WO2000027402A1 - Remedes destines a une administration topique pour lutter contre des maladies allergiques du type iv - Google Patents

Remedes destines a une administration topique pour lutter contre des maladies allergiques du type iv Download PDF

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Publication number
WO2000027402A1
WO2000027402A1 PCT/JP1999/006011 JP9906011W WO0027402A1 WO 2000027402 A1 WO2000027402 A1 WO 2000027402A1 JP 9906011 W JP9906011 W JP 9906011W WO 0027402 A1 WO0027402 A1 WO 0027402A1
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WIPO (PCT)
Prior art keywords
type
allergic disease
ointment
therapeutic agent
allergy
Prior art date
Application number
PCT/JP1999/006011
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English (en)
Japanese (ja)
Inventor
Kazumi Ogata
Takahiro Sakaue
Shinya Ogino
Original Assignee
Senju Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Senju Pharmaceutical Co., Ltd. filed Critical Senju Pharmaceutical Co., Ltd.
Publication of WO2000027402A1 publication Critical patent/WO2000027402A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a useful type IV allergic disease therapeutic agent for local administration. More specifically, the present invention relates to a useful therapeutic agent for type IV allergic disease for local administration, which comprises a phosphodiester compound of ascorbic acid and tocopherol or a pharmaceutically acceptable salt thereof.
  • Allergic reactions that cause tissue damage are type I (immediate type, anaphylaxis type), type 11 (cytotoxic type, cytolytic type), type IM (immune complex type, arthus type) and type IV (Cell immunity type, delayed type).
  • Type I allergic reactions are also referred to as immediate forms, as they manifest within 5 to 20 minutes after antigen exposure.
  • Antibodies belong to IgE, and adhere to the surface of mast cells in tissues and basophils in blood, and release various biologically active chemical mediators of anaphylaxis when combined with antigens. appear.
  • Diseases caused by type I include bronchial asthma and allergic rhinitis.
  • the type 11 allergic reaction is a reaction in which surface cells serve as antigens and the antibody is bound to promote cell destruction.
  • the antibodies belong to IgG or IgM. It is a mechanism of drug-induced leukopenia, thrombocytopenia, and hemolytic anemia.
  • the type 111 allergic reaction is a reaction in which an antigen binds to IgG antibodies present in blood or tissue to form a soluble immunoconjugate and adheres to the blood vessel wall, causing complement activation and leukocyte migration to cause inflammation. is there. Clinically, it is mainly irritable pneumonitis ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ . ⁇ .
  • Type IV allergic reactions are called cell immunity (eel I—mediated immunity, CMI) because they are caused by sensitized lymphocytes. (delayed type hypersens initiative, DTH). Lymphocytes involved in type IV allergic reactions belong to ⁇ cells, and two mechanisms are thought to be involved.
  • T DTH lymphocytes bind to antigens and release lymphokines having various biological activities (lymphokine), in which macrophage activator factor (AF) is converted to lysosomal enzyme.
  • the release can kill or irritate.
  • Type IV allergy is clinically important as a mechanism of atopic dermatitis, drug allergy and contact dermatitis.
  • antiallergic agents include hydrocortisone butyrate, bufexamac, sodium cromoglycate, tranilast, ketotifen, azelastine and oxatomide.
  • the mechanism of action and administration of these antiallergic agents The methods are different and the indications are different.
  • drugs are selected according to the type of allergic reaction. For example, sodium cromoglycate, tranilast, ketotifen, azelastine and oxatomide are effective only for type I allergic reactions, and bufexamac is effective only for type IV allergic reactions.
  • steroids such as hydrocortisone acetate are generally effective for all types I to IV allergies, but have the disadvantage that they have strong side effects.
  • the phosphodiester compound used in the therapeutic agent for type IV allergic disease for topical administration of the present invention is an anticataract agent, a climacteric disorder preventive agent, and a cosmetic product having a beautiful skin effect (Japanese Patent Publication No. 2-44478) , Antioxidants (JP-A-63-139972), anti-ulcer agents (JP-A-63-270626), anti-inflammatory agents (JP-B-11-27044, JP-B-5-23274), ischemic organ damage Various uses such as prophylactic and therapeutic agents (JP-A-2-111722) and Maillard reaction inhibitors (JP-A-3-161444) are already known.
  • this phosphate ester compound is also known as an antiallergic agent (Japanese Patent Application Laid-Open No. 9-187180), but in this patent publication, eyelid conjunctival edema (type I) It only discloses effects on allergic conjunctivitis type 111 and allergic conjunctivitis, but does not disclose any specific pharmacodynamic data on type IV allergy. And the mechanism of development of type I, type III and type IV allergy is different as described above. Therefore, even though the non-steroidal compound diphosphoric acid of this invention is effective for type I and type III allergies, it is excellent for type IV allergies with different onset mechanisms by topical administration such as dermal administration. Is not effective.
  • the present invention provides an excellent therapeutic agent for type IV allergic monotherapy for topical administration, which comprises a phosphodiester compound or a pharmacologically acceptable salt thereof. That is, the present invention provides:
  • R and R 2 are the same or different and represent a hydrogen atom or a methyl group. Or a pharmacologically acceptable salt thereof.
  • a therapeutic agent for type IV allergic disease for topical administration comprising (2) the compound L-ascorbic acid 'DL- ⁇ -tocopherol phosphate diester dipotassium salt (3) The above (1) or (2) wherein the dosage form is an eye drop, an ointment, a lotion or a gel.
  • a therapeutic agent for type IV allergic monogenic disease comprising (2) the compound L-ascorbic acid 'DL- ⁇ -tocopherol phosphate diester dipotassium salt (3) The above (1) or (2) wherein the dosage form is an eye drop, an ointment, a lotion or a gel.
  • the present invention further provides the use of the present compound for the manufacture of a therapeutic agent for type IV allergic disease for topical administration.
  • the present invention also provides a method for treating a type IV allergic disease in a mammal by administering an effective amount of the present compound to a local site of the type IV allergic disease in the mammal.
  • the mammal is preferably, for example, a human.
  • FIG. 1 shows a graph showing the inhibitory effect on the biphasic reaction of mouse contact hypersensitivity.
  • FIG. 2 is a graph showing the inhibitory effect on the biphasic reaction of mouse contact hypersensitivity (after 2 hours).
  • FIG. 3 shows a graph indicating the inhibitory effect (after 24 hours) on the biphasic reaction of mouse contact hypersensitivity.
  • the compound used in the therapeutic agent for type IV allergic disease for topical administration of the present invention may be synthesized, for example, according to the methods described in JP-B-2-44478 and JP-B-5-23274 or appropriately according to these methods. Can be.
  • the present compound used in the therapeutic agent for type IV allergic disease for topical administration of the present invention may be appropriately used for the purpose of the present invention.
  • the pharmacologically acceptable salt include, for example, alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt. Even so, any pharmacologically acceptable salt can be appropriately used. Particularly, a potassium salt is preferable.
  • the type IV allergic disease therapeutic agent for topical administration of the present invention may contain one or more of the present compounds as appropriate, if necessary and desired.
  • the present compound used as an active ingredient in the therapeutic agent for type IV allergic disease for topical administration of the present invention has extremely low toxicity and excellent safety, and therefore can be advantageously used for the purpose of the present invention.
  • LD 5D for L-ascorbic acid and potassium DL- ⁇ -tocopherol phosphate (hereinafter abbreviated as EPC- ⁇ ) is 5 g / kg (rat) by oral administration and 100 mg / kg (rat) or more by intravenous injection. is there.
  • Examples of the type IV allergic disease to be treated by the therapeutic agent for type IV allergic disease for local administration of the present invention include bacterial 'fungus' virus allergy, atopic dermatitis, contact dermatitis, drug allergy and the like. Is mentioned.
  • the therapeutic agent for type IV allergic disease for topical administration of the present invention is suitably used by topical administration such as transdermal or eye drops for the treatment of type IV allergic disease as described above.
  • topical administration such as transdermal or eye drops for the treatment of type IV allergic disease as described above.
  • eye drops, ointments, lotions and gels can be appropriately prepared by a known method.
  • Various additives such as a pH adjuster and the like may be used as appropriate.
  • the dosage depends on the type of compound used, the type of target disease, the age, weight, indication, and dosage form of the patient. Although different, for example, when used as eye drops, apply a drop of about 0.01 (w / v)% to 0.5 (w / v)% once per drop, several times a day. Is good. Further, in the case of ointments, lotions and gels, it is preferred to contain about 1 to 10 (w / w)% in the preparation.
  • the therapeutic agent for type IV allergic disease for topical administration of the present invention may contain scabs, other antiallergic agents, or components exhibiting other kinds of pharmacological effects, contrary to the object of the present invention.
  • L-ascorbic acid and potassium potassium DL- ⁇ -tocopherol phosphate (abbreviation: EPC-II) were dissolved in methanol to 0.5%, 1.0%, and 2.0%. As a control, a methanol group was provided.
  • a negative control a group was prepared in which only the inducer was applied without sensitization.
  • test substance was applied 20 I to the inside and outside of the right pinna 30 minutes before the induction.
  • the thickness of the pinna was measured using a dial thickness gauge (Peacock), and the edema rate was calculated from the thickness at each time of PCL induction and the thickness before PCL induction. .
  • A Thickness before inducing PCL (0.001 x 1mm)
  • B Thickness after each hour inducing PCL (0.001 x 1mm)
  • Test results The test results are shown in Table 1 and FIGS.
  • Fig. 2 shows a graph of the edema rate after 2 hours in Table 1.
  • Table 1 shows a graph of Table 1
  • Fig. 2 shows a graph of the edema rate after 2 hours in Table 1.
  • Table 1 shows a graph of Table 1
  • the edema rates of the group and the negative control group were 81.7 ⁇ 9.63 ⁇ 4, 43.9 ⁇ 6.9%, 32.3 ⁇ 6.7%, 20.2 ⁇ 3.7%, 37.9 ⁇ 4.3%, 18.6 ⁇ 1.5%, 12.3 ⁇ 2.5%, respectively.
  • EPC-K suppressed late response in a dose-dependent manner (P ⁇ 0.001).
  • 0.5% EPC-K is 5% 2.
  • WEPC-K suppressed the late response to the same extent as 0.1% hydrocortisone butyrate.
  • EPC-K ointment was prepared by first dissolving EPC-K in propylene glycol by heating, and then homogeneously mixing it with Plastibase. Note that 5% E
  • the test was performed by partially modifying the method of Van Loveren H. et al. That is, feeling One to three days before the crop, the hair around the right pinna was clipped with a clipper. The hair on the back of the mouse is clipped with a hair clipper, and the hair is further removed using a hair removal cream (trade name: Epilat Hair Removal Cream EJ: Kanebo Co., Ltd .: containing thiocyanate glycolic acid, guaiazulene, and sequinol). Rinse thoroughly with 37 ° C water so that no depilatory remains.
  • Ketalal Selactal (9: 1 ( ⁇ / ⁇ )) was used [Ketalal (Ketalal for animals 50: Ketamine hydrochloride injection, Sankyo Co., Ltd.), Selactal (Selactal 2% injection) : Xylazine hydrochloride, Bayer Corporation].
  • the thickness of the pinna was measured using a dial thickness gauge, and the edema rate was calculated in the same manner as in Example 1 from the thickness of the pinna 24 hours after PCL induction and the thickness of the pinna before PCL induction.
  • the edema inhibition rate of each test substance was calculated by the following equation.
  • Edema inhibition rate (%) ⁇ 1-(Z-X) / (Y— X) ⁇ X100
  • Table 2 shows the test results. Table 2 Effect of ointment containing this compound on PCL-induced contact dermatitis in mice
  • EPC-II ointment significantly suppressed mouse pinna edema in mouse PCL-induced contact dermatitis in a dose-dependent manner.
  • 5% EPC-K ointment was weaker than 0.1% hydrocortisone butyrate ointment, but almost as effective as 1% hydrocortisone acetate ointment.
  • 5% EPC-K ointment was more effective than 5% bufexamac ointment, which is a nonsteroidal anti-inflammatory drug.
  • Example 2 The test was performed in the same manner as in Example 2, except that 48 CBA / J female mice, 8 weeks old, purchased from Nippon Charls River Co., Ltd. were used and the preparations used were different. The edema rate and the edema inhibition rate were calculated.
  • the EPC—K cream significantly suppressed the mouse pinna edema in mouse PCL-induced contact dermatitis in a dose-dependent manner.
  • the 5% EPC-K cream was weaker than the 0.1% hydrocortisone butyrate cream, but had almost the same inhibition rate as the 1% hydrated oral cortisone cream.
  • 5% EPC-K cream showed a stronger effect than 5% bufexamac cream, which is a nonsteroidal anti-inflammatory drug.
  • EPC-K The effects of EPC-K were examined using a mouse model of xazolone-contact delayed dermatitis, a model of the ear edema of type IV allergy.
  • a non-sensitized group a group to which only the inducer was applied without sensitization was provided.
  • EPC-K ointment significantly suppressed mouse ear edema in mouse aged xazolone-induced contact dermatitis in a dose-dependent manner.
  • the 5% EPC-K ointment was weaker than the 0.1% hydrocortisone butyrate ointment, but almost as effective as the 1% hydrocortisone acetate ointment.
  • 5% EPC-K ointment was more effective than 5% bufexamac ointment, a non-steroid anti-inflammatory drug.
  • P0E hydrogenated castor oil 60 2.5 g 2.5 g 2.5 g 2.5 g 2.5 g fatty acid glycerin ester 0.6 g 0.6 g 0.6 g 0.6 g purified water Suitable: £ liquor Total amount 100 g 100 g 100 g 100 g pH 4.98 6.81 6.87 6.86 The following were used as controls.
  • Example 4 The test was performed in the same manner as in Example 4 except that 48 8-week-old female CBA / J mice purchased from Nippon Charls River Co., Ltd. were used and the preparations used were different. The edema rate and the edema inhibition rate were calculated.
  • Table 5 shows the results. Table 5 Efficacy of cream containing the compound on xazozolone-induced contact dermatitis in mice
  • the EPC—K cream significantly inhibited the ear edema of mice in mouse aged xazolone-induced contact dermatitis in a dose-dependent manner.
  • the 5% E-1 cream was weaker than the 0.1% hydrocortisone butyrate cream, but had almost the same inhibition rate as the 1% hydrocortisone acetate cream.
  • the 5% EPC-K cream was more effective than the nonsteroidal anti-inflammatory drug 5% bufexamac cream.
  • this compound was found to be useful as a topical administration type IV allergic disease therapeutic agent.
  • the above components are mixed by a conventional method to form a gel.
  • the above ingredients are mixed by a conventional method to form a lotion, Industrial availability
  • the present invention provides a preparation for topical administration that is useful as a therapeutic agent for type IV allergic diseases such as bacterial / fungal virus allergy, atopic dermatitis, and drug allergy / contact dermatitis.
  • Phosphodiester which is the main component of this drug, has the advantage that it can be used for a long period of time because it has fewer side effects than steroids.

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne des remèdes destinés à une administration topique pour lutter contre des maladies allergiques du type IV. Ces remèdes contiennent des composés diester phosphoriques représentés par la formule générale (I), dans laquelle R1 et R2 sont identiques ou différents et chacun représente hydrogène ou méthyle.
PCT/JP1999/006011 1998-11-06 1999-10-28 Remedes destines a une administration topique pour lutter contre des maladies allergiques du type iv WO2000027402A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/316312 1998-11-06
JP31631298 1998-11-06

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WO2000027402A1 true WO2000027402A1 (fr) 2000-05-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009520697A (ja) * 2005-12-23 2009-05-28 バイタル ヘルス サイエンシズ プロプライアタリー リミティド サイトカイン調節性を有する化合物
WO2014115715A1 (fr) * 2013-01-25 2014-07-31 京都府公立大学法人 Fibre d'amélioration en cas de dermatite atopique, agrégat de fibres, et produit de fibres, procédé d'utilisation de celle-ci, et procédé d'amélioration en cas de dermatite atopique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0754458A1 (fr) * 1995-07-18 1997-01-22 Senju Pharmaceutical Co., Ltd. Composition antiallergique contenant un composé de diester phosphorique
JPH0930965A (ja) * 1995-07-19 1997-02-04 Sekisui Chem Co Ltd 皮膚疾患治療用外用剤
JPH0930964A (ja) * 1995-07-19 1997-02-04 Sekisui Chem Co Ltd 皮膚疾患治療用外用剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0754458A1 (fr) * 1995-07-18 1997-01-22 Senju Pharmaceutical Co., Ltd. Composition antiallergique contenant un composé de diester phosphorique
JPH0930965A (ja) * 1995-07-19 1997-02-04 Sekisui Chem Co Ltd 皮膚疾患治療用外用剤
JPH0930964A (ja) * 1995-07-19 1997-02-04 Sekisui Chem Co Ltd 皮膚疾患治療用外用剤

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009520697A (ja) * 2005-12-23 2009-05-28 バイタル ヘルス サイエンシズ プロプライアタリー リミティド サイトカイン調節性を有する化合物
WO2014115715A1 (fr) * 2013-01-25 2014-07-31 京都府公立大学法人 Fibre d'amélioration en cas de dermatite atopique, agrégat de fibres, et produit de fibres, procédé d'utilisation de celle-ci, et procédé d'amélioration en cas de dermatite atopique
US9867846B2 (en) 2013-01-25 2018-01-16 Kyoto Prefectural Public University Corporation Atopic-dermatitis-suppressing fiber, fiber assembly and fiber product, method for using same, and method for suppressing atopic dermatitis
RU2658056C2 (ru) * 2013-01-25 2018-06-19 Киото Прифекчурал Паблик Юниверсити Корпорэйшн Волокно, подавляющее атопический дерматит, совокупность волокон и изделие из волокон, способ его применения и способ подавления атопического дерматита

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