WO2005053672A1

WO2005053672A1 - Remedy for pruritus comprising cilomilast or salt thereof as the active ingredient

Info

Publication number: WO2005053672A1
Application number: PCT/JP2004/018427
Authority: WO
Inventors: Daisuke Shii; Tomoko Oda; Hideki Miyake
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 2003-12-04
Filing date: 2004-12-03
Publication date: 2005-06-16

Abstract

It is intended to find out a novel pharmacological effect (a medicinal use) of cilomilast. Because of having an excellent antipruritic effect, cilomilast is useful as a remedy for pruritus of any types such ocular pruritus, skin pruritus and systemic pruritus.

Description

Specification

Antipruritic agent containing cilomilast or a salt thereof as an active ingredient

The present invention relates to a therapeutic agent for pruritus containing cilomilast or a salt thereof as an active ingredient. Background art

In pruritus, the pruritic receptors present in the epidermis-dermis junction of the skin and mucous membranes are stimulated by a transmitter (pruritic substance), and the stimulus is transmitted to the central nervous system and is felt as itching. For example, histamine, kinin, bile salts, substance P, and prostaglandins are widely known as mediators that induce itch. It is presumed that histamine and other mediators released from mast cells and the like are involved in the appearance of allergic factors, and it is known that antihistamines have stronger effects than antiallergy agents. .

As pruritus, for example, itching that occurs in humans and animals, pruritus in the skin, pruritus in the ears and nose, and pruritus in the body are known. Eye pruritus is a disease that causes itching of eyes, eyelids, eyelid edges, etc. due to pollen, dust, mites, mold, pet hair, contact lenses, cosmetics, etc. This causes conjunctival hyperemia, and conjunctival papillae reddens and proliferates. In severe cases, lesions appear on the cornea and sclera, and may progress to spring catarrhal.

By the way, in the specification of Japanese Patent No. 28733090, cilomilast [chemical name: cis-1 [4-cyano-4- (3-cyclopentyloxy-14-methoxyphenyl) cyclohexane-1-carbon] It is described that a compound such as an acid is useful in mediating or inhibiting the enzyme activity of phosphodiesterase IV, and is effective as a therapeutic agent for allergic and inflammatory diseases, especially asthma. However, there is no description that the compounds described in the above patent specifications show efficacy against itch, which is the most major symptom associated with allergic diseases. Disclosure of the invention

As described above, cilomilast described in the above patent specification has various pharmacological properties as a medicament. Although it is effective, finding a new pharmacological effect against itch is an interesting issue.

The present inventors have conducted intensive studies to search for new pharmaceutical uses of the above-mentioned compounds, and found that the above-mentioned compounds exert an excellent anti-pruritic effect in an ocular pruritus inhibition test using an albumin-induced ocular pruritus model. This led to the completion of the present invention.

The present invention relates to a therapeutic agent for pruritus comprising cilomilast or a salt thereof as an active ingredient.

Typical pruritus to which the therapeutic agent for pruritus according to the present invention is applied is pruritus of the eye.

A preferred dosage form of the therapeutic agent for pruritus according to the present invention is a liquid, more preferably an eye drop. The concentration of the active ingredient in the eye drops is preferably from 0.01 to 3% (w / V).

Another preferred form of the therapeutic agent for antipruritus according to the present invention is an external preparation, more preferably an ointment such as an eye ointment.

Silomilast, which is an active ingredient of the therapeutic agent for pruritus according to the present invention, is represented by the chemical name of cis- [4-cyano-14- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carbonic acid]. It is represented by the following chemical structural formula.

The salt of cilomilast is not particularly limited as long as it is a pharmaceutically acceptable salt. Salts with inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid, and salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid and tartaric acid Salts, and salts with alkali metals such as sodium, potassium, and calcium or alkaline earth metals are also included. More preferred salts are the sodium and potassium salts. Further, a quaternary ammonium salt of cilomilast is also included in the salt of the present invention. Furthermore, geometric isomers, optical isomers, tautomers, and polymorphs of silomilast are also included in the scope of the present invention. Note that cilomilast may be in the form of a hydrate or a solvate.

The therapeutic agent for pruritus according to the present invention is characterized by It has an excellent antipruritic effect on pruritus, and has therapeutic and inhibitory effects on pruritus such as eye pruritus, skin pruritus, otitis pruritus and systemic pruritus that occur in humans and animals. The therapeutic agent for pruritus according to the present invention is preferably used as a therapeutic agent for ocular pruritus.

Eye pruritus according to the present invention is a disease in which the eyes, eyelids, eyelid margins, etc. become itchy due to pollen, dust, mites, mold, pet hair, contact lenses, cosmetics, eye trauma, etc. Itching is associated with allergic unilateral conjunctivitis, spring catarrh, atopic keratoconjunctivitis, infectious keratoconjunctivitis, blepharitis, dry eye, conjunctivitis, corneal herpes, corneal herpes, etc. and ophthalmic surgery. Includes those that develop.

The therapeutic agent for pruritus according to the present invention can be formulated into a single preparation or a combined preparation by using a commonly used technique, if necessary, by adding a pharmaceutically acceptable additive.

The therapeutic agent for pruritus according to the present invention can be administered parenterally or orally. Examples of oral preparations include liquid preparations for internal use (eg, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, and emulsions), solid preparations for internal use (eg, tablets (sublingual tablets, Disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, micro capsules), powders, granules, troches and the like. Parenteral preparations include, for example, liquid preparations (eg, injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, instillations, etc.), eye drops (eg, 7J eye drops ( 7-based ophthalmic solution, 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.)), etc.), external preparations (for example, Ointments (eg, B gorge ointment), gels, creams, compresses, patches, liniments, etc., sprays, inhalants, sprays, nasal drops, suppositories (eg, rectal suppositories, vaginal suppositories) ) And the like. These preparations may be release controlling agents such as immediate release preparations and sustained release preparations. These formulations can be prepared by known methods, for example, the methods described in the Japanese Pharmacopoeia.

Liquid preparations for oral administration are prepared, for example, by dissolving, suspending or emulsifying the active ingredient in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). The liquid preparation for internal use may further 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.

Solid preparations for internal use as oral preparations include, for example, excipients (e.g., lactose, Ninitol, glucose, microcrystalline cellulose, starch, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrants (eg, calcium cellulose glycolate, etc.), lubricants ( For example, it is mixed with a stabilizer such as magnesium stearate, etc.), a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, etc.) and the like, and prepared according to a conventional method. The solid preparation for internal use may be coated with a coating agent (for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.) if necessary. The coating layer may be two or more layers.

An external preparation as a parenteral preparation is prepared by a known method or a commonly used formulation. For example, ointments are prepared by triturating or melting the active ingredient as a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (eg, 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 (Eg, beeswax, spermaceti, ceresin, etc.), surfactants (eg, polyoxyethylene alkyl ether phosphate, etc.), higher alcohols (eg, cetanol, stearyl alcohol, setosteryl alcohol, etc.), silicone oil (eg, For example, dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene) Glycol, polyethylene glycol, macrogol, etc.), vegetable oils (eg, castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (eg, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancer, anti-rash Those selected from the agents may be used alone or in combination of two or more. The ointment may further contain a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like.

Gels are prepared, for example, by melting the active ingredient in a base. The gel base is selected from those known or commonly used. For example, lower alcohols (eg, ethanol, isopropyl alcohol, etc.), gelling agents (eg, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agents (eg, triethanol Amines, diisopropanolamines, etc.), surfactants (eg, monos Polyethylene glycol theate), gums, water, absorption enhancers, and rash preventives are used alone or as a mixture of two or more. The gel may further contain a preservative, an antioxidant, a flavoring agent and the like.

Creams are prepared, for example, by melting or emulsifying the 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 (for example, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (poly) Those selected from oxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption promoters, and rash inhibitors are used alone or in combination of two or more. The cream may further contain a preservative, an antioxidant, a flavoring agent, and the like.

A poultice is prepared, for example, by melting an active ingredient in a base, forming a kneaded product, and spreading and applying the mixture on a support. The compress base is selected from known or commonly used ones. For example, thickeners (eg, polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (eg, urea, glycerin, propylene glycol, etc.), fillers (eg, kaolin, oxidized) One selected from zinc, talc, calcium, magnesium, etc.), water, a dissolution aid, a tackifier, and a rash inhibitor are used alone or in combination of two or more. The poultice may further contain a preservative, an antioxidant, a flavoring agent and the like.

A patch is prepared by, for example, melting an active ingredient in a base and spreading and applying the composition on a support. The base for the patch is selected from known or commonly used ones. For example, those selected from polymer bases, oils and fats, higher fatty acids, tackifiers, and rash inhibitors are used alone or in combination of two or more. The patch may further contain a preservative, an antioxidant, a flavoring agent, etc. Examples of the liniment include an active ingredient such as water, alcohol (eg, ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, seggen, It is prepared by dissolving, suspending or emulsifying alone or in combination of two or more selected from emulsifiers and suspending agents. The liniment may further contain a preservative, an antioxidant, a flavoring agent and the like.

Sprays and sprays are prepared by known or commonly used formulations. This These include, for example, buffers other than commonly used diluents that provide isotonicity with stable IJ such as sodium bisulfite, for example, isotonic such as sodium chloride, sodium citrate or citric acid. An agent may be contained.

Inhalants include aerosols, PJs: powders to be taken or liquids for inhalation. The liquid preparation for inhalation may be in the form of being dissolved or suspended in water or another suitable medium before use. Liquid preparations for inhalation include preservatives (eg, benzalkonium chloride, paraben, etc.), coloring agents, buffering agents (eg, sodium phosphate, sodium acetate, etc.), and isotonic agents (eg, sodium chloride, concentrated glycerin, etc.) It is prepared by using a thickener (for example, caliperoxy vinyl polymer), an absorption enhancer and the like as required. Powders for inhalation include lubricants (eg, stearic acid and its salts), binders (eg, starch, dextrin, etc.), excipients (eg, lactose, cellulose, etc.), coloring agents, preservatives (eg, , Benzalkonium chloride, paraben, etc.) and absorption enhancers, if necessary. A nebulizer (eg, an atomizer, a nebulizer) is usually used to administer a liquid for inhalation, and a powder inhaler is usually used for administering a powder for inhalation.

Parenteral injections include solutions, suspensions, emulsions, and solid injections that are dissolved or suspended in a solvent before use. Injections are used, for example, by dissolving, suspending or emulsifying the active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, alcohols such as propylene glycol, polyethylene glycol, ethanol and the like and a combination thereof are used. Injectables may further contain stabilizers, solubilizing agents (eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. May be included. Injectables are preferably prepared by sterilization in the final step or prepared by an aseptic procedure.In the case of a sterile solid preparation, for example, a freeze-dried product is prepared and sterilized or sterilized before use. It can also be used after dissolving in distilled water or other solvents.

Preferred dosage forms for using the therapeutic agent for pruritus according to the present invention as a therapeutic agent for ocular pruritus are eye drops, eye ointments, tablets and the like, more preferably eye drops or eye ointments. These can be prepared using commonly used techniques. For example, eye drops are isotonic as an additive It can be prepared by appropriately mixing agents, buffers, pH regulators, solubilizers, thickeners, stabilizers, preservatives and the like. 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 the tonicity agent 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 and the like.

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 solubilizers include polysorbate 80, polyoxetylene hardened castor oil 60, macrogol 400, and the like.

Examples of the thickener and dispersant include cellulosic polymers such as hydroxypropylmethylcellulose and hydroxypropyl cellulose, polyvinyl alcohol, and polyvinylpyrrolidone. Examples of the stabilizer include edetic acid and sodium edetate And so on.

Examples of preservatives (preservatives) include general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl parahydroxybenzoate, propyl benzoate, pill, chlorobutanol, and the like. Can be used in combination.

When the therapeutic agent for pruritus according to the present invention is an eye drop, the pH is preferably set to 4.0 to 8.5, and the osmotic pressure ratio is preferably set to around 1.0.

The present invention also relates to a method for treating pruritus, which comprises administering cilomilast or a salt thereof to a patient in a therapeutically effective amount.

The dosage of the active ingredient when used as a therapeutic agent for pruritus can be appropriately selected depending on the condition, age, dosage form, etc., but for oral preparations, preferably 1 mg to 100 mg, more preferably 5 mg to 30 mg. mg may be administered one to several times a day (eg, one to three times). The eye drops are preferably 0.001 -10% (w / v), more preferably 0.01 to 3% (w / v) at a single dose: ~ Several drops may be instilled one to several times a day (eg, 1 to 8 times). The eye ointment is preferably administered at a concentration of 0.001 to 10% (w / w), more preferably 0.01 to 3% (w / w) once to several times a day (for example, 1 to 4 times). Times).

Of course, as described above, the dose varies depending on various conditions, so that a dose smaller than the above dose may be sufficient, or may be required beyond the range.

In an eye pruritus suppression test, cilomilast exhibited an excellent pruritus suppression effect in an albumin-induced ocular pruritus model, and was useful as a therapeutic agent for all pruritus such as eye pruritus, skin pruritus and systemic pruritus . BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, pharmacological tests and preparation examples are shown, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.

c Pharmacological test:]

Using an albumin-induced ocular pruritus model, the inhibitory effect of cilomilast on ocular pruritus was examined. Eye pruritus suppression test using albumin-induced eye pruritus model

(experimental method)

Aluminum hydroxide gel-adsorbed ovalbumin (20 pg / mL) was dissolved in a physiological saline solution, and active sensitization was performed by injecting 100 g of each of them into the 6-week-old male Hartley guinea pig under the conjunctiva of both eyes. On the 14th day after the sensitization, 1.0% (W / V) saline solution of ovalbumin was instilled into both eyes by 10 L / eye.

As a test compound, a solution in which 0.1% (WZV) and 0.5% (/) of the present compound were suspended in 1.5% Tween80 was prepared. Each eye was instilled at a dose of 10 pL / eye to each eye. In addition, 1.5% Teen80 was used as a control.

A video recording of the behavior of the guinea pig for 60 minutes after instillation of opalbumin was performed, and the number of eye drops when each test compound solution and control were instilled was counted. The antipruritic effect was evaluated. Table 1 shows the eye-drawing behavior suppression rate (average value) for the control calculated according to the following equation. The number of cases is 8 eyes each.

Suppression rate of eye-catching operation (%) = 100-

([Number of eye drops of test compound] ÷ [Number of eye drops of control]) X 100

(Experimental result)

As is evident from Table 1, the number of B dip pulls in guinea pigs to which cilomilast was administered by eye was significantly reduced as compared to the control, and the degree depends on the test compound concentration. From the above results, it was clarified that cilomilast had an excellent inhibitory action on eye irritation.

[Formulation example]

The typical preparation examples used in the present invention are shown below.

1. Eye drops

An eye drop having the following formulation is prepared using a commonly used method.

Prescription example 1

.0 Om 1

Silomilast 10 Omg

Concentrated glycerin 50 Omg

Polysorbate 80 20 Omg

Sodium dihydrogen phosphate hydrate

1N7K acid Nadani Sodium sterilized purified water In the same manner as in Formulation Example 1, eye drops containing 10 mg, 5 Omg, and 1000 mg of cilomilast in 100 ml can be prepared.

2. Eye ointment

An eye ointment having the following formulation is prepared using a commonly used method.

Prescription example 2

In 100 g

Silomilast 200mg

Liquid paraffin 10g

White Vaseline Suitable amount In the same manner as in Formulation Example 2, by appropriately changing the amount of cilomilast added, eye ointments of various concentrations can be prepared. Industrial applicability

Since cilomilast exerts an excellent pruritus-suppressing effect in an albumin-induced ocular pruritus model, it is useful as a therapeutic agent for any pruritus such as ocular pruritus, skin pruritus and systemic pruritus.

Claims

The scope of the claims

1. A therapeutic agent for pruritus comprising cilomilast or a salt thereof as an active ingredient.

2. The therapeutic agent for pruritus according to claim 1, wherein the pruritus is eye pruritus.

3. The therapeutic agent for pruritus according to claim 1, wherein the dosage form is a liquid.

4. The therapeutic agent for pruritus according to claim 3, wherein the liquid preparation is an eye drop.

5. The therapeutic agent for pruritus according to claim 4, wherein the concentration of the active ingredient in the eye drops is 0.01 to 3% (w / v).

6. The therapeutic agent for pruritus according to claim 1, wherein the dosage form is an external preparation.

7. The therapeutic agent for pruritus according to claim 6, wherein the external preparation is an ointment.

8. The therapeutic agent for pruritus according to claim 7, wherein the ointment is an eye ointment.

9. A method for treating pruritus, comprising administering cilomilast or a salt thereof to a patient in a therapeutically effective amount.

10. The method according to claim 9, wherein the pruritus is eye pruritus.

11. The method according to claim 9 or 10, wherein cilomilast or a salt thereof is administered in the form of a liquid preparation.

12. The method according to claim 11, wherein the solution is an eye drop.

13. The method according to claim 12, wherein the concentration of cilomilast or a salt thereof in the eye drops is 0.01 to 3% (w / v).

14. The method according to claim 9 or 10, wherein the administration of cilomilast or a salt thereof is carried out in the form of an external preparation.

15. The method according to claim 14, wherein the external preparation is an ointment.

16. The method according to claim 15, wherein the ointment is an eye ointment.

17. Use of cilomilast or a salt thereof for the manufacture of a therapeutic agent for pruritus.

18. The use according to claim 17, wherein the pruritus is eye pruritus.

19. Use according to claim 17 or claim 18, wherein the dosage form is a liquid.

20. The use according to claim 19, wherein the solution is an eye drop.

21. The method according to claim 20, wherein the concentration of the active ingredient in the eye drops is 0.01 to 3% (w / v). Use.

22. Use according to claim 17 or 18, wherein the dosage form is an external preparation.

23. Use according to claim 22, wherein the external preparation is an ointment.

2 4. The use according to claim 23, wherein the ointment is an eye ointment.