JP2019112335A - Determination method of proper amount treatment in transdermal immune therapy and determination kit development - Google Patents

Abstract

To provide an allergen containing composition which causes less burden to a patient and achieves an effective immune therapy, an allergen use method, and in a determination method of an allergen treatment proper amount in a transdermal immune therapy.SOLUTION: There is provided an allergen containing composition for allergen disease treatment which is intradermally inoculated, an inoculation amount of the allergen containing composition for treatment is determined prior to start of treatment for every inoculation object having an allergy disease, based on a maximum intradermally tolerated dose of the allergy. By combination of a skin prick test and an intradermal test, a treatment proper amount (maximum intradermally tolerated dose) of the allergy in transdermal immune therapy is determined.SELECTED DRAWING: None

Description

  Disclosed are techniques related to allergen-containing compositions for the treatment of allergic diseases, which are intradermally inoculated, and methods of using the allergens.

  As a method for treating allergic diseases, a low dose allergen intradermal injection method and a induced neutralization method have been proposed, in which the patient is repeatedly inoculated with the allergen of the allergic disease suffering from the patient at a low dose.

  As for low-dose allergen intradermal injection, in the group inoculated with 7 ng of major grass allergen and 6 times every 2 weeks, delayed skin reaction (around 24 hours after injection around the inoculation site) compared to the control group It was reported that improvement in redness, swelling, edema and hardening was observed (Non-patent Document 1), and a large-scale clinical trial protocol was announced as PollenLITE (Non-patent document 2). However, it was subsequently reported in Non-Patent Document 3 that low-dose allergen intradermal injection was not effective for systemic symptoms of allergic symptoms.

  Although the induction neutralization method inoculates an allergen in a subcutaneous or intradermal neutralization dose (an amount capable of expanding 2 mm in 10 minutes and 7-8 mm wheal), the induction neutralization method is scientific in Non Patent Literature 4 It is concluded that it lacks effectiveness.

  On the other hand, combining the Prick test and the intradermal test to determine the maximum intradermal tolerated dose (MITD) of each patient's allergen, the MITD allergen is induced daily by the patient to inject himself subcutaneously. The law has been reported (Non-patent Document 5). In Non-Patent Document 5, a second inoculation period (2 weeks) after determining MITD, and a two-week washout period after completion of the first inoculation period, the second inoculation period ( It is described that the symptoms of nasal inflammation etc. were improved by providing 2 weeks.

Rotiroti G, et al, J ALLERGY CLIN IMMUNOL, 2012, Vol 130, No. 4, p918-924, p924e1 Slovick A, et al. Clinical and Translational Allergy, 2013, 3:27, p1 to 14 Slovick A, et al. Journal of Allergy and Clinical Immunology, 2016, doi: 10.1016 / j.jaci.2016.09.024 Jewett DL, et al. The New England Journal of Medicine, 1990, vol. 323, No 7, p429-433 Radcliffe MJ, et al. J Invest Allergol Clin Immunol, July-August 1996; Vo1. 6 (4): 242-247

  The induced neutralization method described in Non-Patent Document 5 raises a certain therapeutic effect on allergic symptoms such as rhinitis by daily inoculation of a low dose of an allergen subcutaneously.

  However, daily subcutaneous injections by patients are a burden for patients, especially pediatric patients. In addition, it is possible to reduce the number of inoculations by the induction neutralization method described in Non-Patent Document 5. However, according to the inventor's investigation, it is found that inoculation is necessary every day at least at the beginning of treatment, and it is necessary to extend inoculation intervals every other day every two days, according to the inventor's investigation. ing.

  Therefore, there is a need to provide allergen-containing compositions and methods of using allergens that are less burdensome to patients and can be effective immunotherapy.

The inventor of the present invention conducted intensive studies and found that the induction described in Non-Patent Document 5 is caused by intradermal inoculation of MITD allergen determined for each inoculation subject by combining skin prick test and intradermal test. It has been found that the number of inoculations is smaller and a higher therapeutic effect can be obtained than the neutralization method. That is, MITD was found to be a therapeutic dose in transdermal immunotherapy.
The present invention has been completed based on the above findings, and includes the following aspects.
Item 1.
An allergen-containing composition for treating allergic diseases, which is intradermally inoculated, comprising:
A composition, wherein the inoculum size of the therapeutic allergen-containing composition is determined prior to the start of treatment for each inoculated subject having an allergic disease, from the maximum intradermally tolerated dose of the allergen.
Item 2.
The item according to item 1, wherein the maximum intradermal tolerance is determined by a skin prick test step including the following step A, and an intradermal test step including the steps B to D and E1 or the steps B to D and E2. Composition;
Step A: A skin prick test using the same allergen as the allergen contained in the therapeutic allergen-containing composition is performed on the inoculated subject, and the threshold amount of the inoculated allergen on the basis of the prick test skin immune response ( Determining a prick test threshold amount);
Step B: determining the inoculum size of the allergen at the start of the intradermal test (the intradermal test start amount) based on the prick test threshold amount,
Step C: Intradermal test starting amount of allergen is inoculated to the first intradermal site to be inoculated, and a predetermined time after inoculation of the allergen in step C, the presence or absence of an intradermal test skin immune response at the inoculation site is determined The process to
Step D: In step C, when it is determined that the intradermal test skin immune reaction is positive, a site different from the first intradermal site of the inoculation target is a smaller amount of the allergen than the intradermal test start amount. After the inoculation of the allergen and a predetermined time after inoculation of the allergen, determining the presence or absence of an intradermal test skin immune response at the site of inoculation, and Step E1: in step D, the intradermal test skin immune response is negative If it is determined, the inoculum size of the allergen in step D is determined as the maximum intradermal tolerance, or step E2: if it is determined in step D that the intradermal test skin immune response is positive. From the inoculation of an intradermal site which has not yet been inoculated with the allergen to which the allergen has been inoculated, in an amount smaller than that of the most recent inoculation, and from the inoculation of this allergen After a predetermined time, it is repeated to determine the presence or absence of the intradermal test skin immune response at the inoculation site until the amount of allergen determined to be negative as the intradermal test skin immune response, the intradermal test skin immune response Determining the amount of the allergen inoculated when it was determined to be negative as the maximum intradermal tolerance amount.
Item 3.
In the item 2, the step D further includes the step of determining the amount of the allergen of the intradermal test starting amount as the maximum intradermal tolerance amount when it is determined in the step C that the intradermal test skin immune response is negative. Composition as described.
Item 4.
Item 4. The composition according to Item 2 or 3, wherein the index for determining the presence or absence of the prick test skin immune response and the intradermal test skin immune response is wheal associated with an inflammatory response.
Item 5.
Item 4. The composition according to any one of Items 2 to 4, wherein the predetermined time is 8 to 20 minutes.
Item 6.
Item 4. The composition according to any one of Items 2 to 4, wherein the predetermined time is 10 to 15 minutes.
Item 7.
Item 7. A kit for treating an allergic disease used for intradermal inoculation, which comprises the combination of the composition for treating an allergic disease to be inoculated intradermally according to any one of items 1 to 6 and a skin puncture device.
Item 8.
The kit used for determining the largest intradermal tolerance amount in any one of claim | item 1-6 which combines an allergen containing composition and a skin puncture apparatus.
Item 9.
A method of using an allergen to determine maximal intradermally tolerated dose,
The maximum intradermal tolerance is determined prior to the start of treatment for each inoculum having an allergic disease, in order to determine the inoculum size of the allergen-containing composition for treating allergic diseases containing an allergen similar to the allergen. The method of use, wherein the therapeutic allergen-containing composition is inoculated into intradermal inoculation.
Item 10.
10. The maximum intradermal tolerance amount is determined by a method including a skin prick test step including the following step A, and an intradermal test step including the steps B to D and E1 or the steps B to D and E2. Method;
Step A: A skin prick test using the same allergen as the allergen contained in the therapeutic allergen-containing composition is performed on the inoculated subject, and the threshold amount of the inoculated allergen on the basis of the prick test skin immune response ( Determining a prick test threshold amount);
Step B: determining the inoculum size of the allergen at the start of the intradermal test (the intradermal test start amount) based on the prick test threshold amount,
Step C: Intradermal test starting amount of allergen is inoculated to the first intradermal site to be inoculated, and a predetermined time after inoculation of the allergen in step C, the presence or absence of an intradermal test skin immune response at the inoculation site is determined The process to
Step D: In step C, when it is determined that the intradermal test skin immune reaction is positive, a site different from the first intradermal site of the inoculation target is a smaller amount of the allergen than the intradermal test start amount. After the inoculation of the allergen and a predetermined time after inoculation of the allergen, determining the presence or absence of an intradermal test skin immune response at the site of inoculation, and Step E1: in step D, the intradermal test skin immune response is negative If it is determined, the inoculum size of the allergen in step D is determined as the maximum intradermal tolerance, or step E2: if it is determined in step D that the intradermal test skin immune response is positive. From the inoculation of an intradermal site which has not yet been inoculated with the allergen to which the allergen has been inoculated, in an amount smaller than that of the most recent inoculation, and from the inoculation of this allergen After a predetermined time, it is repeated to determine the presence or absence of an intradermal test skin immune response at the inoculation site until the amount of the allergen determined to be negative for the intradermal test skin immune response is found, the intradermal test skin Determining the amount of the allergen inoculated when it is determined that the immune reaction is negative as the maximum intradermal tolerance amount.
Item 11.
An allergen composition for determining the maximum intradermally tolerated dose,
The maximum intradermal tolerance is determined prior to the start of treatment for each inoculum having an allergic disease, in order to determine the inoculum size of the allergen-containing composition for treating allergic diseases containing an allergen similar to the allergen. A composition wherein the therapeutic allergen-containing composition is inoculated for intradermal inoculation.

  The burden on patients is less and effective immunotherapy can be performed.

It is the schematic of the determination method of MITD. It is the schematic of subcutaneous inoculation and intradermal inoculation. It is a graph which shows the relationship between SPT threshold value and MITD. The horizontal axis shows the dilution factor from the SPT threshold allergen concentration. The vertical axis represents%. It shows the change of SPT threshold after the induction neutralization immunotherapy (subcutaneous inoculation) is performed.

1. Allergen-Containing Composition for Treating Allergic Disease The composition contains an allergen.
The allergen is not limited as long as it is a substance that causes allergic diseases (including allergic symptoms) in mammals (humans, dogs, cats, monkeys and the like, preferably human, dogs and cats and the like, more preferably human) . For example, pollen such as mugwort, timothy, red pine, akinokirin grass, cannagra, chrysanthemum, black pine, cedar, cypress, cypress, hiragana, ragweed and spinach; Corn, glutinous rice, eddies, cabbage, sesame, shiitake, potato, bamboo shoot, onion, tomato, carrot, spinach, peanut, almond, apple, yeast, cocoa, chocolate, soy, milk, egg, egg yolk, egg white, horse mackerel , Sardines, bonito, flounder, kiss, salmon, salmon, saury, cod, flounder, yellowtail, tuna, clams, shrimp, oysters, crabs, octopus, and clams; chopsticks, rice straw, silk, house Dust, rice husk, dust such as cotton; Animal hair such as dog, cat and rabbit; In Avian feathers such as chicken and duck; fungi such as alternaria, Aspergillus, candida, cladosporium, and penicillium; compounds represented by the following general formula (I): skin prick test or intradermal test Or a salt of a compound represented by the above general formula (I) (chlorine, sodium, potassium, calcium, etc.) which can be prepared as an aqueous solution necessary for
[Wherein, R ¹ represents a linear or branched alkyl group having 1 to 6 carbon atoms; an alkoxycarbonyl group (the alkyl group is a linear or branched chain having 1 to 6 carbon atoms), or an aryloxycarbonyl group; Compounds represented by the general formula (II):
(R ⁵ is a linear or branched alkyl group having 8 to 18 carbon atoms, preferably a linear alkyl group having 8 to 18 carbon atoms),
It is selected from
At least one of R ² , R ³ and R ⁴ is selected from a hydroxyl group and —N = C = O, and the other is a hydrogen atom. ];
The compound represented by the following general formula (III):
(R ⁶ represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, and a saturated or unsaturated ring having 5 to 6 carbon atoms (preferably an unsaturated ring), which constitutes a ring One or two of the carbons selected are selected from an oxygen atom, a nitrogen atom or a ring optionally substituted with a sulfur atom).
Or compounds, such as tobacco smoke, etc. can be mentioned.

  The compounds represented by the above general formula (I) include p-hydroxybenzoic acid ester compounds such as methylparaben, ethylparaben, propylparaben, isopropylparaben, butylparaben, isobutylparaben, and benzylparaben, benzalkonium chloride, toluene, and Toluene isocyanate etc. are contained.

  The compounds represented by the general formula (III) include formaldehyde, furfural and the like.

  These allergens may be contained in the composition as an extract. In addition, an allergen that is not water soluble may be once dissolved in an ambipolar solvent that can be used in the human body such as ethanol, and then diluted with physiological saline.

  Hereinafter, in the present specification, unless otherwise specified, the allergen includes the allergen itself and / or the allergen extract.

  The composition may contain, in addition to the allergen, a solvent such as water, saline or buffer. The composition may also contain at least one selected from pH adjusters, preservatives (such as phenol), salts such as sodium chloride, and glycerin, as necessary.

  The composition is provided in the form of powder of an allergen, and if necessary, a solvent such as water, saline or a buffer (if necessary, a pH adjuster, a preservative such as phenol, a salt such as sodium chloride, And glycerin and the like, and may be used by dissolving in at least one of them.

  The composition may be, for example, a commercially available allergen extract sold by Torii Pharmaceutical Co., Ltd. or the like.

  Preferably, the composition is used to treat an allergic disease (including allergic symptoms) occurring in the mammalian body due to the allergen contained therein. Here, the use for treating includes suppressing the onset of symptoms of allergic disease, reducing the symptoms, not aggravating the symptoms, and / or preventing the recurrence.

  Allergic diseases include diseases caused by allergens or diseases with symptoms caused by allergens. Preferably, the allergic disease is a disease caused by an allergic reaction to an allergen or a disease accompanied by a symptom caused by an allergic reaction to an allergen. As allergic diseases, for example, dermatitis; hay fever (including allergic conjunctivitis, allergic rhinitis); rhinitis; asthma; hypersensitivity to olfactory sensation; unsteady complaints (stiff neck, headache, migraine, myalgia, fatigue, fatigue, fatigue, tinnitus, Irritability, including abdominal pain, etc.) Nervous system / psychosomatic medicine related diseases (including developmental disorders such as attention deficit hyperactivity disorder, memory loss such as loss of familiar numbers and names etc., personality change etc.), urinary system Diseases (including nocturnal enuresis, etc.); and gynecological diseases (including menstrual pain, chocolate cysts, etc.) and the like.

  The target for inoculation of the composition is the above-mentioned mammal, preferably a human, a dog, a cat and the like, more preferably a human.

  The composition is capable of subcutaneous inoculation or intradermal inoculation (including intradermal inoculation), preferably intradermal inoculation.

  The inoculum size of the composition is determined based on the dose of allergen suitable for treatment. Preferably, the inoculum size of the composition is determined from the maximum intradermally tolerated dose (MITD) of the allergen.

  The MITD is determined for each inoculation subject prior to the start of treatment according to the following method.

  The MITD is determined by a method including a skin prick test step including the following step A and an intradermal test step including the steps BD and E1 or steps BD and E2.

  Step A corresponds to the step of “Prick test” shown in FIG. 1 and was carried out on the aforementioned inoculum subject by skin prick test (SPT) using an allergen similar to the allergen contained in the composition. For allergens, the threshold amount (prick test threshold amount) is determined based on the prick test skin immune response. The prick test can be performed according to known methods. The index of the prick test skin immune response is not limited as long as it is a finding showing an inflammatory response. For example, it is preferred that it is a whell associated with an inflammatory reaction, and in particular a wander with redness. In the skin prick test, an allergen solution of a predetermined concentration is dropped on the skin, and a puncture site is confirmed 10 to 15 minutes after the needle is pierced at the dropping site, and the size of wheal with redness is measured. The major axis x minor axis of wheal with redness is about 4 mm x 4 mm is the threshold value of the skin prick test, and in the skin prick test, an allergen that forms a wheal with major axis x minor axis of about 4 mm x 4 mm under the above conditions The amount is the prick test threshold amount. The amount of allergen in the skin prick test is represented by a concentration such as AU / mL, JAU / mL, or dilution rate. AU / mL is an allergen activity unit (Allergy Units / mL) set by the Food and Drug Administration (FDA) based on skin tests of allergic patients. Products of comparable titer relative to FDA's allergen standard (10,000 AU / mL) are displayed as 10,000 AU / mL. JAU / mL is a Japanese Allergy Active Unit (Japanese Allergy Units) set by the Japanese Society of Allergy Society based on skin tests of allergic patients. 100,000 JAU / mL corresponds to 10,000 AU / mL.

  Step B corresponds to the step of “intradermal test 1” shown in FIG. 1 and determines the inoculum size of the allergen at the start of the intradermal test (intradermal test start amount) based on the prick test threshold amount. First, an allergen solution containing a prick test threshold amount of allergen is inoculated intradermally at a volume that causes a wheal of about 2 mm × 2 mm at the time of inoculation. Preferably, the inoculation is performed at an intradermal site not inoculated with an allergen solution in a skin prick test. The wheal is a wheal that is physically formed due to the allergen solution entering the skin, and it is a wheal without redness, preferably without an inflammatory response. For example, a volume in which a 2 mm × 2 mm blister can be made is about 0.01 mL.

  After inoculation of an allergen solution containing a prick test threshold amount of allergen, observation of the inoculation site is performed after a predetermined time has elapsed. The index of the intradermal test skin immune response is not limited as long as it is a finding showing an inflammatory response. For example, it is preferred that it is a whell associated with an inflammatory reaction, and in particular a wander with redness. The major axis and minor axis of the wheal with redness are measured, and when the major axis × minor axis is within 9 mm × 9 mm, it can be determined that the prick test threshold amount is in the safe region. When it is determined that the prick test threshold amount is in the safe region, the intradermal test start amount is about 1/4 to 1/6, preferably 1⁄5 of the allergen amount of the prick test threshold amount. As in the case of the prick test, the amount of allergen is represented by a concentration such as AU / mL, JAU / mL, or dilution rate.

  The predetermined time is about 8 to 20 minutes, preferably about 10 to 15 minutes, and preferably about 10 minutes.

  If the major axis x minor axis of a wheal with flares at the site inoculated with an allergen solution containing a Prick test threshold amount of allergen is larger than 9 mm x 9 mm, further skin prick using an allergen solution thinner than the Prick Test threshold amount Tests were conducted, and an allergen solution containing an allergen in an amount region of the allergen that is negative in the intradermal prick test (long diameter x short diameter of wheal with redness x less than 4 mm, preferably 3 mm x 3 mm or less) is different from the above Inoculate the intradermal site, search for the amount of allergen that makes the major axis x minor axis of the wheal with redness 9 mm x 9 mm or less, and determine the intradermal test start amount in the same manner as above.

  Step C corresponds to “Intradermal test 2” shown in FIG. 1, and an intradermal test starting amount of allergen is inoculated to the first intradermal site to be inoculated, and the intradermal test skin immune response to the intradermal test site is performed. Determine the presence or absence of First, an allergen solution containing an intradermal test starting amount of allergen is inoculated intradermally at a volume that causes a wheal of about 7 mm × 7 mm at the time of inoculation. The wheal is a wheal that is physically formed due to the allergen solution entering the skin, and it is a wheal without redness, preferably without an inflammatory response. The volume that can cause a wheal of about 7 mm × 7 mm is, for example, about 0.05 mL.

  After inoculation of an allergen solution containing an intradermal test starting amount of allergen, observation of the inoculation site is performed after a predetermined time has elapsed. The predetermined time is about 8 to 20 minutes, preferably about 10 to 15 minutes, and preferably about 15 minutes. The index of the intradermal test skin immune response is not limited as long as it is a finding showing an inflammatory response. For example, it is preferred that it is a whell associated with an inflammatory reaction, and in particular a wander with redness. It is determined that the intradermal test skin immune response is negative if no eruption with redness is observed (or the eruption may be flattened or enlarged without redness) in the observation of the inoculation site be able to. Therefore, it is determined that the intradermal test start amount is MITD.

  On the other hand, if a wheal with redness is observed in the observation of the inoculation site after a predetermined time has elapsed since the allergen solution containing the allergen in the intradermal test start amount has been inoculated, the intradermal test skin immune reaction is positive. It is determined that there is, and the process proceeds to step D.

  The method of determining the presence or absence of the intradermal test skin immune response is the same in the following steps.

  Step D corresponds to “intradermal test 3” shown in FIG. 1, and in step C, when it is determined that the intradermal test skin immune response is positive, an amount of allergen smaller than the intradermal test start amount. Is inoculated at a site different from the first intradermal site to be inoculated, and the presence or absence of an intradermal test skin immune response at the site of inoculation is determined. The site different from the first intradermal site is also different from the site where the skin prick test was performed and the site where the prick test threshold amount of allergen was inoculated.

  As the amount of allergen less than the intradermal test starting amount, the intradermal inoculation of the allergen solution diluted more than the allergen solution containing the intradermal testing starting amount of allergen is done intradermally in a volume that causes a wheal of about 7 mm × 7 mm at the time of inoculation . The wheal is a wheal that is physically formed due to the allergen solution entering the skin, and it is a wheal without redness, preferably without an inflammatory response. The volume that can cause a wheal of about 7 mm × 7 mm is, for example, about 0.05 mL. The allergen solution diluted than the intradermal test starting amount is diluted with the saline solution etc. about twice to 10 times, preferably about 3 to 7 times, more preferably about 5 times the allergen solution of the intradermal test starting amount It can be prepared by

  After a predetermined time has elapsed since the allergen solution diluted with the intradermal test starting amount is inoculated, observation of the intradermal site inoculated with the allergen solution in this step is performed. The predetermined time is about 8 to 20 minutes, preferably about 10 to 15 minutes, and preferably about 15 minutes. If it is determined in the observation that the intradermal test skin immune response is negative, in step E1, the amount of allergen inoculated in step D is determined to be MITD.

  In the observation in step D, when it is determined that the intradermal test skin immune response is positive, the process proceeds to step E2.

  Step E2 is a step corresponding to “intradermal test 4” or later shown in FIG. 1, and in the observation in step D, when the intradermal test skin immune reaction is positive, it is more than the amount inoculated immediately before. Inoculating an even smaller amount of an allergen to the intradermal site which has not been inoculated with the allergen to be inoculated and determining the presence or absence of an intradermal test skin immune response at the site of inoculation after a predetermined time, And repeating the test until it is determined that the intradermal test skin immune response is negative.

  As an amount of allergen smaller than the amount inoculated immediately before the allergen solution, the allergen solution further diluted than the allergen solution inoculated immediately before is inoculated intradermally in a volume that causes a wheal of about 7 mm × 7 mm at the time of inoculation. The wheal is a wheal that is physically formed due to the allergen solution entering the skin, and it is a wheal without redness, preferably without an inflammatory response. The volume that can cause a wheal of about 7 mm × 7 mm is, for example, about 0.05 mL. The allergen solution diluted more than the amount of allergen inoculated immediately before is about 2 times to 10 times, preferably about 3 times to 7 times, more preferably about 5 times more preferably the allergen solution containing the amount of allergen inoculated most recently It can be prepared by dilution with saline or the like.

  After inoculation of an allergen solution diluted further than the most recently inoculated allergen solution, after a predetermined time has elapsed, the presence or absence of an intradermal test skin immune response at the inoculation site is confirmed. The predetermined time is about 8 to 20 minutes, preferably about 10 to 15 minutes, and preferably about 15 minutes.

  If the intradermal test skin immune reaction is positive, the presence or absence of the intradermal test skin immunity against the inoculation site of the allergen solution containing the allergen in an amount smaller than the amount of the allergen inoculated most recently and which was further diluted Repeat the above determination to determine the amount of allergen that makes the skin test skin immune reaction negative. Then, the amount of the allergen in which the intradermal test skin immune response is negative is determined to be MITD.

  In the step D or E2, when the allergen solution containing a smaller amount of the allergen further diluted than the amount of the allergen inoculated last time is inoculated, the above-mentioned last inoculation of the allergen or further inoculation of the last allergen solution It may be possible that the wheal with flares formed during the previous inoculation of the allergen solution disappears. In this case, the amount of allergen inoculated at the end may be determined as MITD.

  An intradermal test intradermal reaction skin immune response at the intradermal site inoculated last when the allergen solution containing a small amount of allergen further diluted than the amount of the allergen inoculated last in step D or E2 is inoculated Despite being negative, wheal with a redness formed during inoculation of the last allergen solution or during inoculation of the allergen solution which took place even before the last inoculation of the allergen solution It may be aggravated (extensive redness, increased pruritus, etc.). In this case, it may be determined that the amount of the allergen inoculated last is not MITD. In such a case, the day may be re-determined to determine MITD.

  Inoculation of the allergen solution in the intradermal test can be performed using a substrate (for example, a tuberculin reaction test syringe etc.) used for normal subcutaneous injection.

  Although the determination of MITD is performed prior to the start of treatment, the start of treatment is the start of individual-specific low dose transdermal immunotherapy described below, preferably the start of one course of individual-specific low dose transdermal immunotherapy .

  The inoculum size of the composition is determined from the amount of allergen contained in the composition and the amount of allergen in MITD so that the amount of allergen in MITD is inoculated in a single inoculation.

  The allergen solution used to determine MITD is preferably the composition itself or an allergen solution prepared by diluting the composition or the like.

2. Method of Using Allergen-Allergen Composition for MITD Determination An allergen is used to determine MITD. The MITD is determined to calculate the inoculum size of the allergen-containing composition for treating allergic diseases, which contains an allergen similar to the allergen. The MITD is determined prior to the start of treatment for each inoculated subject with allergic disease (including allergic symptoms).

  The allergen-containing composition for treating allergic diseases is as described in 1. above. It is included in the composition mentioned above. Also, the above 1. The compositions mentioned under are used to determine MITD.

  Allergen, allergic disease, target of inoculation, start of treatment, method of determining MITD, and method of determining inoculum size of composition, etc. For terms that overlap with the above, the above 1. The description of is incorporated herein by reference.

  The allergen solution used to determine MITD may preferably be the composition itself or an allergen solution prepared by diluting the composition or the like.

3. Kit The kit comprises at least the composition as described in 1 above and a lancing device. Preferably, the composition and the puncture device are combined. The combination of the composition and the puncture device is

Here, “combing” means that the sensitizer targeted by the present invention is
(I) when the composition is initially loaded into the puncture device, or (i) when the puncture device is in the state of being impregnated with the composition,
(Ii) if the composition and the lancing device are present in separate packaging forms and sold as a combination, or (iii) the composition and the lancing device are in separate packaging forms and also separate distribution channels In the market, and is used in the sense that it includes cases where it is used in combination at the time of use.

  The kit is preferably used for the treatment of allergic diseases. More preferably, the kit is a kit for use in intradermal inoculation. Also, the kit is used to determine MITD in 1 and 2 above.

  The puncture device can be loaded or impregnated with the composition and the intradermal inoculation is not limited as much as possible. The puncture device may include, for example, a syringe (a needle having a thickness suitable for intradermal inoculation, for example, a syringe with a needle of about 26 to 28 G and a syringe), a microneedle patch, a tube needle for BCG inoculation, etc. .

  The kit includes, in addition to the composition and the puncture device, an instruction manual, a determination method of MITD, a bioffered needle for skin prick test, water for diluting the composition, saline, buffer solution, etc. It may be equipped with a solvent (including at least one selected from pH adjusters, preservatives such as phenol, salts such as sodium chloride, and glycerin etc., if necessary).

4. Inoculum-Specific Low-Dose Transdermal Immunotherapy The composition is inoculated intradermally, with the inoculum size of the allergen determined for each inoculum.

  The inoculum size of the composition is determined prior to the start of treatment from MITD according to the method described in 1 above.

  The treatment is carried out by inoculating a subject to be inoculated with the composition according to the following schedule.

  For example, in the course of treatment, one course is taken from the start of the first inoculation period to the end of the second inoculation period described next. The treatment is initiated within 0 to 2 weeks, preferably within 1 to 5 days, of determining MITD. The composition is inoculated, for example 1 to 3 times a week, preferably twice a week, for 3 to 5 weeks, preferably 4 weeks, at a single inoculation dose determined from MITD (first inoculation period). The end of the first vaccination period is about one week after the last vaccination within the first vaccination period. At the end of the first vaccination period, preferably without vaccination for about 1 to 7 days, the same composition (or a composition containing the same allergen as the allergen inoculated in the first vaccination period) was inoculated again in the first vaccination period At the same single dose, for example 1 to 3 times a week, preferably twice a week, 3 to 5 weeks, preferably 4 weeks (the second inoculation period). The end of the second vaccination period is about one week after the last vaccination within the second vaccination period.

  The treatment period may be repeated, for example, twice or more. Between cool and cool, there may be about 0 to 2 weeks.

  The inoculum size of the composition may be the same in a plurality of courses, but preferably MITD is determined again every course or every 2 to 4 courses, and the inoculum size of the composition may be calculated.

  EXAMPLES The present invention will be specifically described below using examples, but the present invention is not construed as being limited to the examples.

1. Treatment Protocol The prick test (SPT) and the intradermal test were combined to determine the maximum intradermal tolerated dose (MITD) of each patient (Figure 1). MITD measurements were made after obtaining written informed consent for each patient after obtaining approval from the Nabari City Hospital Ethics Committee and obtaining consent.

  First, SPT was performed using the allergen of the allergy that the patient suffers from. A diluted allergen aqueous solution was prepared by diluting an aqueous solution containing an allergen (Torii Pharmaceutical Standardized Allergen Extract Subcutaneous injection “sugi pollen” cedar pollen extract 200 JAU / ml for treatment) with sterile saline in a five-fold step-by-step manner. It was dropped on the crotch side, and the skin at the dropping site was punctured with a bayer caited needle. After 15 minutes, the size of the wheal (major axis x minor axis) was measured, and the SPT threshold amount (allergen concentration at which the size of the wheal was about 4 mm x 4 mm) was determined. SPT was performed according to the usage of the cedar antigen extract provided by Torii.

  Next, a dilution series of an aqueous allergen solution was prepared, in which an allergen concentration of 1⁄5 of the SPT threshold amount was used as an intradermal test start amount (concentration), and each five-fold dilution was made from the intradermal test start concentration. At first, an allergen aqueous solution with an SPT threshold amount of 0.01 ml (about 2 mm × 2 mm blistering at the inoculation site) was intradermally inoculated on the outer arm of the arm opposite to the arm on which the patient SPT was performed (FIG. 1 "Intradermal test 1"). The wheal that occurs when the allergen aqueous solution is inoculated is not due to an inflammatory reaction without flare. After 10 minutes after inoculation, it was confirmed that a wheal with redness was present, and if the size was about 9 mm × 9 mm or less, it was judged as a safe area, and 0.05 ml of the allergen aqueous solution at the starting concentration for intradermal test The site was inoculated at a position slightly away from the above intradermal inoculation site (the extent that approximately 7 mm × 7 mm of wheal could be produced) (“Intradermal test 2” in FIG. 1). The wheal that occurs when the allergen aqueous solution is inoculated is not due to an inflammatory reaction without flare. Wheal was confirmed 15 minutes after inoculation of the allergen aqueous solution at the intradermal test starting concentration. It was determined that the skin immune response in the intradermal test was negative if no flare occurred at the inoculation site, and the concentration of the allergen aqueous solution at the time of inoculation was determined as MITD. If a blistering accompanied by a reddening appears at the inoculation site, an allergen aqueous solution of 1/5 concentration of the allergen aqueous solution inoculated immediately before and a site slightly away from the site of the last inoculation and which has not received the intradermal inoculation of the allergen yet Were inoculated (after “Intradermal test 3” in FIG. 1). It was confirmed 15 minutes after this inoculation whether a wheal with a flare occurred at this inoculation site. When wheal disappeared, the concentration of the aqueous allergen solution was determined as MITD. When disappearance of wheal did not occur, MITD was determined by repeating the inoculation of an allergen aqueous solution of 1/5 concentration of the allergen aqueous solution inoculated immediately and the occurrence of a wheal with a flare at this inoculation site.

  When the above-mentioned SPT threshold amount allergen is inoculated intradermally, if the major axis of wheal exceeds about 9 mm, it is judged not to be a safe region, and 0.01 ml of the allergen aqueous solution diluted with SPT threshold amount The site was inoculated intradermally to a size of about 2 mm x 2 mm) and the allergen concentration of 1/5 of the concentration at which the major axis of the wheal was within about 9 mm was taken as the intradermal test start concentration.

2. Relationship between SPT threshold and MITD Children who visited Nabari municipal hospital from 2010 to 2012, who have at least one of rhinitis due to cedar pollinosis, dermatitis, and asthma I examined whether it was one-half. The results are shown in FIG.

  As a result, those who have MITD 1/5 concentration of SPT threshold are 6.7%, those who are 1/25 concentration are 28.9%, those who are 1/125 concentration are 42.2%, 1/625 concentration It was revealed that 20.0% of the subjects and 2.2% of the subjects who had the 1/3125 concentration, MITD varied depending on the individual, and could not be generally predicted from the SPT threshold. Therefore, it was considered necessary to determine MITD for each individual receiving anti-allergy treatment.

3. Individual-Specific Low-Dose Transdermal Immunotherapy (1) Evaluation of Therapeutic Effect in Pollen Scattering Period The above aqueous allergen solution was used to measure MITD for 4 adult patients with Japanese cedar pollinosis. The wheal area in the wheal area was measured at the time of MITD measurement. One week after the measurement of MITD, MITD amount of cedar allergen was intradermally inoculated twice weekly for 4 weeks. At the end of 4 weeks of inoculation, cedar allergens in the same amount as whealles-inducing area before the start of treatment were inoculated, and the expansion rate of wheal area was calculated. Furthermore, one day after the end of the last 4 weeks of inoculation, MITD amount of cedar allergen was intradermally inoculated twice weekly for 4 weeks (8 weeks from the start of administration). We inoculated the cedar allergen in the same amount as the previous wheal challenge area and calculated the expansion rate of the wheal area. In addition, a comparative Visual analog scale (VAS) of symptoms of cedar pollinosis was performed in the previous year.

  As a result, as shown in Table 1, four weeks after the start of the treatment, a decrease in the area of wheal was observed in all four patients. However, eight weeks after treatment, half of the patients showed a decrease in the area of wheal and those with a slightly larger area than before the treatment. On the other hand, with regard to hay fever symptoms, all patients showed improvement over the previous year, and a high therapeutic effect was observed. From this, it was considered that the inoculation of an MITD allergen was effective for the improvement of allergic symptoms. However, it became clear that this therapeutic effect does not necessarily correlate with wheal symptoms caused by the intradermal inoculation of allergens in the wheal area.

(2) Evaluation of therapeutic effects in pollen disc induction findings. For two patients different from the patients treated in (1), the treatment effect was evaluated by the provocation test of allergic symptoms by pollen disc during the pollen non-scattering period. One week after the measurement of MITD on April 28, 2014 before the start of treatment and the measurement of MITD in which the pollen disk was tested for induction, MITD amount of cedar allergen was intradermally inoculated twice weekly for 4 weeks did. On May 25, 2016, another challenge was conducted using a pollen disk. From 0 to 4 days after the last induction test, MITD amount of cedar allergen was inoculated twice weekly for 4 weeks (8 weeks from the start of administration) intradermally. At the end of the inoculation, on June 30, 2016, the provocation test was performed again using a pollen disc. The induction test of allergic symptoms using pollen disc and its evaluation were conducted according to "Nasal allergy guideline 2013 Pollin disc induction findings type and degree".

As a result, as shown in Table 2, the symptom of nasal inflammation induced by the pollen disk was improved about one month after the start of the treatment for both patients. Two months after the initiation of the treatment, the symptoms of nasal inflammation induced further decreased.
From the above results, individual-specific low-dose transdermal immunotherapy was considered to be useful for amelioration of allergic symptoms.

4. Reference Example (Subcutaneous administration of allergen)
Above 2. In 22 out of 45 patients who examined the relationship between SPT threshold and MITD in the above, MITD amount of allergen was inoculated subcutaneously, and induced neutralization immunotherapy was performed for 3 to 12 months, and changes in SPT threshold were observed. As a result, as shown in FIG. 4, the SPT threshold did not change at 13.6%, but the SPT threshold increased 5 times in 50.0% patients and 25 times in 31.8% patients. The SPT threshold increased 125 times in 4.6% of patients. From this, it was shown that, for some patients, the induction neutralizing immunotherapy makes them tolerant to the allergen.

  In induced neutralization immunotherapy, subcutaneous inoculation of MITD needs to be performed daily at the beginning of treatment. In addition, it took more than three months to set up subcutaneous injection every other day and to extend every two days.

  On the other hand, individual-specific low-dose transdermal immunotherapy in which the intradermal inoculation is performed by MITD may be twice weekly after the initiation of the treatment, and the therapeutic effect can be obtained in 4 weeks with a minimum treatment period. This indicates that individual-specific low-dose transdermal immunotherapy is a more effective therapeutic method than induced neutralization immunotherapy and an effective therapeutic tool that can reduce the number of vaccinations to patients. The

Claims (11)

An allergen-containing composition for treating allergic diseases, which is intradermally inoculated, comprising:
A composition, wherein the inoculum size of the therapeutic allergen-containing composition is determined prior to the start of treatment for each inoculated subject having an allergic disease, from the maximum intradermally tolerated dose of the allergen. The maximum intradermal tolerance amount is determined by a method including a skin prick test step including the following step A and an intradermal test step including the steps B to D and E1 or the steps B to D and E2. The composition of
Step A: A skin prick test using the same allergen as the allergen contained in the therapeutic allergen-containing composition is performed on the inoculated subject, and the threshold amount of the inoculated allergen on the basis of the prick test skin immune response ( Determining a prick test threshold amount);
Step B: determining the inoculum size of the allergen at the start of the intradermal test (the intradermal test start amount) based on the prick test threshold amount,
Step C: Intradermal test starting amount of allergen is inoculated to the first intradermal site to be inoculated, and a predetermined time after inoculation of the allergen in step C, the presence or absence of an intradermal test skin immune response at the inoculation site is determined The process to
Step D: In step C, when it is determined that the intradermal test skin immune reaction is positive, a site different from the first intradermal site of the inoculation target is a smaller amount of the allergen than the intradermal test start amount. After the inoculation of the allergen and a predetermined time after inoculation of the allergen, determining the presence or absence of an intradermal test skin immune response at the site of inoculation, and Step E1: in step D, the intradermal test skin immune response is negative If it is determined, the inoculum size of the allergen in step D is determined as the maximum intradermal tolerance, or step E2: if it is determined in step D that the intradermal test skin immune response is positive. From the inoculation of an intradermal site which has not yet been inoculated with the allergen to which the allergen has been inoculated, in an amount smaller than that of the most recent inoculation, and from the inoculation of this allergen After a predetermined time, it is repeated to determine the presence or absence of the intradermal test skin immune response at the inoculation site until the amount of allergen determined to be negative as the intradermal test skin immune response, the intradermal test skin immune response Determining the amount of the allergen inoculated when it was determined to be negative as the maximum intradermal tolerance amount.   The method according to claim 2, wherein the step D further comprises the step of determining the amount of allergen in the intradermal test starting amount as the maximum intradermal tolerance amount when it is determined in the step C that the intradermal test skin immune response is negative. The composition as described in.   The composition according to claim 2 or 3, wherein the index for determining the presence or absence of the prick test skin immune response and the intradermal test skin immune response is wheal associated with an inflammatory response.   The composition according to any one of claims 2 to 4, wherein the predetermined time is 8 to 20 minutes.   The composition according to any one of claims 2 to 4, wherein the predetermined time is 10 to 15 minutes.   A kit for treating allergic disease used for intradermal inoculation, which comprises the composition according to any one of claims 1 to 6 and the composition for treating an allergen disease for intradermal inoculation according to any one of claims 1 to 6 and a skin puncture device. .   The kit used to determine the maximum intradermal tolerance in any one of claims 1 to 6, which combines an allergen-containing composition and a skin piercing device. A method of using an allergen to determine maximal intradermally tolerated dose,
The maximum intradermal tolerance is determined prior to the start of treatment for each inoculum having an allergic disease, in order to determine the inoculum size of the allergen-containing composition for treating allergic diseases containing an allergen similar to the allergen. The method of use, wherein the therapeutic allergen-containing composition is inoculated into intradermal inoculation. 10. The maximum intradermal tolerance amount is determined by a method including a skin prick test step including the following step A and an intradermal test step including the steps B to D and E1 or the steps B to D and E2. the method of;
Step A: A skin prick test using the same allergen as the allergen contained in the therapeutic allergen-containing composition is performed on the inoculated subject, and the threshold amount of the inoculated allergen on the basis of the prick test skin immune response ( Determining a prick test threshold amount);
Step B: determining the inoculum size of the allergen at the start of the intradermal test (the intradermal test start amount) based on the prick test threshold amount,
Step C: Intradermal test starting amount of allergen is inoculated to the first intradermal site to be inoculated, and a predetermined time after inoculation of the allergen in step C, the presence or absence of an intradermal test skin immune response at the inoculation site is determined The process to
Step D: In step C, when it is determined that the intradermal test skin immune reaction is positive, a site different from the first intradermal site of the inoculation target is a smaller amount of the allergen than the intradermal test start amount. After the inoculation of the allergen and a predetermined time after inoculation of the allergen, determining the presence or absence of an intradermal test skin immune response at the site of inoculation, and Step E1: in step D, the intradermal test skin immune response is negative If it is determined, the inoculum size of the allergen in step D is determined as the maximum intradermal tolerance, or step E2: if it is determined in step D that the intradermal test skin immune response is positive. From the inoculation of an intradermal site which has not yet been inoculated with the allergen to which the allergen has been inoculated, in an amount smaller than that of the most recent inoculation, and from the inoculation of this allergen After a predetermined time, it is repeated to determine the presence or absence of an intradermal test skin immune response at the inoculation site until the amount of the allergen determined to be negative for the intradermal test skin immune response is found, the intradermal test skin Determining the amount of the allergen inoculated when it is determined that the immune reaction is negative as the maximum intradermal tolerance amount. An allergen composition for determining the maximum intradermally tolerated dose,
The maximum intradermal tolerance is determined prior to the start of treatment for each inoculum having an allergic disease, in order to determine the inoculum size of the allergen-containing composition for treating allergic diseases containing an allergen similar to the allergen. A composition wherein the therapeutic allergen-containing composition is inoculated for intradermal inoculation.