or more skin permeability enhancers are mixed and used, it is preferable that the mixture finally becomes liquid at room temperature (25 ° C.) and has a skin permeation promoting effect.
- a hydrophobic liquid component is preferable from the viewpoint of compatibility in the pressure-sensitive adhesive layer.
- the skin permeability enhancer examples include higher alcohols, fatty acid esters, polyhydric alcohol fatty acid esters, and the like.
- the higher alcohol a higher alcohol having 8 to 18 carbon atoms is preferable, and a higher alcohol having 8 to 14 carbon atoms is more preferable.
- the fatty acid ester is preferably a fatty acid ester of a fatty acid having 8 to 18 carbon atoms and a monohydric alcohol having 1 to 18 carbon atoms, and a fatty acid having a fatty acid having 12 to 16 carbon atoms and a monohydric alcohol having 1 to 18 carbon atoms. Esters are more preferred. Of these, fatty acid esters are preferable, and isopropyl myristate, isopropyl palmitate, and diethyl sebacate are particularly preferable.
- the content of the skin permeability enhancer is preferably 0.1% to 70% by weight, more preferably 1% to 65% by weight, based on the total weight of the pressure-sensitive adhesive layer, and 5% to 60%. More preferred is mass%.
- the ratio of the skin permeability enhancer is 0.1% by mass or more, a high transdermal absorption promoting effect is obtained.
- the content is 70% by mass or less, high transdermal absorbability can be obtained while suppressing a decrease in the adhesive strength and cohesive strength of the entire pressure-sensitive adhesive layer.
- the skin permeability enhancer examples include higher alcohols such as oleyl alcohol and octyldodecanol; polyhydric alcohols such as glycerin, ethylene glycol and polypropylene glycol; higher fatty acids such as oleic acid and caprylic acid; isopropyl myristate and palmitic acid.
- Fatty acid esters such as isopropyl and ethyl oleate; polybasic acid esters such as diethyl sebacate and diisopropyl adipate; diglyceryl triisostearate, sorbitan monooleate, propylene glycol dicaprylate, polyethylene glycol monolaurate, polyoxytetraoleate
- Polyhydric alcohol fatty acid esters such as ethylene sorbit; Polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; Hydrocarbons such as fins; olive, vegetable oils such as castor oil; silicone oils; N- methylpyrrolidone, pyrrolidones such as N- dodecyl pyrrolidone; sulfoxides such as decyl methyl sulfoxide.
- These skin permeability enhancers can be used alone or in combination of two or more.
- examples of the skin permeability enhancer include polyvinyl pyrrolidone, crospovidone, polypropylene glycol, polyvinyl alcohol, carboxyvinyl polymer, hydroxypropyl cellulose, or a mixture thereof. Can be used. Of these, polyvinylpyrrolidone, crospovidone, and polypropylene glycol are preferable.
- the thickness of the pressure-sensitive adhesive layer is not particularly limited, but is preferably 10 to 1000 ⁇ m. By setting it as the thickness of the said range, it becomes easy to make the said adhesive layer contain an effective amount of the said compounding component, to exhibit sufficient adhesive force, and to form the said adhesive layer.
- the support is not particularly limited, but is substantially impermeable to the compounding ingredients, that is, the antigen contained in the pressure-sensitive adhesive layer, the intracellular ionic concentration agonist, and if necessary, the above It is preferable that the activator or the like is lost from the back surface through the support and does not cause a decrease in the content.
- the support examples include polyester, polyamide, polyvinylidene chloride, polyethylene, polypropylene, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, ionomer resin, a single film such as a metal foil, or the like.
- a laminated film etc. are mentioned.
- the support is preferably a laminated film of a non-porous plastic film made of the above-described material and a porous film in order to improve adhesiveness (throwing property) with the pressure-sensitive adhesive layer.
- the pressure-sensitive adhesive layer is preferably formed on the porous film side.
- the porous film is not particularly limited as long as the anchoring property with the pressure-sensitive adhesive layer is improved.
- paper, woven fabric, non-woven fabric, knitted fabric, a mechanically perforated sheet, etc. Can be mentioned. Of these, paper, woven fabric, and non-woven fabric are preferable from the viewpoint of handleability and the like.
- the thickness of the porous film is preferably 1 to 200 ⁇ m from the standpoints of improvement in anchoring property, flexibility of the tape agent and sticking operability.
- the basis weight of the porous film is preferably 5 ⁇ 30g / m 2, more preferably 6 ⁇ 15g / m 2.
- a laminated film of a polyester film preferably a polyethylene terephthalate film having a thickness of 1.5 to 6 ⁇ m and a nonwoven fabric made of polyester (preferably polyethylene terephthalate) having a basis weight of 6 to 15 g / m 2 is used. Is preferred.
- the release liner is not particularly limited as long as a release treatment is performed and a sufficiently light release force can be secured.
- the release treatment can be performed by applying a silicone resin, a fluorine resin, or the like on the contact surface with the pressure-sensitive adhesive layer.
- a film such as polyester, polyvinyl chloride, polyvinylidene chloride, or polyethylene terephthalate, a paper such as high-quality paper or glassine paper, a high-quality paper or a laminate film of glassine paper and the like, and the like are used.
- the thickness of the release liner is preferably 10 to 200 ⁇ m, more preferably 25 to 100 ⁇ m.
- the release liner is preferably made of a polyester (particularly, polyethylene terephthalate) resin from the viewpoints of barrier properties and cost. In this case, the thickness is preferably about 25 to 100 ⁇ m from the viewpoint of handleability.
- the therapeutically effective amount of the antigen varies widely depending on the severity of the disease, the age and relative health of the subject, other known factors, etc. In general, however, satisfactory results are obtained at a daily dosage of about 0.1 ⁇ g to 1 g / kg body weight.
- the immunity induction promoter which is an intracellular ion concentration agonist is administered simultaneously or sequentially with the antigen, preferably simultaneously.
- the composition for promoting immunity induction of the present invention when administered to a subject, and when a vaccine pharmaceutical composition containing the composition for promoting immunity induction is administered to a subject, the immunity which is the above-mentioned intracellular ion concentration agonist
- the therapeutically effective amount of the induction promoter can vary widely depending on the specific intracellular ion concentration agonist used, the presence or absence of other immune induction promoters, etc., but generally a daily dose of about 0.01 ⁇ g Satisfactory results are obtained at ⁇ 1 g / kg body weight.
- the daily dose may be administered once, but it may be divided into two or more (for example, 2, 3, 4, 5, etc.). It is preferable that the continuous administration time per time is appropriately selected between 1 minute and 7 days.
- the dosing interval is daily to once a year (eg once a day, once every two days, once every three days, once a week, once every two weeks, once a month, 3 Once a month, once in June, once a year) or longer, depending on the patient's condition, disease severity, therapeutic or preventive purpose, etc. It is preferable.
- the vaccine pharmaceutical composition of the present invention is administered at a higher frequency and / or a higher dose for the purpose of treating patients who actually have a severe disease, and less frequently and for the purpose of preventing patients without a disease. It is preferable to administer the vaccine pharmaceutical composition of the present invention at a low dose.
- the vaccine pharmaceutical composition of the present invention changes the intracellular ion concentration by using the first immunity induction promoter that is an intracellular ion concentration acting agent that acts on an ion channel or an ion pump. And / or can effectively induce humoral immunity.
- the intracellular ionic concentration agonists found by the present invention have many widely recognized safety as pharmaceuticals and are considered to be excellent in terms of side effects.
- the vaccine pharmaceutical composition of the present invention can be administered not only subcutaneously and intradermally, intramuscularly, but also transdermally or mucosally, excellent compliance such as noninvasive administration, painlessness, fear of injection, etc.
- the efficacy of the vaccine pharmaceutical composition of the present invention is remarkably improved as compared with the administration of an antigen alone.
- transdermal administration and mucosal administration of the vaccine pharmaceutical composition of the present invention also have the advantage that strong immunity can be induced compared with injection administration.
- FIG. 3 is a graph showing the evaluation results of the number of IFN- ⁇ producing cell spots in mouse spleen cells when the cream for transdermal administration obtained in Examples 1 to 14 and Comparative Examples 1 and 2 was transdermally administered.
- 6 is a graph showing the evaluation results of the number of IFN- ⁇ producing cell spots in mouse spleen cells when the transdermal administration tapes obtained in Examples 15 to 26 and Comparative Examples 3 to 8 were transdermally administered.
- 6 is a graph showing the results of OVA-specific IgG antibody titers in mouse serum when the nasal administration solution obtained in Examples 27 to 34 and Comparative Example 9 was administered nasally.
- FIG. 4 is a graph showing the results of OVA-specific IgG antibody titers in mouse serum when sublingual administration solutions obtained in Examples 35 to 42 and Comparative Example 10 were administered sublingually.
- 6 is a graph showing the results of OVA-specific IgG antibody titers in mouse serum when the sublingual solid preparations obtained in Examples 43 to 58 and Comparative Examples 11 to 12 were administered sublingually.
- FIG. 6 is a graph showing the results of OVA-specific IgG antibody titers in mouse serum when the subcutaneous administration solutions obtained in Examples 59 to 63 and Comparative Example 13 are administered subcutaneously.
- 6 is a graph showing the results of OVA-specific IgG antibody titers in mouse serum when the transdermal creams obtained in Examples 64-68 and Comparative Example 14 were transdermally administered.
- Examples 1 to 14, Comparative Examples 1 and 2 Preparation of cream for transdermal administration
- a cream for transdermal administration having the composition shown in Table 1 below was prepared. Specifically, with the compounding amounts shown in Table 1 below, 5% by mass of the antigen shown below, 3% by mass of the first immune induction promoter, and 1% by mass of the second immune induction promoter as needed And 15% by mass of dimethyl sulfoxide (DMSO) were added, and a base material (base cream) was added thereto to make a total of 100% by mass, followed by mixing to obtain a cream for transdermal administration.
- the base cream used was prepared by blending ingredients with the composition shown in Table 8 and mixing them.
- White petrolatum, sorbitan monostearate, isostearic acid, benzyl alcohol, stearyl alcohol, polysorbate 60, concentrated glycerin, and dimethyl sulfoxide (DMSO) were purchased from Wako Pure Chemical Industries, Ltd. Cetanol was purchased from Tokyo Chemical Industry Co., Ltd.
- a composite base material was prepared in which a PET film / PET nonwoven fabric laminate (area 0.7 cm 2 ) was bonded to the center of the fixing adhesive tape with the PET film side as the tape side.
- a 4 mg cream for transdermal administration was applied to the non-woven fabric portion of the composite substrate, and this was used as a sample for immunization test.
- Antigens HER2 / neu_E75 (HER2 / neu_E75 peptide, cancer antigen peptide), IPEP87 (IPEP87 peptide, antigen peptide derived from infectious pathogen), MAGE-A3_A02 (MAGE3_A02 peptide, cancer antigen peptide), and second immune induction promotion PADRE, which is an agent (helper T cell activation peptide), was chemically synthesized and HPLC purified.
- OVAp manufactured by SIGMA-ALDRICH
- SIGMA-ALDRICH was used as a model antigen.
- Model animal for immunity evaluation means a model animal for evaluating the immunity induction characteristics of a vaccine pharmaceutical composition (herein, cream for transdermal administration). Specifically, it means a model animal for evaluating the cellular immunity induction level of a cream for transdermal administration. As a model animal for immunity evaluation, it is possible to evaluate the induction of cellular immunity by the antigen in the cream for transdermal administration, considering the compatibility between the antigen in the cream for transdermal administration and the MHC class 1 molecule of the animal Animals were used.
- Examples 15 to 26, Comparative Examples 3 to 8 Preparation of transdermal tape
- a tape for transdermal administration having the composition shown in Table 2 below was prepared. Specifically, an antigen, a first immunity induction promoter, and a second immunity induction promoter are blended in the blending amounts shown in Table 2 below, and the adhesive groups shown in Table 2 below are blended therein.
- An adhesive and an organic solvent (ethyl acetate) were blended so that the total of each component after drying the organic solvent and the adhesive base was 100% by mass, and mixed to prepare an adhesive solution.
- the obtained pressure-sensitive adhesive solution was spread on a release liner so that the thickness after drying was about 80 ⁇ m, and the organic solvent was removed by drying to form a pressure-sensitive adhesive layer.
- a polyethylene terephthalate (PET) liner (thickness 75 ⁇ m) subjected to silicone release treatment was used.
- a support was bonded to the obtained adhesive layer to obtain a tape for transdermal administration.
- a polyethylene terephthalate (PET) film (thickness 25 ⁇ m) was used.
- This transdermal administration tape was cut to an area of 0.7 cm 2 and used as a sample for immunization experiments. At the time of administration, the release liner was peeled off.
- Examples 27 to 42, Comparative Examples 9 to 10 Preparation of solution for transmucosal administration
- Solutions for transmucosal administration (nasal administration or sublingual administration) having the compositions shown in Tables 3 and 4 below were prepared. Specifically, in the blending amounts shown in Tables 3 and 4 below, an antigen (ovalbumin (OVA)) and a first immunity induction promoter are blended, physiological saline is added thereto, and nasal administration 10 ⁇ L or 30 ⁇ L for sublingual administration and mixed to obtain a solution for transmucosal administration (nasal administration or sublingual administration).
- OVA ovalbumin
- Examples 43 to 58, Comparative Examples 11 to 12 preparation of solid preparation for sublingual administration
- a solid preparation for sublingual administration (lyophilized preparation or film preparation) having the composition shown in Table 5 below was prepared.
- antigen ovalbumin (OVA)
- first immunity induction promoter base hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.)
- physiological saline was added thereto and mixed to obtain a preparation solution.
- 25 mg of the preparation solution was dispensed and freeze-dried to obtain a freeze-dried preparation, or vacuum-dried to obtain a film preparation.
- the immunity induction promoter that is a nuclear receptor ligand, the same immunity induction promoter used for the preparation of the liquid preparation for transmucosal administration was used.
- mice Female 7 weeks old
- mice Male-prepared mice (BALB / c mice, female 7 weeks old) were subjected to anesthesia treatment
- 10 ⁇ L of the solution for transmucosal administration was administered in the sublingual administration (Examples 35 to 42, Comparative Example 10)
- a solid preparation for sublingual administration Examples 43 to 58 and Comparative Examples 11 to 12
- mice were anesthetized again and administered in the same manner.
- mouse serum was collected.
- ELISA method Method for measuring antigen-specific IgG antibody titer in mouse serum (ELISA method) 100 ⁇ L of OVA-containing solution (100 ⁇ g / mL) diluted with carbonate buffer was added to a 96-well plate for ELISA, and allowed to stand overnight. The wells were washed three times with a preliminarily prepared washing solution (Tween20-containing PBS), and a blocking solution (Block Ace, manufactured by Dainippon Sumitomo Pharma Co., Ltd.) diluted with purified water to 4 g / 100 mL was added to the wells in an amount of 200 ⁇ L. Left at room temperature for 2 hours.
- the wells were washed three times with a washing solution.
- the collected mouse serum was centrifuged at 3000 g for 10 minutes at 4 ° C., and the supernatant was collected.
- the supernatant was serially diluted 2-fold, and 50 ⁇ L of the solution was added to each well for 2 hours. Left at room temperature. Thereafter, the wells were washed three times with a washing solution.
- HRP-labeled anti-mouse IgG antibody (Goat-anti mouse IgG Fc HRP, BETHYL) is diluted 10,000 times with a solution obtained by diluting the blocking agent to 0.4 g / 100 mL with a phosphate buffer (Nacalai Tesque). Was added to each well in an amount of 100 ⁇ L and left at room temperature for 1 hour. Thereafter, the wells were washed three times with a washing solution, and 100 ⁇ L of TMB solution (ELISA POD TMB kit, manufactured by Nacalai Tesque) was added to each well and left in the dark for 30 minutes.
- TMB solution ELISA POD TMB kit, manufactured by Nacalai Tesque
- Example 59 to 63 Comparative Example 13
- preparation of solution for subcutaneous administration A preparation for subcutaneous administration having the composition shown in Table 6 below was prepared. Specifically, an antigen (ovalbumin (OVA)) and a first immunity induction promoter were blended in the blending amounts shown in Table 6 below, and physiological saline was added thereto to make 200 ⁇ L, and mixed. A solution for subcutaneous administration was obtained.
- OVA ovalbumin
- mice prepared in advance (BALB / c mice, female 7 weeks old)
- 200 ⁇ L was administered subcutaneously to the back of each mouse.
- the mice were anesthetized again and administered in the same manner.
- mouse serum was collected.
- Examples 64 to 68, Comparative Example 14 Preparation of cream for transdermal administration
- a cream for transdermal administration having the composition shown in Table 7 below was prepared. Specifically, an antigen (ovalbumin (OVA)) and a first immunity induction promoter are blended in the blending amounts shown in Table 7 below, and a base material (base cream) is added thereto for a total of 100 mass. And mixed to obtain a cream for transdermal administration.
- the base cream used was prepared by blending ingredients with the composition shown in Table 8 and mixing them.
- White petrolatum, sorbitan monostearate, isostearic acid, benzyl alcohol, stearyl alcohol, polysorbate 60, and concentrated glycerin were purchased from Wako Pure Chemical Industries. Cetanol was purchased from Tokyo Chemical Industry Co., Ltd.
- a composite base material was prepared in which a PET film / PET nonwoven fabric laminate (area 0.7 cm 2 ) was bonded to the center of the fixing adhesive tape with the PET film side as the tape side.
- a 4 mg cream for transdermal administration was applied to the nonwoven fabric portion of the composite substrate, and this was used as a sample for administration in a mouse immunity test.
- ⁇ Evaluation 5> The following evaluations were performed on the creams for transdermal administration obtained in Examples and Comparative Examples.
- the composition for promoting immunity induction and the pharmaceutical composition for vaccine of the present invention can be universally used for induction of cellular immunity and / or humoral immunity against various antigens, and has high cellular immunity and / or humoral properties. It can exert immunity induction effect.
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Abstract
Description
注射による免疫誘導において一般的に使用されるアジュバントとしては、水酸化アルミニウムやリン酸アルミニウム、塩化アルミニウムのようなアルミニウム塩、MF59やAS03といったスクワレンを含むエマルション等が実用化されており、これら以外にも鞭毛成分や核酸、サイトカイン、カチオンポリマー、ポリペプチド等が広く検討されている。
しかし、注射以外の経路、例えば、経皮投与や経粘膜投与による液性免疫誘導において検討されているアジュバントとしては、水酸化アルミニウムやリン酸アルミニウム、塩化アルミニウムのようなアルミニウム塩、コレラトキシンや大腸菌易熱性毒素のような毒素類等が挙げられるが、実用化には至っていない。さらに、抗原の経皮投与による液性免疫誘導において用い得る有効な免疫賦活化剤はほとんど報告されておらず、また注射と比較して十分な液性免疫誘導効果が得られない場合が多い。
上記細胞内イオン濃度作用薬は、ナトリウムチャネル作用薬、カルシウムチャネル作用薬、カリウムチャネル作用薬、塩素チャネル作用薬、及び、ナトリウム-カリウムポンプ作用薬からなる群より選択される少なくとも1種であることが好ましい。
本発明は、免疫誘導のための抗原と、上記免疫誘導促進用組成物とを含むワクチン医薬組成物でもある。
上記ワクチン医薬組成物は、更に、Toll様受容体(TLR)リガンド、環状ジヌクレオチド、及び、ヘルパーペプチドから選択される少なくとも一種の免疫賦活化剤である第二の免疫誘導促進剤を含むことが好ましい。
上記ワクチン医薬組成物は、体表面上に投与されることが好ましい。
上記ワクチン医薬組成物は、皮内注射、皮下注射又は筋肉内注射により投与されることが好ましい。
以下、本発明について詳述する。
液性免疫誘導効果を定量的に測定する方法は特に限定されず、様々な方法が開発されているが、例えば、免疫評価用モデル動物を用いた免疫誘導実験及びELISA法(抗原特異的IgG抗体)により測定することができる。液性免疫を測定するためのサンプルとしては、例えば、免疫評価用モデル動物の血液等が挙げられる。
細胞性免疫誘導効果を定量的に測定する方法は特に限定されず、様々な方法が開発されているが、例えば、免疫評価用モデル動物を用いた免疫誘導実験及びELISPOT法(抗原特異的CTL数)により測定することができる。細胞性免疫を測定するためのサンプルとしては、例えば、免疫評価用モデル動物より採取した脾臓細胞等が挙げられる。
本明細書において使用するとき、用語「細胞内イオン濃度作用薬」は、免疫担当細胞のイオンチャネル又はイオンポンプに作用して、共に投与された抗原の細胞性免疫及び/又は液性免疫を誘導する効率を、それなしでの効率と比較して改善しうるあらゆる物質を意味するものであり、細胞性免疫及び/又は液性免疫を促進する作用機構によって限定されないが、本願明細書で特定されたものを意味する。
上記電位依存性ナトリウムチャネル作用薬としては、リドカイン、メピバカイン、ブピバカイン、レボブピバカイン、ロピバカイン、プロカイン、テトラカイン、ベンゾカイン、ジブカイン、プリロカイン、コカイン、メキシレチン、フレカイニド、キニジン、カルバマゼピン、ゾニサミド、ラモトリジン、アンブロキソール、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記上皮性ナトリウムチャネル作用薬としては、アミロライド、トリアムテレン、スラミン、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記ナトリウムチャネル作用薬は、アミロライド、スラミン、トリアムテレンが好ましい。
上記電位依存性カルシウムチャネル作用薬としては、シルニジピンン、ジコノタイド、ドロネダロン、アムロジピン、フェロジピン、イスラジピン、ニカルジピン、ニフェジピン、ニモジピン、ニソルジピン、ニトレンジピン、ラシジピン、ニルバジピン、マニジピン、バルニジピン、ベニジピン、クレビジピン、ベラパミル、ガロパミル、ジルチアゼム、フェンジリン、ベプリジル、ペルヘキシリン、トピラマート、アラニジピン、アゼルニジピン、ダロジピン、エホニジピン、キレニジピン、ミベフラジル、エトスクシミド、バルプロ酸、ゾニサミド、ペンフルリドール、フルナリジン、アラニジピン、エホニジピン、プロピトカイン、ガバペンチン、プレガバリン、ガバペンチンエナカルビル、レルカニジピン、リドフラジン、メタルビタール、フルスピリレン、ベルホスジル、ブロビンカミン、クレンチアゼム、フロルジピン、ロメリジン、バタニジピン、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記イオンチャネル内蔵型受容体カルシウムチャネル作用薬としては、トピラマート、カイニン酸、テザンパネル、ペランパネル、ファランペーター、テザンパネル、タランパネル、ゾナンパネル、ベソンプロジル、トラキソプロジル、イフェンプロジル、ケタミン、エスケタミン、エトベミドン、フルピルチン、メマンチン、メタドン、アカンプロサート、デキストロメトルファン、アプチガネル、デルセミン、デキストロルファン、ジゾシルピン、ガベスチネル、レボメタドン、リコスチネル、ラトレピルジン、ネラメキサン、ペウジンフォテル、フェンシクリジン、レマセミド、セルフォテル、チレタミン、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記カルシウムチャネル作用薬は、アムロジピン、マニジピンが好ましい。
上記電位依存性カリウムチャネル作用薬としては、ピルジカイニド、ベラパミル、プロパフェノン、ベプリジル、クロフィリウム、フレカイニド、アミオダロン、テジサミル、ドロネダロン、ニフェカラント、リノピルジン、アジミリド、リノピルジン、エゾガビン、トシル酸ブレチリウム、アプリンジン、ドフェチリド、イブチリド、テジサミル、ソタロール、コカイン、アジミリド、クロフィリウム、デキスソタロール、ニフェカラント、セマチリド、テリカラント、テトラエチルアンモニウム、4-アミノピリジン、デンドロトキシン、カプサイシン、ズカプサイシン、マバトレプ、ノニバミド、メントール及びそれらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記カルシウム依存性カリウムチャネル作用薬としては、トピラマート、カイニン酸、テザンパネル、ペランパネル、ファランペーター、テザンパネル、タランパネル、ゾナンパネル、ベソンプロジル、トラキソプロジル、イフェンプロジル、ケタミン、エスケタミン、エトベミドン、フルピルチン、メマンチン、メタドン、アカンプロサート、デキストロメトルファン、アプチガネル、デルセミン、デキストロルファン、ジゾシルピン、ガベスチネル、レボメタドン、リコスチネル、ラトレピルジン、ネラメキサン、ペウジンフォテル、フェンシクリジン、レマセミド、セルフォテル、チレタミン、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記内向き整流カリウムチャネル作用薬としては、グリベンクラミド、トルブタミド、ジアゾキシド、ピナシジル、アミオダロン、ドロネダロン、ベプリジル、エジサミル、ニフェカラント、テリカラント、ニコランジル、ミノキシジル、レブクロマカリウム、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記直列ポアドメインカリウムチャネル作用薬としては、ハロタン、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記カリウムチャネル作用薬は、ドフェチリド、グリベンクラミドが好ましい。
上記CIC塩素チャネル作用薬としては、ルビプロストン、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記カルシウム依存性塩素チャネル作用薬としてはニフルム酸、及び、それらの誘導体、並びにそれらの薬理学的に許容される塩等が挙げられる。
上記塩素チャネル作用薬は、ニフルム酸が好ましい。
本明細書において使用するとき、用語「ナトリウム-カリウムポンプ作用薬」は、ナトリウム-カリウムポンプであるNa+/K+-ATPaseに作用し細胞内のイオン濃度を変化させる物質を意味する。
上記ナトリウム-カリウムポンプ作用薬としては、ジギトキシン、ジゴキシン、ラナトシドC、デスラノシド、メチルジゴキシン、アセチルジゴキシン、アセチルジギトキシン、ギトホルマート、プロスシラリジン、G-ストロファンチン、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
上記ナトリウム-カリウムポンプ作用薬は、ジギトキシン、ジゴキシンが好ましい。
本明細書において使用するとき、用語「プロトン-カリウムポンプ作用薬」は、プロトン-カリウムポンプであるH+/K+-ATPaseに作用し細胞内のイオン濃度を変化させる物質を意味する。
上記プロトン-カリウムポンプ作用薬としては、オメプラゾール、パントプラゾール、ラベプラゾール、エソメプラゾール、デクスランソプラゾール、ランソプラゾール、レミノプラゾール、ピコプラゾール、テナトプラゾール、チモプラゾール、及び、それらの誘導体、並びに、それらの薬理学的に許容される塩等が挙げられる。
本明細書において使用するとき、用語「薬理学的に許容される塩」は、投与対象に有害な作用を及ぼさず、かつ、ワクチン医薬組成物中の配合成分の薬理活性を消失させない塩を意味し、例えば、無機酸塩(例えば、塩酸塩、リン酸塩)、有機酸塩(例えば、酢酸塩、フタル酸塩、TFA塩)、金属塩(例えば、アルカリ金属塩(例えば、ナトリウム塩、カリウム塩)、アルカリ土類金属塩(例えば、カルシウム塩、マグネシウム塩)、アルミニウム塩)、アミン塩(例えば、トリエチルアミン塩、ベンジルアミン塩、ジエタノールアミン塩、t-ブチルアミン塩、ジシクロヘキシルアミン塩、アルギニン塩、ジメチルアンモニウム塩、アンモニウム塩)等が挙げられる。
上記第一の免疫誘導促進剤の含有量が、0.0001質量%未満であると、免疫誘導効果を充分に得られないことがあり、上記第一の免疫誘導促進剤の含有量が、100質量%を超えると、安全性が問題となることがある。
上記添加剤としては、例えば、等張化剤、防腐・殺菌剤、酸化防止剤、溶解剤、溶解補助剤、懸濁化剤、充填剤、pH調節剤、安定化剤、吸収促進剤、放出速度制御剤、着色剤、可塑剤、架橋剤、粘着剤等が挙げられる。これらの添加材は単独で又は2種以上を組合せて用いることができる。
上記抗原と、上記免疫誘導促進用組成物とを含むことで、本発明のワクチン医薬組成物は、抗原特異的な細胞性免疫及び/又は液性免疫を効果的に誘導することができる。
本明細書において使用するとき、用語「遺伝子の異常な発現」は、ある細胞におけるその遺伝子の発現レベルが、同じ組織の他の細胞と比較して、例えば、2倍以上、4倍以上等の倍率で顕著に上昇又は低下していることを意味する。
本明細書において使用するとき、用語「過剰発現」は、異常な発現が発現レベルの上昇であることを意味する。遺伝子の発現レベルは、当該技術分野で周知のいずれかの方法を用いて、容易に測定できる。
上記サバイビン遺伝子の異常な発現を伴う癌には、悪性リンパ腫、膀胱癌、肺癌、大腸癌等が含まれるが、これらに限定されない。上記GPC3遺伝子の異常な発現を伴う癌には、肝癌、胆管癌、胃癌等が含まれるが、これらに限定されない。上記HER2/neu遺伝子の異常な発現を伴う癌には、乳癌、胃癌、卵巣癌、子宮癌、膀胱癌、非小細胞肺癌、前立腺癌等が含まれるが、これらに限定されない。上記MAGE3遺伝子の異常な発現を伴う癌には、メラノーマ、肺癌、頭頚部癌、膀胱癌、胃癌、食道癌、肝臓癌等が含まれるが、これらに限定されない。上記プロテイナーゼ-3遺伝子の異常な発現を伴う癌には、急性骨髄性白血病、膵臓癌等が含まれるが、これらに限定されない。
本明細書において使用するとき、用語「癌抗原ペプチド」は、癌抗原タンパク質に由来する部分ペプチドであって、細胞性免疫応答を誘導しうるものをいう。通常、癌抗原ペプチドは、癌遺伝子の産物である癌抗原タンパク質が癌細胞内で分解されることによって生じ、MHCクラスI分子によって癌細胞の表面に提示される。
改変XXペプチドには、例えば、
(a)XXペプチドのアミノ酸配列において、1個から数個、例えば、1個、2個、3個、4個又は5個のアミノ酸が置換、欠失又は付加されたアミノ酸配列からなるペプチド;及び
(b)XXペプチドのアミノ酸配列において、全部又は一部のアミノ酸、例えば、1個又は複数個、例えば、1個、2個、3個、4個、5個、6個、7個、8個、9個又は10個のアミノ酸が修飾されたアミノ酸配列からなるペプチドが含まれる。
改変XXペプチドが有し得るアミノ酸の「修飾」としては、これらに限定されないが、例えば、アセチル化、メチル化等のアルキル化、グリコシル化、ヒドロキシル化、カルボキシル化、アルデヒド化、リン酸化、スルホニル化、ホルミル化、ミリストイル化やパルミトイル化やステアロイル化のような脂肪鎖付加修飾、オクタノイル化、エステル化、アミド化、脱アミド化、シスチン修飾やグルタチオン修飾やチオグリコール酸修飾のようなジスルフィド結合形成修飾、糖化、ユビキチン化、スクシンイミド形成、グルタミル化、プレニル化等が挙げられる。改変XXペプチドは、1個以上のアミノ酸の置換、欠失又は付加と、1個以上のアミノ酸の修飾を組み合わせて含むものであってもよい。
上記に列挙したペプチドは、遊離形又は薬理学的に許容される任意の塩形、例えば、酸塩(酢酸塩、TFA塩、塩酸塩、硫酸塩、リン酸塩、乳酸塩、酒石酸塩、マレイン酸塩、フマル酸塩、シュウ酸塩、臭化水素酸塩、コハク酸塩、硝酸塩、リンゴ酸塩、クエン酸塩、オレイン酸塩、パルミチン酸塩、プロピオン酸塩、蟻酸塩、安息香酸塩、ピクリン酸塩、ベンゼンスルホン酸塩、ドデシル硫酸塩、メタンスルホン酸塩、p-トルエンスルホン酸塩、グルタル酸塩、種々のアミノ酸塩等)、金属塩(アルカリ金属塩(例えば、ナトリウム塩、カリウム塩)、アルカリ土類金属塩(例えば、カルシウム塩、マグネシウム塩)、アルミニウム塩等)、アミン塩(トリエチルアミン塩、ベンジルアミン塩、ジエタノールアミン塩、t-ブチルアミン塩、ジシクロヘキシルアミン塩、アルギニン塩、ジメチルアンモニウム塩、アンモニウム塩等)の形態でありうる。好ましい薬理学的に許容される塩は、酢酸塩又はTFA塩である。本発明において抗原として用い得る上記のペプチドは、周知の方法で合成又は産生し、単離及び精製したものを使用できる。
上記感染性病原体から罹る疾患としては特に限定されず、例えば、アデノウイルス(例えば、ヒトアデノウイルス)、ヘルペスウイルス(例えば、単純ヘルペスウイルス、水痘・帯状疱疹ウイルス、サイトメガロウイルス、ヒトヘルペスウイルス又はカポジ肉腫関連ヘルペスウイルス)、ピコルナウイルス(例えば、ポリオウイルス、風邪ウイルス又はA型肝炎ウイルス)ポックスウイルス(例えば、痘瘡ウイルス、ワクシニアウイルス又は伝染性軟属腫ウイルス)、ピコルナウイルス(例えば、ライノウイルス又はエンテロウイルス)、オルソミクソウイルス(例えば、インフルエンザウイルス)、パラミクソウイルス(例えば、パラインフルエンザウィルス、おたふく風邪ウイルス、はしかウイルス、呼吸器合胞体ウイルス(RSV)又はニューカッスル病ウイルス)、パルボウイルス(例えば、アデノ随伴ウイルス)、トガウイルス(例えば、風疹ウイルス)、コロナウイルス(例えば、SARSコロナウイルス)、ヘパドナウイルス(例えば、B型肝炎ウイルス)、フラビウイルス(例えば、日本脳炎ウイルス、黄熱病ウイルス、デング熱ウイルス、西ナイル熱ウイルス、セントルイス脳炎ウイルス、マレーバレー脳炎ウイルス、C型肝炎ウイルス又はG型肝炎ウイルス)、ヘペウイルス(例えば、E型肝炎ウイルス)、パピローマウイルス(例えば、ヒト乳頭腫ウイルス)、カリシウイルス(例えば、ノロウイルス)、ラブドウイルス(例えば、狂犬病ウイルス又は水疱性口内炎ウイルス)、フィロウイルス(例えば、エボラ出血熱ウイルス)、アレナウイルス(例えば、ラッサウイルス又はD型肝炎ウイルス)、ブニヤウイルス(例えば、カリフォルニア脳炎ウイルス又はリフトバレー熱ウイルス)、レオウイルス(例えば、ロタウイルス)又はレトロウィルス(例えば、ヒト免疫不全ウイルス(HIV)又は成人T細胞白血病ウイルス)による感染から罹る疾患等のウイルス疾患、エシェリキア属、エンテロバクター、サルモネラ、ブドウ球菌、赤痢菌、リステリア、アエロバクター、ヘリコバクター、クレブシエラ、プロテウス、シュードモナス、連鎖球菌、クラミジア、マイコプラズマ、肺炎球菌、ナイセリア、クロストリジウム、バシラス、コリネバクテリウム、マイコバクテリウム、カンピロバクター、ビブリオ、セラチア、プロビデンシア、クロモバクテリウム、ブルセラ、エルシニア、ヘモフィルス、又はボルデテラ等の細菌感染から罹る疾患等の細菌疾患、クラミジア、カンジダ症、アスペルギルス症、ヒストプラスマ症、クリプトコックス髄膜炎をはじめとするがこれに限定されるものではない真菌疾患と、又は、マラリア、ニューモシステイスカリニ肺炎、レーシュマニア症、クリプトスポリジウム症、トキソプラズマ症、及び、トリパノソーマ感染等が挙げられる。
上記抗原の含有量が、ワクチン医薬組成物の総質量に基づき、0.000001質量%未満であると、感染症の予防又は治療剤としての機能が不充分となることがあり、50質量%を超えると、安全性に関して問題となることがある。
また、本発明のワクチン医薬組成物において、上記第一の免疫誘導促進剤の含有量は特に限定されないが、1質量部の抗原に対して、好ましくは0.001~10000質量部、より好ましくは0.01~10000質量部である。
上記第一の免疫誘導促進剤の含有量が、1質量部の抗原に対して、0.001質量部未満であると、免疫誘導効果が充分に得られないことがあり、第一の免疫誘導促進剤の含有量が、1質量部の抗原に対して、10000質量部を超えると、安全性が問題となることがある。
上記第二の免疫誘導促進剤を併用することで、細胞性免疫及び/又は液性免疫を更に促進することができる。
上記第二の免疫誘導促進剤としてヘルパーペプチドを用いる場合は、細胞性免疫誘導用の免疫部活化剤として用いることがより好ましい。
上記ヘルパーペプチドである第二の細胞性免疫誘導促進剤としては、例えば、結核菌由来ヘルパーペプチド、麻疹ウイルス由来ヘルパーペプチド、B型肝炎ウイルス由来ヘルパーペプチド、C型肝炎ウイルス由来ヘルパーペプチド、トラコーマクラミジア由来ヘルパーペプチド、熱帯性マラリア原虫スポロゾイド由来ヘルパーペプチド、keyhole limpet haemocyanin由来ヘルパーペプチド、破傷風毒素由来ヘルパーペプチド、百日咳毒素由来ヘルパーペプチド、ジフテリア毒素由来ヘルパーペプチド、癌細胞由来ヘルパーペプチド(例えば、IMA-MMP-001ヘルパーペプチド、CEA-006ヘルパーペプチド、MMP-001ヘルパーペプチド、TGFBI-004ヘルパーペプチド、HER-2/neu(aa776-790)ヘルパーペプチド、AE36ヘルパーペプチド、AE37ヘルパーペプチド、MET-005ヘルパーペプチド、BIR-002ヘルパーペプチド)、ユニバーサルヘルパーアナログ(例えば、PADRE)、それらの改変ペプチド等が挙げられる。なかでも、Peptide-25、改変Peptide-25、PADREが好ましい。
上記含有量が下限値未満であると、免疫誘導効果が充分に得られないことがある。上記含有量が上限値を超えると、安全性が問題となることがある。
本明細書において使用するとき、用語「対象」は、実用段階においてワクチン医薬組成物を投与して免疫応答を誘導し得るいずれかの動物を意味する。上記対象は、典型的にはヒトを含む哺乳類(例えば、マウス、ラット、イヌ、ネコ、ウサギ、ウマ、ウシ、ヒツジ、ブタ、ヤギ、サル、チンパンジー)である。特に好ましい対象は、ヒトである。
本発明の経粘膜投与用ワクチン医薬組成物は、対象における種々の抗原の経粘膜投与において高い液性免疫誘導効果を発揮するものである。
上記経粘膜投与として、例えば、舌(例えば、舌下、舌の後ろ)への投与、経鼻投与、頬側投与、直腸投与、膣投与等が挙げられる。
上記経粘膜投与用ワクチン医薬組成物の剤形は、例えば、ゲル剤(ゼリー剤)、クリーム剤、軟膏剤、硬膏剤等の半固形剤、液剤、散剤、細粒剤、顆粒剤、フィルム剤、錠剤、口腔内崩壊錠等の固形製剤、エアゾール剤等の粘膜用スプレー剤、吸引剤等であってよい。これらの組成物の区分、定義、性質、製法等は、当該技術分野において周知であり、例えば、日本薬局方第16版を参照されたい。
本発明の皮内、皮下又は筋肉内投与用ワクチン医薬組成物は、対象における種々の抗原の皮内、皮下又は筋肉内への投与において高い細胞性免疫誘導効果を発揮するものである。
上記皮内、皮下又は筋肉内投与用ワクチン医薬組成物の剤形は、例えば、液剤、水溶性又は疎水性の懸濁剤、クリーム剤等の注射投与可能なある程度の流動性を有する剤形であればよい。これらの組成物の区分、定義、性質、製法等は、当該技術分野において周知であり、例えば、日本薬局方第16版を参照されたい。
上記経皮投与用ワクチン医薬組成物の剤形は、例えば、リニメント剤、ローション剤等の外用液剤、エアゾール剤等の外用スプレー剤、ゲル剤、テープ剤及びパップ剤等の貼付剤、軟膏剤、硬膏剤、クリーム剤であってよい。これらの組成物の区分、定義、性質、製法等は、当該技術分野において周知であり、例えば日本薬局方第16版を参照されたい。
上記経皮投与用ワクチン医薬組成物中の上記抗原及び上記細胞内イオン濃度作用薬の含有量は特に限定されないが、上記抗原の含有量は0.01~40質量%が好ましく、0.1~30質量%がより好ましい。上記細胞内イオン濃度作用薬の含有量は0.001~30質量%が好ましく、0.01~20質量%がより好ましい。
また、上記粘着剤層中の上記抗原及び上記細胞内イオン濃度作用薬の含有量は特に限定されないが、上記抗原の含有量は0.01~40質量%が好ましく、0.1~30質量%がより好ましい。上記細胞内イオン濃度作用薬の含有量は0.001~30質量%が好ましく、0.01~20質量%がより好ましい。
上記第1の単量体としては、アルキル基の炭素数が1~18の直鎖状、分岐鎖状又は環状アルキル基(例えば、メチル、エチル、プロピル、ブチル、ペンチル、へキシル、シクロヘキシル、へプチル、オクチル、2-エチルヘキシル、ノニル、デシル、ウンデシル、ドデシル、トリデシル等)を有する(メタ)アクリル酸アルキルエステル等が挙げられる。更に、アルキル基の炭素数が4~18の直鎖状、分岐鎖状又は環状アルキル基(例えば、ブチル、ペンチル、へキシル、シクロヘキシル、へプチル、オクチル、2-エチルヘキシル、ノニル、デシル、ウンデシル、ドデシル、トリデシル等)を有する(メタ)アクリル酸アルキルエステルが好ましい。更に、常温で粘着性を与えるために、重合体のガラス転移温度を低下させるモノマー成分の使用が更に好適であることから、アルキル基の炭素数が4~8の直鎖状、分岐鎖状又は環状アルキル基(例えば、ブチル、ペンチル、へキシル、シクロヘキシル、へプチル、オクチル、2-エチルヘキシル等、好ましくは、ブチル、2-エチルヘキシル、シクロヘキシル、特に好ましくは2-エチルヘキシル)を有する(メタ)アクリル酸アルキルエステルがより好ましい。
上記第1の単量体として、具体的には、アクリル酸ブチル、アクリル酸2-エチルへキシル、メタクリル酸2-エチルへキシル、アクリル酸シクロへキシル、メタクリル酸シクロへキシルが好ましく、中でもアクリル酸2-エチルへキシルが特に好ましい。これら第1の単量体は単独で又は2種以上を組み合わせて用いることができる。
上記第2の単量体しては、例えば、(メタ)アクリル酸ヒドロキシエチルエステル、(メタ)アクリル酸ヒドロキシプロピルエステル、N-ヒドロキシアルキル(メタ)アクリルアミド、(メタ)アクリル酸、イタコン酸、マレイン酸、無水マレイン酸、メサコン酸、シトラコン酸、グルタコン酸等が挙げられる。なかでも、入手の容易性の観点から、アクリル酸、メタクリル酸、アクリル酸ヒドロキシエチルエステル(特に、アクリル酸2-ヒドロキシエチル)が好ましく、アクリル酸が特に好ましい。これら第2の単量体は単独で種又は2種以上を組み合わせて用いることができる。
上記粘着剤付与剤の含有量は、上記ゴム系粘着剤の総重量に基づいて50質量%以下が好ましく5~40質量%がより好ましい。
本明細書において使用するとき、用語「皮膚透過性増強剤」は、経皮投与される抗原が皮膚を透過する効率を改善しうるあらゆる物質を意味する。
上記皮膚透過性増強剤としては、室温(25℃)で液状である(即ち、流動性を有する)ことが好ましい。2種以上の皮膚透過性増強剤を混合して用いる場合には、最終的に混合物が室温(25℃)で液状となり、皮膚透過促進効果を有することが好ましい。このような有機液状成分としては、上記粘着剤層における相溶性の観点から、疎水性液状成分が好ましい。
上記高級アルコールとしては、炭素数8~18の高級アルコールが好ましく、炭素数8~14の高級アルコールがより好ましい。上記脂肪酸エステルとしては、炭素数8~18の脂肪酸と炭素数1~18の1価アルコールとの脂肪酸エステルが好ましく、炭素数12~16の脂肪酸と炭素数1~18の1価アルコールとの脂肪酸エステルがより好ましい。なかでも、脂肪酸エステルが好ましく、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、セバシン酸ジエチルが特に好ましい。
特に上記支持体としては、厚さ1.5~6μmのポリエステルフィルム(好ましくは、ポリエチレンテレフタレートフィルム)と、目付量6~15g/m2のポリエステル(好ましくは、ポリエチレンテレフタレート)製不織布との積層フィルムが好ましい。
上記剥離ライナーの厚みは、10~200μmが好ましく、25~100μmがより好ましい。
特に上記剥離ライナーとしては、バリアー性、価格等の点から、ポリエステル(特に、ポリエチレンテレフタレート)樹脂からなるものが好ましい。この場合、取り扱い性の点から、厚みは25~100μm程度であることが好ましい。
また、本発明の免疫誘導促進用組成物を対象に投与する際、及び、免疫誘導促進用組成物を含有するワクチン医薬組成物を対象に投与する際、上記細胞内イオン濃度作用薬である免疫誘導促進剤の治療上有効量は、用いる具体的な細胞内イオン濃度作用薬、他の免疫誘導促進剤の有無等に依存して広範に変化しうるが、一般に、1日用量約0.01μg~1g/kg体重で満足のいく結果が得られる。
また、本発明により見出された細胞内イオン濃度作用薬は、医薬品として安全性が広く認められたものが多く、副作用の点からも優れていると考えられる。
また本発明のワクチン医薬組成物は、皮下及び皮内注射、筋肉注射だけでなく、経皮投与又は粘膜投与が可能であるため、優れたコンプライアンス、例えば、非侵襲的投与、無痛、注射の恐怖からの解放、投与が簡便なため患者が自ら投与可能であり、医療従事者の針刺し感染事故のリスクも回避でき、繰返し投与を行う場合の通院頻度の低減が可能となり患者の生活の質の向上に貢献でき、注射針のような特殊廃棄の必要な医療廃棄物が生じないという利点を有する。また、パップ剤やテープ剤等の貼付剤の形態であれば、所定の投与量を確実に投与でき、薬物放出速度を任意に制御でき、また投与に際して他の部位に付着することがないという利点がある。さらに、貼付剤は容易に着脱可能であるため、副作用が生じた場合等に適用部位から貼付剤を除去することによって患者自らが即座に投与を中止することができるという利点も有する。さらに、本発明のワクチン医薬組成物の効能が、抗原の単独投与と比較して、顕著に向上するという利点も有する。更に、本発明のワクチン医薬組成物の経皮投与及び粘膜投与は、注射投与と比較して強い免疫を誘導可能であるという利点も有する。
なお、特に断りのない限り、「%」は「質量%」を意味し、「部」は「質量部」を意味する。
(経皮投与用クリーム剤の調製)
下記表1の組成を有する経皮投与用クリーム剤を調製した。
具体的には、下記表1中に示した配合量で、下記に示した抗原5質量%、第一の免疫誘導促進剤3質量%、必要に応じて第二の免疫誘導促進剤1質量%及びジメチルスルホキシド(DMSO)15質量%を配合し、そこに基材(ベースクリーム)を加えて全100質量%とし、混和して、経皮投与用クリーム剤を得た。用いたベースクリームは、表8に記載の組成にて材料を配合し、混和して調製したものとした。白色ワセリン、モノステアリン酸ソルビタン、イソステアリン酸、ベンジルアルコール、ステアリルアルコール、ポリソルベート60、濃グリセリン、ジメチルスルホキシド(DMSO)は和光純薬工業(株)から購入した。セタノールは東京化成工業(株)から購入した。
PETフィルム/PET不織布積層品(面積0.7cm2)を固定用粘着テープの中央部にPETフィルム側をテープ側にして貼り合わせた複合基材を用意した。この複合基材の不織布部分に経皮投与用クリーム剤4mgを塗布し、これを免疫試験の投与サンプルとした。
スラミンナトリウム(和光純薬工業社製)
塩酸アミロライド(Sigma-Aldrich社製)
アムロジピン(Sigma-Aldrich社製)
バルプロ酸ナトリウム(和光純薬工業社製)
ニコランジル(和光純薬工業社製)
ミノキシジル(LKT Laboratories社製)
ニフルム酸(Sigma-Aldrich社製)
トリアムテレン(Sigma-Aldrich社製)
マニジピン(LKT Laboratories社製)
ドフェチリド(Sigma-Aldrich社製)
グリベンクラミド(和光純薬工業社製)
ジギトキシン(和光純薬工業社製)
ジゴキシン(東京化成工業社製)
モデル抗原として、OVAp(SIGMA-ALDRICH社製)を用いた。
実施例、比較例で得られた経皮投与用クリーム剤について、以下の評価を行った。
以下の手順に従って、経皮投与用クリーム剤を用いて、免疫評価用モデル動物を用いたマウス免疫試験を行った。その後、ELISPOT法により、抗原特異的な細胞性免疫の誘導レベルを評価した。評価結果を図1に示した。
ここにいう「免疫評価用モデル動物」は、ワクチン医薬組成物(ここでは経皮投与用クリーム剤)の免疫誘導特性を評価するためのモデル動物を意味し、具体的には、経皮投与用クリーム剤の細胞性免疫誘導レベルを評価するためのモデル動物を意味する。
免疫評価用モデル動物としては、経皮投与用クリーム剤中の抗原と、動物のMHCクラス1分子との適合性を考慮し、経皮投与用クリーム剤中の抗原による細胞性免疫誘導が評価可能な動物を用いた。
下記表1中に示したマウスの背部を毛刈りし、毛刈りによる皮膚ダメージを回復させるための飼育期間を設けた後、マウスの背部皮膚に経皮投与用クリーム剤4mgを24時間投与して除去し、6日間の飼育を行った。投与から6日間経過後に脾臓を摘出し、脾細胞懸濁液を調製した。抗マウスIFN-γ抗体を固定化したELISPOTプレートのウェルに、脾細胞(1×106cells/well)と抗原ペプチド(100μM)とを培養液とともに入れ、37℃、5%CO2の培養条件にて20時間、共培養し、ELISPOT法にてIFN-γ産生細胞スポット数を評価した。IFN-γ産生細胞スポット数を「免疫結果」として下記表1に示した。
(経皮投与用テープ剤の調製)
下記表2の組成を有する経皮投与用テープ剤を調製した。具体的には、下記表2中に示した配合量で、抗原、第一の免疫誘導促進剤、及び、第二の免疫誘導促進剤を配合し、そこに下記表2中に示した粘着基剤及び有機溶媒(酢酸エチル)を、有機溶媒乾燥後の各成分と粘着基剤との合計が100質量%となるように配合し、混和して、粘着剤溶液を調製した。得られた粘着剤溶液を乾燥後の厚みが約80μmになるように剥離ライナーに展延し、乾燥により有機溶媒を除去して、粘着剤層を形成した。剥離ライナーには、シリコーン剥離処理を施したポリエチレンテレフタレート(PET)製ライナー(厚さ75μm)を用いた。得られた粘着剤層に支持体を貼り合わせて経皮投与用テープ剤を得た。支持体には、ポリエチレンテレフタレート(PET)フィルム(厚さ25μm)を用いた。
この経皮投与用テープ剤を面積0.7cm2になるようカットし、これを免疫実験の投与サンプルとした。投与時には剥離ライナーを剥して投与した。
実施例、比較例で得られた経皮投与用テープ剤について、以下の評価を行った。
経皮投与用クリーム剤の評価と同様の操作により、抗原特異的な細胞性免疫の誘導レベルを評価した。評価結果を図2に示した。
(経粘膜投与用液剤の調製)
下記表3及び4の組成を有する経粘膜投与(経鼻投与又は舌下投与)用液剤を調製した。具体的には、下記表3及び4中に示した配合量で、抗原(オボアルブミン(OVA))、第一の免疫誘導促進剤を配合し、そこに生理食塩水を加え、経鼻投与では10μL又舌下投与では30μLとし、混和して、経粘膜投与(経鼻投与又は舌下投与)用液剤を得た。
(舌下投与用固形製剤の調製)
下記表5の組成を有する舌下投与用固形製剤(凍結乾燥製剤又はフィルム剤)を調製した。具体的には、下記表5中に示した配合量で、抗原(オボアルブミン(OVA))、第一の免疫誘導促進剤、基剤であるヒドロキシプロピルセルロース(HPC-SSL、日本曹達社製)を配合し、そこに生理食塩水を加え、混和して、製剤溶液を得た。その後、製剤溶液25mgを分注し、凍結乾燥を行なって凍結乾燥製剤を得るか又は減圧乾燥を行なってフィルム剤を得た。核内受容体リガンドである免疫誘導促進剤としては、経粘膜投与用液剤の調製に用いた免疫誘導促進剤と同様のものを用いた。
実施例、比較例で得られた経粘膜投与用液剤又は舌下投与用固形製剤について、以下の評価を行った。
以下の手順に従って、経粘膜投与用液剤又は舌下投与用固形製剤を用いて、免疫評価用モデル動物を用いたマウス免疫試験を行った。その後、マウス血清中の抗原(OVA)特異的IgG抗体を測定することにより、全身性免疫応答を評価した。評価結果を図3~5に示した。
予め準備したマウス(BALB/cマウス、メス7週齢)に麻酔処理を行った後、それぞれのマウスに対し、経鼻投与(実施例27~34、比較例9)では10μL、舌下投与(実施例35~42、比較例10)では30μLの経粘膜投与用液剤を投与し、また、舌下投与用固形製剤(実施例43~58、比較例11~12)を投与した。た。当該投与から1週間後、再度マウスに麻酔をかけ、それぞれ同様の投与を行った。2度目の投与から更に1週間後に、マウス血清を採取した。
(マウス血清中の抗原特異的IgG抗体価測定方法(ELISA法))
ELISA用96ウェルプレートに炭酸緩衝液にて希釈したOVA含有溶液(100μg/mL)を100μLずつ添加し、一晩放置した。
予め準備した洗浄液(Tween20含有PBS)で3回ウェルを洗浄し、ブロッキング剤(Block Ace、大日本住友製薬社製)を精製水で4g/100mLに希釈したブロッキング溶液をウェルに200μLずつ添加し、2時間室温で放置した。その後、洗浄液で3回ウェルを洗浄した。
採取したマウス血清を4℃、3000gで10分間遠心分離し、上清を回収した。ブロッキング剤をリン酸緩衝液(ナカライテスク社製)で0.4g/100mLに希釈した溶液を用いて、上清を2倍ずつ段階希釈し、その溶液をウェルにそれぞれ50μLずつ添加し、2時間室温で放置した。
その後、洗浄液で3回ウェルを洗浄した。ブロッキング剤をリン酸緩衝液(ナカライテスク社製)で0.4g/100mLに希釈した溶液でHRP標識抗マウスIgG抗体(Goat-anti mouse IgG Fc HRP、BETHYL)を10000倍に希釈し、その溶液をウェルに100μLずつ添加し、1時間室温で放置した。
その後、洗浄液で3回ウェルを洗浄し、TMB溶液(ELISA POD TMBキット、ナカライテスク社製)をウェルに100μLずつ添加し、暗所にて30分放置した。
その後、1M硫酸用液をウェルに100μLずつ添加し、当該96ウェルプレートについてマイクロプレートリーダー(SpectraMax M2e、モレキュラーデバイス社製)で450nmの吸光度を測定した。段階希釈時の吸光度を基に、マウス血清中のIgG抗体価をLog2で求めた。評価結果を図3~5に示した。
(皮下投与用液剤の調製)
下記表6の組成を有する皮下投与用製剤を調製した。具体的には、下記表6中に示した配合量で、抗原(オボアルブミン(OVA))、第一の免疫誘導促進剤を配合し、そこに生理食塩水を加え200μLとし、混和して、皮下投与用液剤を得た。
実施例、比較例で得られた皮下投与用製剤について、以下の評価を行った。
以下の手順に従って、皮下投与用製剤を用いて、免疫評価用モデル動物を用いたマウス免疫試験を行った。その後、マウス血清中の抗原(OVA)特異的IgG抗体を測定することにより、全身性免疫応答を評価した。評価結果を図6に示した。
予め準備したマウス(BALB/cマウス、メス7週齢)に麻酔処理を行った後、それぞれのマウスに対し、200μLをマウス背部皮下に投与した。当該投与から1週間後、再度マウスに麻酔をかけ、それぞれ同様の投与を行った。2度目の投与から更に1週間後に、マウス血清を採取した。
<評価3>と同様の操作により、マウス血清中の抗原(OVA)特異的IgG抗体価をELISA法により測定した。
(経皮投与用クリーム剤の調製)
下記表7の組成を有する経皮投与用クリーム剤を調製した。具体的には、下記表7中に示した配合量で、抗原(オボアルブミン(OVA))、第一の免疫誘導促進剤を配合し、そこに基材(ベースクリーム)を加えて全100質量部とし、混和して、経皮投与用クリーム剤を得た。用いたベースクリームは、表8に記載の組成にて材料を配合し、混和して調製したものとした。
白色ワセリン、モノステアリン酸ソルビタン、イソステアリン酸、ベンジルアルコール、ステアリルアルコール、ポリソルベート60、濃グリセリンは和光純薬工業(株)から購入した。セタノールは東京化成工業(株)から購入した。
PETフィルム/PET不織布積層品(面積0.7cm2)を固定用粘着テープの中央部にPETフィルム側をテープ側にして貼り合わせた複合基材を用意した。この複合基材の不織布部分に経皮投与用クリーム剤4mgを塗布し、これをマウス免疫試験の投与サンプルとした。
<評価5>
実施例、比較例で得られた経皮投与用クリーム剤について、以下の評価を行った。
以下の手順に従って、経皮投与用クリーム剤を用いて、免疫評価用モデル動物を用いたマウス免疫試験を行った。その後、マウス血清中の抗原(OVA)特異的IgG抗体価を測定することにより、全身性免疫応答を評価した。評価結果を図7に示した。
予めマウス(C57BL/6 NCrマウス、メス7週齢)右背部を毛刈りし、毛刈りによる皮膚ダメージを回復させるための飼育期間を設けた後、マウスの右背部皮膚に経皮投与用クリーム剤4mgを投与した。同時に左背部を毛刈りした。24時間後、右背部の経皮投与用クリーム剤を除去した。当該投与から1週間後、マウスの左背部皮膚に同様に経皮投与用クリーム剤を投与し、24時間後に除去した。2度目の投与から更に1週間後に、マウス血清を採取した。
<評価3>と同様の操作により、マウス血清中の抗原(OVA)特異的IgG抗体価をELISA法により測定した。
Claims (6)
- イオンチャネル又はイオンポンプに作用する細胞内イオン濃度作用薬である第一の免疫誘導促進剤を含むことを特徴とする免疫誘導促進用組成物。
- 細胞内イオン濃度作用薬は、ナトリウムチャネル作用薬、カルシウムチャネル作用薬、カリウムチャネル作用薬、塩素チャネル作用薬、及び、ナトリウム-カリウムポンプ作用薬からなる群より選択される少なくとも1種である請求項1記載の免疫誘導促進用組成物。
- 免疫誘導のための抗原と、請求項1又は2記載の免疫誘導促進用組成物とを含むことを特徴とするワクチン医薬組成物。
- 更に、Toll様受容体(TLR)リガンド、環状ジヌクレオチド、及び、ヘルパーペプチドから選択される少なくとも一種の免疫賦活化剤である第二の免疫誘導促進剤を含む請求項3記載のワクチン医薬組成物。
- 体表面上に投与されるものである請求項3又は4記載のワクチン医薬組成物。
- 皮内注射、皮下注射又は筋肉内注射により投与されるものである請求項3又は4記載のワクチン医薬組成物。
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CN201780009693.2A CN108601827A (zh) | 2016-02-02 | 2017-02-01 | 免疫诱导促进用组合物和疫苗药物组合物 |
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JP6967457B2 (ja) | 2021-11-17 |
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