JP2007191495A - Pruritus treating agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find out a new pharmacological effect (medical application) of cannabinoids. <P>SOLUTION: A cannabinoid agonist such as palmidrol exhibits excellent pruritus-suppressing effects and therefore is useful as a treating agent for every kind of pruritus such as eye pruritus, skin pruritus or systemic pruritus. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an agent for treating pruritus containing a cannabinoid agonist as an active ingredient.

  Itching is perceived as itching because 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. Itching is presumed that itch caused by allergic factors involves a transmitter such as histamine released from mast cells, and antihistamines are widely used.

  Examples of pruritus include eye itching, skin pruritus, and systemic pruritus that occur in humans and animals. Examples of diseases associated with itching include allergic conjunctivitis, spring catarrh, atopic keratoconjunctivitis, infectious horn. Examples include pruritus associated with eye surgery such as conjunctivitis, blepharitis, and cataract surgery. Allergic conjunctivitis is known to develop due to various causes such as pollen, dust, mites, molds, pet hair, contact lenses, cosmetics, and the eyes, eyelids, eyelids become itchy and scratches the eyes. Causes the conjunctiva to become congested and the condylar teat to become red and proliferate. In severe cases, lesions appear in the cornea and sclera and may progress to more severe spring catarrh.

  By the way, cannabinoid is a general term for active ingredients of cannabis and is known to act on the central nerve. As cannabinoid agonists, for example, peripheral cannabinoid receptor agonists such as indomethacin morpholinamide and palmidolol, and non-selective cannabinoid receptor agonists such as anandamide and tetrahydrocannabinoid are known. It is also known that 2-oxoquinoline derivatives having immunomodulatory action, anti-inflammatory action and anti-allergic action described in Patent Document 1 are also excellent cannabinoid agonists.

Patent Document 2 discloses that cannabinoids are useful for the treatment of diseases related to modulation of peripheral cannabinoid receptors. Specifically, diseases associated with pain degeneration, multiple sclerosis, diseases associated with pressure modulation of intraocular pressure, chronic respiration It is described that it can be used for chronic degenerative diseases such as genital disorders, senile dementia, and Alzheimer's. Patent Document 3 describes an invention relating to a pharmaceutical composition containing an N-acyl derivative of an amino alcohol such as N-palmitoyl-ethanolamide (palmidol), which is a cannabinoid agonist, and these pharmaceutical compositions. Has pharmaceutical use as a therapeutic agent for autoimmune diseases such as atopic dermatitis, dermatomyositis, sympathetic ophthalmitis, autoimmune uveitis, uveoretinopathy, and dry keratoconjunctivitis. The publication discloses that administration of an N-acyl derivative of aminoalcohol suppresses mast cell degranulation reaction and no transmitter substances such as histamine are released from mast cells. It has been described to suppress autoimmune diseases by participating in mast cells.
JP 2000-256323 A. Japanese National Patent Publication No. 11-500411. JP-A-5-345722.

  Although cannabinoid agonists are known to have various pharmacological effects as pharmaceuticals, finding new pharmacological effects is an interesting subject.

  By conducting a pharmacological test, the present inventors have found that cannabinoid agonists such as palmidolol, indomethacin morpholinamide, anandamide, and 2-oxoquinoline derivatives described in JP-A No. 2000-256323 are effective against eye itch. Have been found to exhibit excellent pruritus-suppressing action. Moreover, from the results of the pruritus inhibition test of the histamine-induced model and the platelet-activating factor-induced model, the cannabinoid agonist of the present invention suppresses the transmission of itch signals in nerve cells by acting directly on peripheral nerve endings. Became clear.

  That is, the present invention is an agent for treating pruritus containing cannabinoid agonists such as palmidolol, indomethacin morpholinamide, anandamide, 2-oxoquinoline derivatives as active ingredients. The 2-oxoquinoline derivative refers to a compound described in JP-A No. 2000-256323.

  Cannabinoid agonists such as palmidolol, indomethacin morpholinamide, anandamide, and 2-oxoquinoline derivatives exhibit an excellent pruritus-suppressing effect on eye itching. Since these cannabinoid agonists act directly on peripheral nerve endings and suppress the transmission of itch signals in nerve cells, they can exert an excellent pruritus-suppressing effect against itch caused by all factors.

  The cannabinoid agonist of the present invention has a therapeutic / inhibitory effect on pruritus occurring in humans and animals. More preferably, it is used as a therapeutic agent for eye itch. The pruritus may be pruritus that does not involve mast cells, such as eye itching that does not involve mast cells.

  Examples of the disease accompanied by eye itching include allergic conjunctivitis, spring catarrhal, atopic keratoconjunctivitis, infectious keratoconjunctivitis, blepharitis, and pruritus associated with ophthalmic surgery such as cataract surgery.

  The cannabinoid agonist of the present invention may be a peripheral cannabinoid receptor agonist or a non-selective cannabinoid receptor agonist. Peripheral cannabinoid receptor agonists include, for example, indomethacin morpholinamide, N-acyl derivatives of amino alcohols such as palmidolol described in JP-A-5-345722, and 2-2000 described in JP-A-2000-256323. Oxoquinoline derivatives, 2-imino-1,3-thiazine derivatives described in WO01 / 19807, pyridone derivatives described in WO02 / 53543, 3,4-dihydro described in WO02 / 10135 Examples thereof include isoquinoline derivatives and pyrazole derivatives described in JP-A No. 2001-516361, and preferably palmidolol, indomethacin morpholinamide, and 2-oxoquinoline derivatives are used. Specific examples of 2-oxoquinoline derivatives include, for example, N- (benzo [d] [1,3] dioxol-5-ylmethyl) -7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline. -3-carboxamide, 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid and the like. Examples of non-selective cannabinoid receptor agonists include anandamide and tetrahydrocannabinoid, and anandamide is preferably used.

  The agent for treating pruritus according to the present invention acts directly on peripheral nerve endings and transmits itching signals in nerve cells, as is apparent from the results of the histamine-inducing model and the platelet-activating factor-inducing model in the pharmacological test. Since it suppresses, it is possible to exert an excellent pruritus suppressing effect against itch caused by any factor.

  The agent for treating pruritus according to the present invention can be formulated by adding a pharmaceutically acceptable additive, if necessary, using a technique widely used for obtaining a single preparation or a combination preparation. Moreover, the therapeutic agent for pruritus of the present invention can be administered parenterally or orally.

  Preferred dosage forms for use as an eye itch treatment agent include eye drops, eye ointments, tablets and the like, but more preferred dosage forms are eye drops or eye ointments. These can be formulated using widely used techniques. For example, an eye drop can be prepared by appropriately blending an isotonic agent, buffer, pH adjuster, solubilizer, thickener, stabilizer, preservative and the like as an additive. In addition, a stable ophthalmic solution 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, ε-aminocaproic acid, trometamol, and the like.

  Examples of the pH adjuster 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. It can also be used.

  In the ophthalmic solution containing the agent for treating pruritus of the present invention, it is desirable to set the pH to 4.0 to 8.0, and it is desirable to set the osmotic pressure ratio to around 1.0.

  The dosage for use as an eye itch treatment agent can be appropriately selected depending on symptoms, age, dosage form, etc., but in the case of eye drops, it is 0.001 to 10% (w / v), preferably 0.01 to 1%. What is necessary is just to instill the thing of the density | concentration of (w / v) 1 to several times a day.

  Formulation examples and pharmacological test results are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.

[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
Palmidolol 500mg 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, 100 mg, and 1000 mg of palmidolol in 100 ml can be prepared. Further, indomethacin morpholinamide, anandamide, or 2-oxoquinoline derivative can be used in place of palmidolol.

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

Formulation Example 2
300mg Palmidolol 300mg
Liquid paraffin 10g
White petrolatum

  In the same manner as in Formulation Example 2, various concentrations of eye ointment can be prepared by appropriately changing the amount of palmidolol added. Further, indomethacin morpholinamide, anandamide, or 2-oxoquinoline derivative can be used in place of palmidolol.

[Pharmacological test]
Using a histamine-inducing model, an allergic conjunctivitis model, and a platelet-activating factor-inducing model, the effect of cannabinoid agonists on the suppression of eye itching was examined.

(1) Anti-pruritic action on histamine-induced model (experimental method)
Palmidolol was suspended in physiological saline to a concentration of 0.1% and 0.5% (W / V), and the resulting suspension was applied to both eyes of 5-week-old male Hartley guinea pigs at 10 μL / eye respectively. Instillation was carried out one by one, and 10 minutes after that, the same concentration of palmidolol suspension was instilled (twice in total). In addition, physiological saline was used as a control.

  Five minutes after the second administration of palmidolol, a physiological saline solution containing 1.0% (W / V) histamine was administered to both eyes of the guinea pig at 10 μL / eye to induce eye scratching behavior. did.

  The behavior of guinea pigs after instillation of histamine was videotaped, and 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 12 eyes each.

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

(Experimental result)
From Table 1, it was confirmed that the number of eye scratches of guinea pigs administered with eyedrops of palmidolol markedly decreased compared with the control, so that palmidolol has an effect of suppressing eye itching. The degree depends on the concentration of palmidolol.

(2) Anti-pruritic effect on allergic conjunctivitis model (experimental method)
Aluminum hydroxide gel adsorbed ovalbumin (20 μg / mL) was dissolved in physiological saline, and 100 μL each of the resulting solution was injected under the conjunctiva of both eyes of a 4-week-old male Hartley guinea pig for active sensitization. went. On the 14th, 16th, 18th, 21st, 23rd and 25th days after sensitization, 10 μL / eye of ovalbumin 2.5% (W / V) physiological saline was administered. And caused allergic conjunctivitis. In addition, physiological saline was used as a control.

  On the 16th, 18th, 21st, 23rd, and 25th day after sensitization, 0.1% (W / V) was suspended in both eyes of the guinea pig by 10 μL / eye.

Video of guinea pig behavior for 30 minutes after instillation of ovalbumin on day 21, 23 and 25 after sensitization, and counting the number of eye scratches when palmidolol and control were instilled. Itching was evaluated. Table 2 shows the inhibition rate (average value) of the eye scratching behavior relative to the control. The number of examples is 12 eyes each.

(Experimental result)
As is apparent from Table 2, the eye scratching behavior of guinea pigs administered with eyedrops of palmidolol was significantly suppressed as compared with the control, and it was thus confirmed that palmidolol has an effect of suppressing eye itching.

(3) Eye itching inhibitory action on platelet activating factor induction model Anandamide (test compound A), indomethacin morpholinamide (test compound B) and N- (benzo [d] [1,3] dioxol-5-ylmethyl) Inhibition of eye itching on a platelet activating factor (PAF) induction model using -7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide (test compound C) It was investigated.

(experimental method)
Test compound A (50 mg / ml in EtOH) is suspended in physiological saline to a concentration of 0.01% (W / V), and test compound B is suspended in 1.0% Tween80 / physiological saline in 0.001% and Suspend to a concentration of 0.01% (W / V) and test compound C in 0.001%, 0.001% and 0.01% (W / V) in 5.0% Tween 80 / saline solution. Each test compound suspension was prepared by suspending at a concentration of 1 to 5%.

 For test compounds A and B, each test compound suspension was instilled into both eyes of a 5-week-old male Hartley guinea pig at 10 μL / eye, and 10 minutes later, each test compound suspension was kept at the same concentration. Were administered by instillation (total 2 times). For test compound C, the test compound suspension was instilled into both eyes of a 5-week-old male Hartley guinea pig at 10 μL / eye.

 Next, for test compounds A and B, 5 minutes after the second instillation of each test compound suspension, and for test compound C, 15 times after the test compound suspension was instilled. After a minute, a physiological saline solution in which platelet activating factor 0.1% (W / V) was dissolved was instilled into both eyes of the guinea pig 10 μL / eye to induce eye scratching behavior. As controls for test compounds A, B, and C, 2.0% ethanol / physiological saline, physiological saline, and 5.0% Tween 80 / physiological saline were used, respectively.

The behavior of guinea pigs after instillation of platelet activating factor was videotaped, and eye itching was evaluated by counting the series of behaviors of scratching the eyes with the hind limb for each eye. Table 3 shows the average value of the eye scratching behavior inhibition rate for 30 minutes after administration of the platelet activating factor. The number of examples is 8 eyes each.

(Experimental result)
From Table 3, since the number of eye scratches of guinea pigs to which test compounds A, B and C were administered by instillation was significantly reduced as compared with the control, it was confirmed that each test compound had an eye itching inhibitory effect. In addition, the degree is almost dependent on the concentration of each test compound suspension.

  As apparent from the results of the pharmacological test, palmidolol, indomethacin morpholinamide, anandamide, and 2-oxoquinoline derivative exhibit an excellent pruritus-suppressing effect on eye itching. The cannabinoid agonist of the present invention acts directly on the peripheral nerve endings and suppresses transmission of the itch signal in the nerve cell, and therefore can exhibit an excellent pruritus-suppressing effect against itch caused by all factors.

Claims (7)

A therapeutic agent for pruritus comprising a cannabinoid agonist as an active ingredient. The cannabinoid agonist is palmidolol, indomethacin morpholinamide, anandamide or N- (benzo [d] [1,3] dioxol-5-ylmethyl) -7-methoxy-2-oxo-8-pentyloxy-1,2- The therapeutic agent for pruritus according to claim 1, which is dihydroquinoline-3-carboxamide. The agent for treating pruritus according to claim 1 or 2, wherein the pruritus is eye pruritus. The therapeutic agent for pruritus according to claim 3, wherein the pruritus is allergic conjunctivitis, spring catarrh, atopic keratoconjunctivitis, infectious keratoconjunctivitis, blepharitis, and pruritus associated with ophthalmic surgery. The pruritus treatment agent according to claim 3 or 4, wherein the dosage form is an eye drop or an eye ointment. The agent for treating pruritus according to claim 1 or 2, wherein the pruritus is pruritus not involving mast cells. The agent for treating pruritus according to claim 3, wherein the pruritus is ocular pruritus not involving mast cells.