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WO2019021476A1 - Agent de traitement prophylactique ou thérapeutique pour symptôme allergique - Google Patents

Agent de traitement prophylactique ou thérapeutique pour symptôme allergique Download PDF

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Publication number
WO2019021476A1
WO2019021476A1 PCT/JP2017/027526 JP2017027526W WO2019021476A1 WO 2019021476 A1 WO2019021476 A1 WO 2019021476A1 JP 2017027526 W JP2017027526 W JP 2017027526W WO 2019021476 A1 WO2019021476 A1 WO 2019021476A1
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WIPO (PCT)
Prior art keywords
administration
water
preparation
therapeutic agent
soluble base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2017/027526
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English (en)
Japanese (ja)
Inventor
英寿 松波
慎 林
典子 佐々木
智美 吉川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sosai Kosei Kai Clinical Foundation Matsunami Research Park
Original Assignee
Sosai Kosei Kai Clinical Foundation Matsunami Research Park
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Priority to PCT/JP2017/027526 priority Critical patent/WO2019021476A1/fr
Publication of WO2019021476A1 publication Critical patent/WO2019021476A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present specification relates to an agent for the prophylaxis or treatment of allergic symptoms.
  • Substances that occur routinely such as food, drugs, pollen, mites, house dust, etc., become allergens for humans, and diseases causing allergic symptoms are allergic diseases.
  • Representative allergic diseases include food allergy, drug allergy, hay fever, atopic dermatitis, allergic rhinitis, bronchial asthma and the like.
  • allergic reactions that cause allergic diseases Among the allergic reactions that cause allergic diseases, allergic reactions that cause allergic symptoms within several hours immediately after the entry of an allergen into the body are classified into type I (immediate type). Many allergic diseases are classified into this immediate type.
  • anaphylaxis is the most severe one. Anaphylaxis causes systemic allergic symptoms in a very short time, or multiple allergic symptoms appear simultaneously. Furthermore, when a shock symptom such as a drop in blood pressure or consciousness level or dyspnea appears, it is referred to as anaphylactic shock. When anaphylaxis or anaphylactic shock occurs, life may be at risk if appropriate measures and treatments are not taken promptly.
  • Adrenaline self-injection medication should be given.
  • a combination drug with an antidepressant is disclosed as an adrenergic self-injection drug (Patent Document 1).
  • anaphylaxis and anaphylaxis shock There are various measures for anaphylaxis and anaphylaxis shock.
  • patients who die due to anaphylactic shock and the like are not, however, on the decrease.
  • adrenergic self-injection drugs it may be difficult to judge the administration by surrounding family members or faculty members, and there may be fear and resistance to injection.
  • they are low in the level of expertise in administration of injections and can not always be administered reliably.
  • adrenergic self-injection drugs can only be prescribed for people with high potential for anaphylaxis, and can only be used by those who are prescribed. For this reason, if an anaphylaxis has never occurred before, it may not be possible to take emergency measures.
  • self-injection drugs also require regular education and training for their administration.
  • patients with high potential such as anaphylaxis need to carry an adrenaline self-injection drug at all times.
  • the present specification provides an agent for the prophylaxis or treatment of allergic symptoms suitable for prompt and simple administration in response to allergic symptoms including anaphylaxis and anaphylactic shock.
  • the present inventors as a dosage form which can easily and rapidly and easily administer adrenalin without resistance to administration, can be easily administered by using a water-soluble base as a dosage form containing an active ingredient.
  • a water-soluble base as a dosage form containing an active ingredient.
  • a preparation for preventing or treating allergic symptoms which is A water soluble base, An active ingredient useful for the prevention or treatment of the allergic condition, which is contained by being dissolved or dispersed in the water-soluble base;
  • a preparation that is a transmucosal administration agent comprising: [2] The preparation according to [1], wherein the water-soluble base material comprises an emulsifier having an HLB value of 14.0 or more.
  • [5] The preparation according to any one of [1] to [4], which is an agent for oral mucosal administration.
  • [6] The preparation according to any one of [1] to [5], which is for sublingual administration.
  • a preparation for preventing or treating allergic symptoms which is A water soluble base, Adrenaline contained in a solution or dispersion in the water-soluble base, Equipped with The water-soluble substrate comprises an emulsifier having an HLB value of 14.0 or more,
  • the allergic symptoms are anaphylaxis or anaphylactic shock,
  • the disclosure of the present specification relates to an agent for preventing or treating allergic symptoms.
  • the agent for the prophylaxis or treatment of allergic symptoms disclosed in the present specification (hereinafter simply referred to as the present therapeutic agent) comprises a water-soluble base and a preventive for allergic symptoms contained in the water-soluble base in a dissolved or dispersed state. Or an active ingredient effective for treatment.
  • the therapeutic agent is applied not only to primates including humans but also to companion animals such as dogs, cats and rabbits, and mammals such as domestic animals such as cattle, horses, pigs, sheep and goats.
  • the therapeutic agent can be a transmucosal administration agent which uses a mucous membrane as an administration route.
  • the agent for transmucosal administration refers to a dosage form in which a mucous membrane easily accessible from the outside, such as a body cavity mucous membrane, is used as the administration route.
  • the agent for transmucosal administration uses the mucous membrane of the body cavity as the administration route.
  • it is a simple method of supplying the therapeutic agent to mucous membranes such as oral mucosa of individual mammals such as human patients for the prevention or treatment of allergic symptoms.
  • the active ingredient can be reliably administered for the prevention of allergic symptoms and the like.
  • a dosage form for example, the patient himself / herself and surrounding people also do not need any special training for administration, and the required medicines can be promptly obtained without any loss compared to the conventional administration form by intramuscular injection. It can be administered.
  • a dosage form that requires no fluid and does not require swallowing, in particular, supply to body cavity mucous membranes such as oral mucous membranes is particularly useful in the case of anaphylaxis or anaphylactic shock where urgency is required.
  • the therapeutic agent is administered sublingually.
  • Sublingual administration makes it easy to identify the position of administration and to maintain the oral cavity during administration to an allergic individual, and is less likely to be accidentally swallowed.
  • oral administration subcutaneous injection, intramuscular injection, intravenous injection, intraarterial injection
  • buccal administration including sublingual administration, rectal administration, vaginal administration, eye drop, nasal administration , Inhalation (transtracheal), transdermal administration (poultice etc.).
  • injection subcutaneous injection, intramuscular injection, intravenous injection, intraarterial injection
  • buccal administration including sublingual administration, rectal administration, vaginal administration, eye drop, nasal administration , Inhalation (transtracheal), transdermal administration (poultice etc.
  • adrenaline When adrenaline is orally administered, adrenaline absorbed from the small intestine passes through the portal vein to the liver and passes to systemic blood, but there are many enzymes in the liver and the adrenaline is metabolized, so pharmacological action is Attenuates (first pass effect).
  • adrenaline when adrenaline is administered, it is in the form of injection such as intravenous injection or self-injection, but in buccal or sublingual administration, the active ingredient is directly transferred from the capillary network to the systemic circulation. Because it enters, it is rapidly transferred to tissues without being affected by the first pass effect and absorbed and immediate action is obtained.
  • the active ingredient is absorbed from the rectal mucosa and directly enters the systemic circulation through the inferior vena cava, so that it is rapidly absorbed without immediate effect and immediate action is obtained.
  • Sublingual administration is preferred because of the simplicity of the administration method.
  • the therapeutic agent can comprise a water soluble base. In this case, it can be administered via the mucous membrane etc. without intake of water at the time of administration. Furthermore, even when administered in the oral cavity of an individual with anaphylaxis or the like, the therapeutic agent is effectively retained on the oral mucosa and then disintegrates or dissolves to absorb the active ingredient from the oral mucosa. It will be realized quickly.
  • the water-soluble base of the present therapeutic agent has the form of a film or a tablet, it is convenient for carrying, excellent in portability, and convenient for administration.
  • there is no need to administer water and only supply to body cavity mucous membranes such as the oral cavity can be easily administered to individuals such as dysphagia, human patients of a wide range of ages from infants to elderly people. .
  • One embodiment of the present therapeutic agent can comprise a water-soluble base and an active ingredient useful for the prevention or treatment of allergic symptoms, which is contained by being dissolved or dispersed in the water-soluble base.
  • the present therapeutic agent contains a water-soluble base
  • the present therapeutic agent can have solubility or disintegrability on mucous membranes such as various body cavities.
  • the water-soluble base can have. It may be a molded body having a predetermined three-dimensional shape. When the water-soluble base is a molded product, the three-dimensional shape thereof is not particularly limited, and in addition to various forms, so-called films, tablets and the like, it may be shaped according to other portions to be administration sites.
  • the water-soluble base may be in the form of an irregular gel which can be filled in a container such as a tube or a capsule.
  • the film agent when the water-soluble base is a film agent having a film shape, the film agent can be in the form of a sheet having an appropriate planar shape and an appropriate thickness.
  • the thickness is not particularly limited, but in consideration of administration in the body cavity, it is preferable that the thickness is about 5 mm or less as a whole. More preferably, it is about 1 mm or less. More preferably, it is about 10 ⁇ m to 800 ⁇ m. Further, the upper limit is more preferably 600 ⁇ m or less, still more preferably 500 ⁇ m or less, and still more preferably 400 ⁇ m or less. The lower limit is preferably 40 ⁇ m or more. More preferably, it is 60 ⁇ m or more. Moreover, it is also preferable that they are 40 micrometers or more and 70 micrometers or less. Such a thickness is particularly preferable as a human sublingual administration.
  • the planar form of the film agent is not particularly limited. It is appropriately set according to the administration subject, administration site, content and the like. For example, a square shape, a rectangular shape, a circular shape, a shape in which these are combined, or a shape having a design imitating any natural product can be mentioned.
  • the size (area) is also not particularly limited, but can be, for example, about 30 mm 2 or more and 1500 mm 2 or less. More preferably, the lower limit is 40 mm 2 or more, more preferably 60 mm 2 or more, still more preferably 80 mm 2 or more, and still more preferably 100 mm 2 or more.
  • the upper limit is more preferably 1300 mm 2 or less, still more preferably 1000 mm 2 or less, and still more preferably 800 mm 2 or less.
  • the above area is particularly preferable as a human sublingual administration.
  • the mass of the film agent is not particularly limited, but can be 5 mg or more and 300 mg or less. More preferably, it is 10 mg or more and 100 mg or less, and still more preferably 40 mg or more and 80 mg or less.
  • the tablet When the water-soluble base is a tablet having a tablet shape, the tablet may be in the form of a cylinder or rod having a suitable shape and thickness, or in the form of a body cavity serving as an administration site. it can.
  • the rectal mucosa when used as the administration route, it may be in the form of a so-called suppository spindle.
  • its size can be arbitrarily set in accordance with the administration site and the like as compared to a film.
  • the thickness is not particularly limited, but it is preferably about 10 mm or less as a whole, and more preferably about 5 mm or less.
  • the present therapeutic agent may have a laminated structure having two or more water-soluble base layers, and the active ingredient may be contained in at least one water-soluble base layer.
  • the water-soluble base is a formed article such as a film or a tablet having a predetermined three-dimensional form, it is preferable that the present therapeutic agent has such a laminated structure.
  • the therapeutic agent When the therapeutic agent has such a layered structure, it may have a layered structure having three or more water-soluble base layers. Preferably it is four or less layers, More preferably, it is three or less layers.
  • the active ingredient may be contained in each layer, or may be contained in one or more specific layers.
  • one layer can contain two or more active ingredients, and different layers can contain different active ingredients.
  • an active ingredient is included in at least one layer, another active ingredient other than the active ingredient of this therapeutic agent can also be included in one or more other layers.
  • the mucoadhesive layer, the intermediate layer and the outer layer can be formed in the order of mucous membrane.
  • Mucoadhesive layers can be used primarily to improve adhesion to mucous membranes.
  • the intermediate layer can also be used mainly to contain the active ingredient.
  • the outer layer can be used mainly as a disintegrating control layer and a layer for imparting flavor and the like.
  • a mucoadhesive layer and an intermediate layer can also be used for controlling disintegrability and imparting a flavor.
  • the component for the stability of an active ingredient and the stability of a water-soluble base can be provided with respect to one or more layers, or all the layers as needed.
  • a component for example, glycerin, surfactant, etc.
  • glycerin, surfactant, etc. for imparting or improving the flexibility or the followability of the water-soluble base may be appropriately provided to any layer, two or more layers, or all layers. it can.
  • water-soluble matrix material As the water-soluble base, known water-soluble matrix materials intended for mucosal administration including oral mucosal administration can be appropriately selected and used.
  • the water-soluble matrix material is a material having water solubility and capable of contributing to the form as a solid, although having a predetermined shape or an irregular shape.
  • Water soluble polymers can generally be used as the water soluble matrix material.
  • Such water-soluble matrix materials are not particularly limited, and examples thereof include polyvinyl pyrrolidone, polyvinyl alcohol, sodium polyacrylate, carboxymethyl cellulose, starch, xanthan gum, karaya gum, sodium alginate, methyl cellulose, carboxyvinyl polymer, agar, hydroxy Propyl cellulose, hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (alias: cellulose acetate phthalate, CAP), carboxymethyl ethyl cellulose (CMEC), ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, tragacanth, gum arabic, locust bean gum, Guar gum, gellan gum, carrageenan ( Lagenan), dextrin, dextran, amylose, carboxymethylcellulose potassium, carboxymethylcellulose sodium, carboxymethylcellulose calcium, pullulan, chitosan, carboxymethylstarch sodium, plantago
  • the water-soluble matrix material is preferably one that exhibits adhesiveness by the action of saliva when introduced into the oral cavity and exhibits high adhesiveness to the oral mucous membrane, and specifically, in particular, pullulan, polyvinyl alcohol ( Particularly preferred is a base selected from the group consisting of PVA), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), gelatin, starch and mixtures thereof.
  • PVA polyvinyl alcohol
  • HPC hydroxypropyl cellulose
  • PVP polyvinyl pyrrolidone
  • gelatin starch and mixtures thereof.
  • water-soluble matrix material it is preferable to use a water-soluble matrix material composed of a polysaccharide having glucose as a basic structural unit and having no gelling point and a carboxylic acid or a sulfur-containing polysaccharide.
  • polysaccharides having glucose as a basic constituent unit include pullulan, alginic acid, starch and the like.
  • gellan gum, carrageenan etc. can be mentioned as carboxylic acid or sulfur-containing polysaccharide.
  • the content of the water-soluble matrix material is not particularly limited, but can be, for example, 10 parts by mass or more and 60 parts by mass or less with respect to the total mass of solid components other than the medium in the water-soluble base.
  • the upper limit is preferably 50 parts by mass or less, and may be 40 parts by mass or less.
  • the lower limit is preferably 15 parts by mass or more and 20 parts by mass or more.
  • an emulsifier By adding an emulsifier, the dispersibility of the drug etc. in the solution of the water-soluble matrix material can be enhanced, and the coatability at the time of applying the solution for forming the water-soluble base in the production process can be secured.
  • an emulsifier can use an emulsifier of 14.0 or more. When the HLB value is 14.0 or more, absorption of an active ingredient such as adrenaline can be improved.
  • the HLB value is also, for example, 14.5 or more, for example, 15.0 or more, for example, 15.5 or more, for example, 16.0 or more, for example, 16.5 Or more, for example, 17.0 or more, and for example, 18.0 or more.
  • the emulsifier having an HLB value of 14.0 or more is not particularly limited.
  • polyglycerin fatty acid ester sucrose fatty acid ester such as sucrose stearate, organic monoglycerin fatty acid ester, polysorbate, polyglycerin Condensed ricinoleate ester, lauroyl macrogol-32 glycerides and lauroyl polyoxyl-32 glycerides lauroyl macrogol glycerides, stearoyl macrogol glycerides, caprylocaproyl macrogol-8 glycerides, caprylocaproyl polyoxyl-8 glycerides, etc.
  • Caprocaproyl macrogol and the like can be exemplified.
  • an emulsifier for example, “Surf Hope” (trade name of sucrose fatty acid ester, manufactured by Mitsubishi Chemical Foods), “M-7D” (commercial product of polyglycerin fatty acid ester, manufactured by Mitsubishi Chemical Foods), “Suncrude” It is also possible to use commercially available products such as “Lecithin A-1” (commercially available product of soybean derived lecithin, manufactured by Sun Chemical Co., Ltd.), Polysorbate 80HM (manufactured by NOF Corporation), Gelucire 44/14, Labrasol (all, CBC Corporation) it can.
  • the amount of the emulsifier used varies depending on the type of the water-soluble matrix material, the type of the active ingredient, and the content thereof, but for example, about 0.1 to 40 parts by mass with respect to 100 parts by mass of the water-soluble matrix material It is preferable to use, more preferably, 1 part by weight or more and 20 parts by weight or less, and still more preferably 10 parts by weight or less.
  • surfactants such as polyoxyethylene sorbitan oleate, sucrose fatty acid ester, polyglycerin fatty acid ester, soy bean-derived lecithin, etc. may be mentioned as appropriate, and may be used alone or in combination of two or more. Can.
  • the water soluble base can contain various additives in addition to the water soluble matrix material.
  • additives generally used in preparations intended for known oral mucosal administration can be appropriately selected and used.
  • filler, etc. are mentioned, for example.
  • the plasticizer is not particularly limited, and examples thereof include glycerin, sorbitol, polyglycerin and the like, and when used, they can be used singly or in combination of two or more. Among them, glycerin is preferred. Moreover, a commercial item can also be used.
  • the plasticizer can impart flexibility to the water soluble base. The amount of plasticizer used varies depending on the type of water-soluble matrix material, the type and content of the active ingredient, etc. For example, 5 parts by mass to 15 parts by mass with respect to 100 parts by mass of the water-soluble matrix material Is preferred.
  • the excipient is not particularly limited.
  • precipitated calcium carbonate, crystalline cellulose, corn starch, partially pregelatinized starch, magnesium stearate, glucomannan, potato starch, low substituted hydroxypropyl cellulose (hydroxypropyl Those obtained by physically modifying cellulose, L-HPC) and the like can be mentioned, and when used, they can be used alone or in combination of two or more.
  • the content of the excipient is not particularly limited.
  • the water-soluble group is preferably used per 100 parts by mass of the water-soluble matrix material.
  • the agent can be 0.5 parts by mass or more and 20 parts by mass or less. More preferably, it is 1 part by weight or more and 20 parts by weight or less, still more preferably 2 parts by weight or more and 15 parts by weight or less.
  • the gelling agent can be used to adjust the solubility of the water-soluble base.
  • the gelling agent is not particularly limited, and, for example, metal salts such as titanium dioxide, sodium phosphate, potassium phosphate, sodium stearate, potassium stearate and the like can be used.
  • the amount of the gelling agent used is preferably 0.1 parts by mass to 5 parts by mass with respect to 100 parts by mass of the water-soluble matrix material, and more preferably 0.5 parts by mass to 3 parts by mass .
  • the content is preferably 1% by mass or less, more preferably 0.5% by mass or less. Furthermore, it is 0.2% by mass or less, and may not contain a gelling agent.
  • the water-soluble base may be any other additive as long as the effect intended by the present therapeutic agent is not impaired, for example, a gelation promoter such as potassium phosphate, malt reducing sugar syrup, sucrose, lactose, fructose or saccharin Sweeteners such as aspartame, aspartame and L-phenylalanine compounds, sucralose, thaumatin, acesulfame potassium and stevia, peppermint, peppermint oil, cherry flavor, orange oil, fennel oil, ethylmaltol, l-menthol and other flavors, benzoic acid, Containing preservatives such as sodium benzoate, benzyl benzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, opacifiers such as titanium oxide, and colorants such as ferric oxide and yellow ferric oxide You can also.
  • a gelation promoter such as potassium phosphate, malt reducing sugar
  • the present therapeutic agent may have a coloring and / or design such as letters, numbers, or patterns for clarifying the formulation identification property and the content and clarifying the urgency.
  • a coloring and / or design such as letters, numbers, or patterns for clarifying the formulation identification property and the content and clarifying the urgency.
  • the water-soluble base has a film shape, various indications can be made on the drug itself, and in particular, in the case of an oral mucous membrane administration preparation, allergic onset individual due to taste or smell simultaneously with administration of the drug. It is advantageous in being able to give a sense of security to infants and children who are
  • As a coloring agent Asen Yaku tannin powder, yellow ferric oxide, turmeric extract, brown iron oxide, carbon black, caramel, carmine, carotene solution, ⁇ -carotene, licorice extract, gold foil, silver foil, platinum foil, black iron oxide Light anhydrous silicic acid, titanium oxide, ferric oxide, food blue 1, food yellow 4, food yellow 4 aluminum lake, food yellow 5, food yellow 5 aluminum lake, food red 2, food red 3 No. food red No.
  • talc copper chlorophyllin sodium, copper chlorophyll, green leaf extract extract, octyldodecyl myristate, medicinal charcoal, riboflavin, riboflavin butyrate ertel, riboflavin ester, green tea powder, rose oil etc.
  • medicinal charcoal riboflavin, riboflavin butyrate ertel, riboflavin ester, green tea powder, rose oil etc.
  • the active ingredient is a ingredient useful for the prevention or treatment of allergic symptoms.
  • allergic symptoms generally refer to symptoms resulting from type I allergy.
  • Specific examples of allergic symptoms include atopic dermatitis, bronchial asthma, allergic rhinitis, hay fever, hives, food allergy, drug allergy, bee venom allergy, serum allergy, anaphylaxis, anaphylactic shock and the like.
  • Anaphylaxis is a symptom in which an allergic reaction occurs in a short period of time and becomes systemic and in multiple organs (skin, mucous membranes, respiratory organs, digestive organs, circulatory organs, etc.). Anaphylaxis can be triggered by any allergen, but among them, drugs, insect venoms such as bee venom, certain foods such as eggs, fish and shellfish, nuts, allergy injection (allergen immunotherapy), natural gum, etc. Latex is considered to be the main cause. Anaphylaxis shock is a condition that causes blood pressure drop and impaired consciousness among anaphylaxis.
  • allergic symptoms include anaphylaxis and anaphylactic shock caused by oral allergy syndrome, food-dependent exercise-induced anaphylaxis, and the like.
  • the components effective for preventing or treating allergic symptoms generally include various antihistamines, ⁇ -agonists which are bronchodilators, various steroids, glucagon, adrenalin or noradrenaline.
  • ⁇ -agonists which are bronchodilators
  • various steroids glucagon
  • adrenalin an active ingredient
  • the active ingredients can also be used in combination of one or more depending on the purpose and the like.
  • optical isomers such as adrenaline and noradrenaline are present, isomers or racemates suitable for the purpose of administration can be appropriately selected and used.
  • adrenaline includes free adrenaline and various forms such as hydrochloride, tartrate and hydrogen tartrate. From the viewpoint of solubility, absorbability, stability, etc., preferably hydrochloride can be used.
  • the active ingredient is dissolved or dispersed in a water-soluble base, and in particular, the present embodiment in the water-soluble base is not limited. Preferably, in consideration of absorbability, it is contained by being dissolved in a water-soluble base.
  • the content of the active ingredient with respect to the water-soluble base is not particularly limited, but is not limited, but preferably 0.5 parts by mass or more and 50 parts by mass or less with respect to 100 parts by mass of the water-soluble base. More preferably, it is 30 parts by mass.
  • the therapeutic agent can take a dosage form formulated for transmucosal administration.
  • body cavity mucosa is preferred.
  • the mucous membrane of the body cavity is not particularly limited, and examples thereof include oral mucous membrane, pharyngeal mucous membrane, nasal mucous membrane, vaginal mucous membrane, rectal mucous membrane and the like.
  • the therapeutic agent can more preferably take a dosage form formulated for buccal administration.
  • the amount of active ingredient that can be contained in the present therapeutic agent varies depending on the type of allergic condition, purpose of treatment, etc., and the subject of administration (species, body weight, sex, adult or child, etc.).
  • a preparation for oral mucosal administration in the case of a preparation for oral mucosal administration, it can be a preparation for oral administration, in particular, a preparation for sublingual administration.
  • the therapeutic agent when it is a preparation for sublingual administration, it may be adhered and held directly on the tongue lining mucosa, or the lower jaw surface of the lower tongue so that the therapeutic agent can easily contact the tongue lining mucosa.
  • the present therapeutic agent may be adhered and held.
  • the therapeutic agent when the therapeutic agent is a preparation for sublingual administration, the therapeutic agent can itself be provided with a form easy to be administered sublingually and an applicator for administration.
  • the water-soluble base is a preparation having a predetermined three-dimensional shape such as a film or a tablet (hereinafter simply referred to as a molded preparation)
  • the form itself can be easily administered sublingually. It may have a three-dimensional form along the shape of.
  • an insertion part 4 having a form that can be inserted easily under the tongue, and a cover part that holds and covers the molded preparation on the insertion part 4 6 and an elongated gripping portion 8 gripped with fingers for inserting the insertion portion 4 under the tongue.
  • the applicator 2 is formed in a spatula as a whole.
  • the insertion portion 4 is concave on the back side of the tongue so as to facilitate the attachment of the formed preparation to conform to the tongue shape. And so on.
  • the formed preparation when it is intended to attach the formed preparation to the mucous membrane of the tongue, it may be formed to be convex toward the sublingual mandible side so that the formed preparation adheres easily to conform to the shape of the sublingual mandible.
  • the cover portion 6 is a member that covers and holds the formed preparation on the insertion portion 4 so that the formed preparation does not adhere to other than the intended site.
  • the cover 6 may include at least a tip 10 capable of covering a molded preparation, and a support 12 connected to the tip 10 and disposed along the long axis of the grip 8.
  • the support portion 12 is provided slidably along the long axis of the grip portion 8 and is provided in a groove shape or the like in the grip portion 8 from the position covering the molded preparation to the position for exposing the cover
  • the slide guide 14 can be pulled to the side opposite to the insertion portion 4.
  • the formed preparation in the insertion portion 4 of the applicator 2 it is possible to dispose the formed preparation in the insertion portion 4 of the applicator 2, cover the formed preparation by the cover portion 6, and hold the formed preparation on the insertion portion 4.
  • the insertion part 4 is inserted in the oral cavity of the allergy onset individual with the holding part 8 of the applicator 2, and the insertion part 4 is arranged under the tongue or under the tongue, and then the cover 6 is turned to the front (outside the oral cavity
  • the slide movement exposes the formed preparation on the insertion part 4 and adheres the formed preparation to the sublingual oral mucosa.
  • the cover portion 6 is not necessarily required as long as the formed preparation can be held to a certain degree of strength with respect to the insertion portion 4.
  • the applicator 2 can be appropriately applied to the pharyngeal mucosa etc. in addition to the oral mucosa, in addition to the sublingual oral mucosa.
  • the insertion portion 4, the cover portion 6, and the grip portion 8 of the applicator 2 are made of a plastic, wood-based material, etc. having flexibility and elasticity that do not damage the mucous membrane such as silicone resin and strength that does not easily break. Is preferred. Further, as described later, the molded preparation may be provided in advance at a predetermined position of the insertion portion 6, and the therapeutic agent may be inserted at the time of use by using the present therapeutic agent and the applicator 2 as a kit. You may make it hold.
  • the applicator 22 shown in FIG. 2 is for inserting a shaped preparation into the nasal cavity, vagina and anus using fingers.
  • the applicator 22 can be composed of a sack or band-like insertion portion 24 for covering the fingers over a predetermined length, and a cover portion 26 for covering the tip of the insertion portion 24.
  • the tip of the sack portion 24 is adapted to be able to hold a shaped preparation.
  • the cover portion 26 is configured to cover the molded preparation held at the distal end of the insertion portion 24 and to be exposed thereafter. Specifically, as shown in FIG.
  • the cover portion 26 is a cylindrical body covering the outer peripheral surface of the insertion portion 24 so that the whole can be slid forward (for example, outside the anus etc.) It has become.
  • the cover portion 26 may be configured to pull the whole toward the front, or may be provided with a guide 28 in the form of a string or a stick as shown in FIG.
  • the insertion portion 24 and the cover portion 26 are preferably made of a material such as rubber or resin which is rich in flexibility.
  • the therapeutic agent can be used to prevent or treat allergic symptoms.
  • the allergic symptoms to which the present therapeutic agent is applied are as described above. Allergic symptoms are caused at regular intervals after exposure to an allergen. Therefore, allergic symptoms can be prevented by administering the present therapeutic agent as soon as exposure to the allergen is known.
  • the therapeutic agent can be administered to treat or support the allergic symptoms, and at least temporarily alleviate the progression of symptoms to prevent shock.
  • the present therapeutic agent is useful for the prophylaxis or adjuvant treatment of anaphylactic and anaphylactic shock which require urgent treatment for administration among allergic symptoms.
  • This therapeutic agent is convenient for emergency administration to an individual who has developed anaphylaxis or anaphylactic shock, in particular, by a third party who is not a healthcare professional.
  • the mucous membrane of the body cavity is used as the administration route, unlike injections and inhalants, even without special equipment, administration can be performed immediately, easily, and without any need for training. .
  • it is excellent in portability, and is suitable for carrying a plurality for multiple administration.
  • a sublingual administration is preferred for the treatment of anaphylaxis or anaphylactic shock. If it is a sublingual administration, even if it is a third party who is not a medical worker, this therapeutic agent can be more easily appropriately administered in response to an emergency situation.
  • the present therapeutic agent in the case where the present therapeutic agent is intended for the prevention or treatment of nafiquilacy or anaphylactic shock and uses adrenaline as an active ingredient, it may vary depending on the type of adrenaline, body weight of the subject, sex, adult or child, etc.
  • the dose of the present therapeutic agent for single administration for sublingual administration is preferably set as 0.001 mg or more and 10 mg or less / kg body weight. More preferably, it is 0.01 mg to 1 mg / kg body weight, still more preferably 0.01 mg to 0.1 mg / kg body weight, and still more preferably 0.05 mg to 0.08 mg / kg body weight.
  • an active ingredient such as adrenaline can be contained as a single dose from 0.01 mg to 300 mg.
  • the active ingredient is preferably 0.1 mg or more and 10 mg or less, more preferably 1.5 mg or more and 2.4 mg or less.
  • the present therapeutic agent as a single-dose agent for sublingual administration for administration to human patients weighing 15 kg or more and less than 30 kg can contain 0.005 mg or more and 150 mg or less of an active ingredient such as adrenaline.
  • the active ingredient is preferably 0.05 mg or more and 5 mg or less, more preferably 0.75 mg or more and 1.2 mg or less.
  • adrenaline when adrenaline is used as an active ingredient at about 20 mg / kg body weight and administered sublingually to rabbits, up to 900 ng / ml can be reached even 10 minutes after administration, and up to 600 up to 20 minutes after administration within 20 minutes after administration A plasma adrenaline concentration of 900 ng / ml can be provided.
  • the reaching time to the maximum value of plasma adrenaline concentration is comparable to the reaching time (about 8 minutes) when intramuscularly injecting adrenaline, supporting the efficacy and fast-acting effect of mucosal administration preparations such as sublingual administration Ru.
  • the present therapeutic agent can be in the form of a single dose formulation containing at least the required dose for an allergy-induced individual. That is, when the therapeutic agent is a shaped preparation, individual shaped preparations can be packaged individually. In addition, when the therapeutic agent is an unshaped and amorphous preparation, a single dose can be filled into a container such as a tube filled with each individually.
  • the therapeutic agent may be formed so as to be easily divided into individual single doses. That is, when the therapeutic agent is a molded preparation having a shape such as a film or a tablet, the therapeutic agent may be provided with a fragile portion such as a dividing line which can be divided into unit doses.
  • the therapeutic agent may also be equipped with application elements suitable for sublingual administration such as the applicators 2 and 22 described above in order to enable sublingual administration and the like promptly.
  • application elements suitable for sublingual administration such as the applicators 2 and 22 described above in order to enable sublingual administration and the like promptly.
  • the therapeutic agent may be pre-attached to the site most suitable for sublingual administration of such an application element.
  • a separate application element may be provided as a kit for the present therapeutic agent.
  • the present therapeutic agent can adopt various forms of packaging forms in consideration of the stability of the active ingredient. Since the present therapeutic agent is a water-soluble preparation, it does not become bulky by packaging. Further, since the preparation is a water-soluble preparation, it is possible to easily remove elements which may accelerate the decomposition of the active ingredient, such as light and gas, depending on the external form and the internal form.
  • the present therapeutic agent is a water-soluble preparation, it can easily produce a unit dose containing an active ingredient at various contents. For this reason, it is excellent also in administration property, portability, etc. when multiple administration is required.
  • the present disclosure further comprises the step of administering the therapeutic agent to the mammal in an amount effective to prevent or treat the allergic condition in the mammal, preventing or treating the allergic condition in the mammal. (Hereinafter referred to as the present treatment method).
  • the various symptoms described above for the present therapeutic agent can be applied to the allergic condition, the present therapeutic agent, the dosage form thereof and the dose thereof, etc. in the present treatment method, including the preferred embodiments.
  • Adrenaline-containing water-soluble film formulations (40 mg formulation / unit and 0.4 mg formulation / unit) of compositions 1 and 2 shown below were produced in the steps shown below.
  • the adrenalin solution prepared in the preparation step was degassed using an aspirator.
  • composition 3 a water-soluble film preparation containing 80 mg / unit of adrenaline was produced.
  • This water-soluble film preparation was administered to a Japanese white rabbit (male) (body weight about 3.4 kg) to measure its plasma adrenaline concentration and blood pressure.
  • the sucrose fatty acid ester had an HLB value of 16.0, as in the examples.
  • the rabbit was intravenously administered with an anesthetic (mitazolam, butorphanol and medetomidine), the blood pressure was measured in the right ear artery, and blood was collected from the left ear artery.
  • anesthetic mitazolam, butorphanol and medetomidine
  • the plasma adrenaline concentration tended to rise to about 900 ng / ml 10 minutes after administration, and then to decrease generally.
  • the blood pressure gradually increased after showing a tendency to decrease once.
  • blood pressure tended to decrease gradually in control rabbits that received placebo.
  • the trend of blood pressure and adrenaline plasma concentration tended to be 0.3 mg of adrenergic injection and 40 mg of adrenergic sublingual tablet, however, adrenergic intramuscular and sublingual tablets had 30 ng of adrenergic plasma concentration at 30 minutes after administration.
  • the film formulation exhibited excellent absorbability, since the concentration was 25 ng / ml at 20 ml / ml and 20 minutes (“Epinephrine (adrenaline) absorption from new-generation, taste-masked sublingual tablets: A preliminary study ", J. Allegy. Clin. Immumnol. Vol. 131, Number 1, P. 236-238).

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Abstract

Une préparation contenant une base soluble dans l'eau et un principe actif qui est contenu sous une forme dissoute ou dispersée dans la base soluble dans l'eau et est utile pour la prévention ou le traitement du symptôme allergique. Lorsque la préparation est administrée par voie transmuqueuse, il devient possible d'administrer le principe actif sans crainte, de manière simple et fiable même lorsque l'urgence est élevée.
PCT/JP2017/027526 2017-07-28 2017-07-28 Agent de traitement prophylactique ou thérapeutique pour symptôme allergique Ceased WO2019021476A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001508037A (ja) * 1996-10-18 2001-06-19 ビロテックス コーポレイション 粘膜表面への、薬学的化合物の送達に適する薬学的キャリアデバイス
JP2006518761A (ja) * 2003-02-24 2006-08-17 ファーマシューティカル プロダクションズ， インコーポレイテッド 経粘膜薬物送達システム
JP2011506337A (ja) * 2007-12-07 2011-03-03 シェーリング−プラウ ヘルスケア プロダクツ，インコーポレイテッド 経粘膜吸収のためのフェニレフリンの医薬調合物および医薬組成物
WO2017135195A1 (fr) * 2016-02-03 2017-08-10 社会医療法人蘇西厚生会 まつなみリサーチパーク Préparation pour la prévention ou le traitement de symptômes allergiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001508037A (ja) * 1996-10-18 2001-06-19 ビロテックス コーポレイション 粘膜表面への、薬学的化合物の送達に適する薬学的キャリアデバイス
JP2006518761A (ja) * 2003-02-24 2006-08-17 ファーマシューティカル プロダクションズ， インコーポレイテッド 経粘膜薬物送達システム
JP2011506337A (ja) * 2007-12-07 2011-03-03 シェーリング−プラウ ヘルスケア プロダクツ，インコーポレイテッド 経粘膜吸収のためのフェニレフリンの医薬調合物および医薬組成物
WO2017135195A1 (fr) * 2016-02-03 2017-08-10 社会医療法人蘇西厚生会 まつなみリサーチパーク Préparation pour la prévention ou le traitement de symptômes allergiques

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Title
ALAYOUBI,A. ET AL.: "Development of a fast dissolving film of epinephrine hydrochloride as a potential anaphylactic treatment for pediatrics", PHARM. DEV. TECHNOL., 6 January 2016 (2016-01-06), pages 1 - 5, ISSN: 1097-9867, Retrieved from the Internet <URL:http://dx.doi.org/10.3109/10837450.2015.1131715> *
BUANZ, A. B. ET AL.: "Preparation of personalized-dose salbutamol sulphate oral films with thermal ink-jet printing", PHARM. RES., vol. 28, no. 10, October 2011 (2011-10-01), pages 2386 - 92, XP019950368, ISSN: 1573-904X, DOI: 10.1007/s11095-011-0450-5 *
JACHID, 0. ET AL.: "Epinephrine (adrenaline) absorption from new-generation, taste-masked sublingual tablets:a preclinical study", J. ALLERGY CLIN. IMMUNOL., vol. 131, no. 1, January 2013 (2013-01-01), pages 236 - 8, ISSN: 0091-6749 *
KUMAR, S. V. ET AL.: "Overview of fast dissolving films", INT. J. PHARM. PHARM. SCI., vol. 2, no. 3, July 2010 (2010-07-01), pages 29 - 33, ISSN: 0975-1491 *
SAYED, S. ET AL.: "Fast-dissolving sublingual films of terbutaline sulfate: formulation and in vitro/in vivo evaluation", MOL. PHARM., vol. 10, no. 8, 5 August 2013 (2013-08-05), pages 2942 - 7, XP055404711, ISSN: 1543-8392, DOI: 10.1021/mp4000713 *

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