JP2005325104A - Antipruritic agent with p2x antagonist as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find new pharmacological effects(pharmaceutical applications) of P2X antagonists. <P>SOLUTION: The P2X antagonists including hexasodium 8,8'-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonate(NF279) and lithium trisodium 2',3'-O-(2,4,6-trinitrophenyl)adenosine 5'-triphosphate(TNP-ATP) have high pruritus inhibitory effect, therefore being useful as therapeutic agents for all pruritus including ocular pruritus, dermal pruritus and systemic pruritus. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a therapeutic agent for pruritus containing a P2X antagonist as an active ingredient.

  Itching is perceived as itching when the itching receptor present at the skin-mucosal epidermis-dermis junction is stimulated by a transmitter (pruritus-inducing substance), and the stimulation is transmitted to the central nervous system. As a transmitter that induces itch, for example, histamine, kinin, bile salt, substance P, prostaglandin and the like are widely known.

  As pruritus, for example, eye pruritus, skin pruritus, ear / nose pruritus, general pruritus, etc. occurring in humans and animals are known. Examples of the disease accompanied by eye itching include allergic conjunctivitis, spring catarrhal, atopic keratoconjunctivitis, infectious keratoconjunctivitis, dry eye, blepharitis, and pruritus associated with ophthalmic surgery. Moreover, as a disease accompanied by skin pruritus, for example, atopic dermatitis, urticaria, xeroderma, skin infection etc. are known. Pruritus not only reduces the QOL of the patient's daily life, but also causes the symptoms to worsen by scratching.

The P2X receptor is a subtype of the P2 receptor that has ATP as a ligand (there is another P2Y receptor), and functions as an ion channel that is permeable to Na ⁺ , K ^+, and Ca ⁺⁺ . It is thought to be involved in pain perception in cells. Patent Document 1 describes that a P2 antagonist is effective for treatment of hyperimmunity and allergic diseases. Patent Document 2 describes that P2-purinoceptor inhibitors (particularly P2Y-purinoceptor inhibitors) are effective in treating diseases such as asthma, allergies, inflammatory lung diseases, bronchial stenosis and the like. . However, in these patent documents, the pruritus suppressing action of the P2X receptor is not studied at all.
WO 02/71062 pamphlet JP-T-2001-518118

  As described above, P2X antagonists have various pharmacological effects as pharmaceuticals, but it is an interesting subject to find efficacy in itch treatment as a new pharmacological effect.

  The inventors of the present invention conducted intensive research to search for new pharmaceutical uses of P2X antagonists. In an eye itch suppression test using a histamine-induced pruritus evaluation model, 8,8 ′-[carbonylbis (imino-4 , 1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)] bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt (NF279), 2 ', 3'-O- (2,4,6- P2X antagonists such as trinitrophenyl) adenosine 5′-triphosphate monosodium trisodium salt (TNP-ATP) act directly on peripheral nerve endings to control the transmission of itch signals in neurons The present inventors have found that it exhibits an excellent pruritus inhibitory action, and has completed the present invention.

That is, the present invention
(1) an agent for treating pruritus comprising a P2X antagonist as an active ingredient,
(2) The P2X antagonist is 8,8 ′-[carbonylbis (imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)] bis-1,3,5-naphthalenetrisulfonic acid or 2 ′. The itching therapeutic agent according to the above item (1), which is 3′-O- (2,4,6-trinitrophenyl) adenosine 5′-triphosphate or a pharmaceutically acceptable salt thereof,
(3) 8,8 ′-[carbonylbis (imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)] bis-1,3,5-naphthalenetrisulfonic acid or 2 ′, 3′- An itching therapeutic agent comprising as an active ingredient O- (2,4,6-trinitrophenyl) adenosine 5′-triphosphate or a pharmaceutically acceptable salt thereof,
(4) The pruritus treatment agent according to (1) to (3) above, wherein the pruritus is eye itching,
(5) The pruritus treatment according to (4) above, wherein the pruritus is allergic conjunctivitis, spring catarrh, atopic keratoconjunctivitis, infectious keratoconjunctivitis, dry eye, blepharitis, and pruritus associated with ophthalmic surgery, and (6) The agent for treating pruritus according to the above item (4-5), wherein the dosage form is an eye drop or an eye ointment.

  In the present invention, pharmaceutically acceptable salts are not particularly limited, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, In addition, salts with alkali metals or alkaline earth metals such as sodium, potassium, lithium, calcium, and the like can be given. More preferred salts are sodium salt, lithium salt and potassium salt. Quaternary ammonium salts, hydrates and solvates are also encompassed by the pharmaceutically acceptable salts of the present invention. Furthermore, geometric isomers, optical isomers, tautomers, polymorphs and the like are also included in the scope of the present invention.

  The P2X antagonist of the present invention is not particularly limited as long as it is a P2X antagonist. For example, NF279, TNP-ATP, 6,6-[(3,3′-dimethyl [1,1′-biphenyl] -4,4′- Diyl) bis (azo) bis [4-amino-5-hydroxy-1,3-naphthalenedisulfonic acid] (Evans Blue), pyridoxal phosphate-6-azophenyl-2 ′, 4′-disulfonic acid (PPADS), 8 , 8 ′-[carbonylbis (imino-3,1-phenylenecarbonylimino)] bis-1,3,5-naphthalene-trisulfonic acid hexasodium salt (NF023), 4-[(2S) -2-[( 5-Isoquinolinylsulfonyl) methylamino] -3-oxo-3- (4-phenyl-1-piperazinyl) propyl] phenyl isoquinolinesulfonate (K N62), 2-[(1,5-dihydro-3,9-dihydroxy-8-methyl-3-oxide [1,3,2] dioxaphosfepino [5,6-c] pyridin-6-yl ) Azo] -1,4-benzenedisulfonic acid (MRS2220).

For itch, the itch receptor present in the peripheral nerve endings is stimulated by a transmitter (pruritus-inducing substance) such as histamine, and the ion channel expressed on the peripheral nerve cell membrane opens, causing the cation to flow into the cell. When the nerve cells are excited, the stimulation is transmitted to the central nerve, and it is felt as an itching. On the other hand, the P2X receptor is an ion channel that is permeable to Na ⁺ , K ⁺ and Ca ⁺⁺ , and has been reported to be expressed on peripheral nerve cells (Neuroscience Letters 337: 81-84, 2003). Therefore, a representative of P2X antagonists known as P2X antagonists is based on the hypothesis that transmission of itch stimulation to the center can be suppressed by suppressing the inflow of cations into peripheral nerve cells. Were validated using a typical compound.

  The agent for treating pruritus according to the present invention acts directly on peripheral nerve endings to control the transmission of pruritus signals in nerve cells, as is apparent from the results of an eye pruritus suppression test using a histamine-induced pruritus evaluation model described later. Therefore, it exerts an excellent pruritus suppression effect against itching caused by all factors. Therefore, this can be expected to have a therapeutic / suppressive effect on pruritus such as eye pruritus, skin pruritus, ear / nose pruritus and systemic pruritus occurring in humans and animals. Particularly preferably, it is used as a therapeutic agent for eye itch.

  There are various types of eye diseases such as allergic conjunctivitis, spring catarrh, atopic keratoconjunctivitis, infectious keratoconjunctivitis, blepharitis, dry eye, conjunctivitis, corneal herpes, corneal ulcer, etc. included.

  The agent for treating pruritus according to the present invention can be formulated using a technique widely used as a single preparation or a combination preparation by adding a pharmaceutically acceptable additive as necessary.

  Moreover, the therapeutic agent for pruritus of the present invention can be administered parenterally or orally. Examples of oral preparations include liquids for internal use (for example, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions), solid preparations for internal use (for example, tablets (sublingual tablets, buccal cavity) Disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and troches. Examples of parenteral agents include liquids (eg, injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drops, etc.), eye drops (eg, aqueous eye drops (aqueous eye drops) Liquid, aqueous suspension ophthalmic solution, viscous ophthalmic solution, solubilized ophthalmic solution, etc.), non-aqueous ophthalmic solution (non-aqueous ophthalmic solution, non-aqueous suspension ophthalmic solution, etc.))), and external preparations (eg, ointment (eye ointment) Etc.), gels, creams, poultices, poultices, liniments, etc.), sprays, inhalants, sprays, nasal drops, suppositories (eg rectal suppositories, vaginal suppositories), etc. . These preparations may be release control agents such as immediate-release preparations and sustained-release preparations. These preparations can be produced by a known method, for example, a method described in the Japanese Pharmacopoeia.

  The liquid for internal use as an oral preparation is produced, for example, by dissolving, suspending or emulsifying the active ingredient in a diluent (for example, purified water, ethanol or a mixture thereof) generally used. Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

  The solid preparation for internal use as an oral preparation includes, for example, an active ingredient as an excipient (eg, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (eg, hydroxypropylcellulose, polyvinylpyrrolidone, aluminum metasilicate). Magnesium oxide, etc.), disintegrating agents (eg, calcium calcium glycolate), lubricants (eg, magnesium stearate), stabilizers, solubilizing agents (glutamic acid, aspartic acid, etc.), etc. According to the formulation. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers.

  An external preparation as a parenteral preparation is produced and prepared by a known method or a commonly used formulation. For example, an ointment is manufactured and prepared by kneading or melting an active ingredient in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (E.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene) Recall, macrogol, etc.), vegetable oil (eg, castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancer, anti-rash agent Can be used alone or in admixture of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The gel is produced and prepared, for example, by melting an active ingredient in a base. The gel base is selected from known or commonly used ones. For example, lower alcohol (eg, ethanol, isopropyl alcohol, etc.), gelling agent (eg, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agent (eg, triethanolamine, diisopropanolamine, etc.), One selected from surfactants (for example, polyethylene glycol monostearate), gums, water, absorption enhancers, and anti-rash agents, or a mixture of two or more types may be used. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The cream is produced and prepared, for example, by melting or emulsifying an active ingredient in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene alkyl ethers) , Fatty acid esters, etc.), water, absorption accelerators, rash prevention agents, or a mixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The poultice is produced, for example, by melting an active ingredient in a base, and applying it as a kneaded product on a support. The poultice base is selected from known or commonly used ones. For example, thickeners (eg, polyacrylic acid, polyvinyl pyrrolidone, gum arabic, starch, gelatin, methyl cellulose, etc.), wetting agents (eg, urea, glycerin, propylene glycol, etc.), fillers (eg, kaolin, zinc oxide, Talc, calcium, magnesium, etc.), water, a solubilizing agent, a tackifier, and a rash prevention agent may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The patch is produced, for example, by melting an active ingredient in a base and spreading and applying it on a support. The base for patch is selected from known or commonly used ones. For example, those selected from a polymer base, fats and oils, higher fatty acids, tackifiers and anti-rash agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The liniment is, for example, an active ingredient dissolved, suspended in or alone or selected from water, alcohol (eg, ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent, etc. Produced and prepared by emulsification. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The spray and the spray are produced by a known or commonly used formulation. For example, in addition to commonly used diluents, it contains a buffer that provides isotonicity with a stabilizer such as sodium bisulfite, for example, an isotonic agent such as sodium chloride, sodium citrate, or citric acid. May be.

  Inhalants include aerosols, inhalable powders or inhalable liquids, and the inhalable liquids may be used by dissolving or suspending in water or other suitable medium at the time of use. These inhalants are, for example, in the case of inhalation solutions, antiseptics (for example, benzalkonium chloride, parabens, etc.), coloring agents, buffering agents (for example, sodium phosphate, sodium acetate, etc.), isotonicity An agent (for example, sodium chloride, concentrated glycerin, etc.), a thickener (for example, cariboxyvinyl polymer, etc.), an absorption accelerator, etc. are appropriately selected as necessary. In the case of powders for inhalation, lubricants (for example, stearic acid and its salts), binders (for example, starch, dextrin, etc.), excipients (for example, lactose, cellulose, etc.), colorants, antiseptics An agent (for example, benzalkonium chloride, paraben, etc.), an absorption accelerator and the like are appropriately selected as necessary. A nebulizer (for example, an atomizer or a nebulizer) is usually used when administering an inhalation solution, and an inhalation administration device for powder medicine is usually used when administering an inhalable powder.

  The parenteral injection includes solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent when used. An injection is used, for example, by dissolving, suspending or emulsifying an active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Furthermore, this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like. Also good. These are sterilized in the final process or manufactured and prepared by aseptic manipulation. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.

  Preferred dosage forms for use as an eye itch treatment agent include eye drops, eye ointments, tablets and the like, and more preferably eye drops or eye ointments. These can be formulated using widely used techniques. For example, in the case of eye drops, isotonic agents, buffers, pH adjusters, solubilizers, thickeners, stabilizers, preservatives and the like can be appropriately added as additives. In addition, a stable eye drop can be obtained by adding a pH adjuster, a thickener, a dispersant and the like to suspend the drug.

  Examples of isotonic agents include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.

  Examples of the buffer include phosphoric acid, phosphate, citric acid, acetic acid, and ε-aminocaproic acid.

  Examples of the pH regulator include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.

  Examples of the solubilizer include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, and the like.

  Examples of thickeners and dispersants include cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and the like. Examples of stabilizers include edetic acid and sodium edetate. be able to.

  Examples of preservatives (preservatives) include general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, and chlorobutanol. These preservatives are combined. Can also be used.

  The eye drop containing the agent for treating pruritus according to the present invention desirably has a pH set to 4.0 to 8.5, and preferably has an osmotic pressure ratio set to around 1.0.

  The dose of the active ingredient when used as an agent for treating pruritus can be appropriately selected depending on the symptom, age, dosage form, etc., but if it is an oral preparation, it is preferably 1 mg to 100 mg, more preferably 5 mg to 30 mg. What is necessary is just to administer several times (for example, 1-3 times). If it is an eye drop, it preferably has a concentration of 0.001 to 10% (w / v), more preferably 0.01 to 3% (w / v). What is necessary is just to instill several times (for example, 1 to 8 times). In the case of an eye ointment, a concentration of 0.001 to 10% (w / w), more preferably 0.01 to 3% (w / w) is preferably used once to several times a day (for example, 1 (4 times) may be applied.

  Of course, as described above, the dose varies depending on various conditions, and therefore, a dose smaller than the above dose may be sufficient or may be necessary beyond the range.

  When an eye pruritus suppression test was conducted, P2X antagonists such as NF279 and TNP-ATP exert an excellent pruritus inhibitory effect in a histamine-induced pruritus evaluation model. Therefore, treatment of all pruritus including eye pruritus, skin pruritus, and systemic pruritus. Useful as an agent.

  Pharmacological tests and formulation examples are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.

[Pharmacological test]
Eye itching inhibition test using histamine-induced pruritus evaluation model 8,8 '-[carbonylbis (imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)] bis using histamine-induced pruritus evaluation model -1,3,5-naphthalene trisulfonic acid hexasodium salt (NF279) and 2 ′, 3′-O- (2,4,6-trinitrophenyl) adenosine 5′-triphosphate monolithium trisodium salt ( TNP-ATP) was examined for the effect of suppressing eye itching.

(experimental method)
NF279 and TNP-ATP were dissolved in physiological saline to a concentration of 0.1% and 1.0% (W / V), and 10 μL / day was added to both eyes of 5-week-old male Hartley guinea pigs. Eye drops were administered eye by eye. Ten minutes after administration, the same concentrations of NF279 and TNP-ATP were instilled (total number of administrations: 2). In addition, physiological saline was used as a control.

  Five minutes after the second instillation of NF279 and TNP-ATP, a physiological saline solution in which histamine 0.3% (W / V) was dissolved was instilled into both eyes of the guinea pig at 10 μL / eye. Eye itch was induced.

  The eye scratching behavior of guinea pigs after instillation of histamine was video-recorded, and the effect of suppressing eye itching was evaluated by counting a series of behaviors of scratching the eyes with the hind limb for each eye. Table 1 shows the average value of the number of eye scratches and the eye scratching behavior inhibition rate for 30 minutes after histamine administration. The number of examples is 8 eyes each.

Eye scratching behavior inhibition rate = 100− [number of eye scratches of test compound] ÷ [number of eye scratches of control] × 100

(Experimental result)
From Table 1, since the number of eye scratches of guinea pigs instilled with NF279 and TNP-ATP is remarkably reduced as compared with the control, these P2X antagonists have an excellent eye itching inhibitory action.

[Formulation example]
The typical formulation example used for this invention is shown below.

1. Eye Drops An eye drop of the following formulation is prepared using a widely used method.

Formulation Example 1
NF279 100mg in 100ml
Concentrated glycerin 500mg
Polysorbate 80 200mg
Sodium dihydrogen phosphate dihydrate appropriate amount 1N sodium hydroxide appropriate amount hydrochloric acid appropriate amount sterilized purified water appropriate amount

  In the same manner as in Formulation Example 1, eye drops containing 10 mg, 50 mg, and 1000 mg of NF279 in 100 ml can be prepared.

2. Eye ointment An eye ointment of the following formulation is prepared using a commonly used method.

Formulation Example 2
TNP-ATP 200mg in 100g
Liquid paraffin 10g
White petrolatum

  Similar to Formulation Example 2, various concentrations of eye ointment can be prepared by appropriately changing the amount of TNP-ATP added.

Claims (6)

A pruritus treatment agent comprising a P2X antagonist as an active ingredient. The P2X antagonist is 8,8 '-[carbonylbis (imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)] bis-1,3,5-naphthalenetrisulfonic acid or 2', 3'- The agent for treating pruritus according to claim 1, which is O- (2,4,6-trinitrophenyl) adenosine 5'-triphosphate or a pharmaceutically acceptable salt thereof. 8,8 ′-[carbonylbis (imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)] bis-1,3,5-naphthalenetrisulfonic acid or 2 ′, 3′-O— ( A therapeutic agent for pruritus comprising 2,4,6-trinitrophenyl) adenosine 5′-triphosphate or a pharmaceutically acceptable salt thereof as an active ingredient. The agent for treating pruritus according to claim 1, wherein the pruritus is eye pruritus. The therapeutic agent for pruritus according to claim 4, wherein the pruritus is allergic conjunctivitis, spring catarrh, atopic keratoconjunctivitis, infectious keratoconjunctivitis, dry eye, blepharitis, and pruritus associated with ophthalmic surgery. The pruritus treatment agent according to claim 4 or 5, wherein the dosage form is an eye drop or an eye ointment.