WO2000007594A1

WO2000007594A1 - Use of il-2 inhibitors in the treatment of rheumatoid arthritis

Info

Publication number: WO2000007594A1
Application number: PCT/JP1999/004149
Authority: WO
Inventors: Susumu Miyata
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1998-08-05
Filing date: 1999-08-02
Publication date: 2000-02-17
Also published as: GB9817064D0

Abstract

A new use of IL-2 inhibitor for treating or preventing rheumatoid arthritis by topical administration is provided.

Description

DESCRI PT ION SE OF IL-2 INHIBITORS IN THE TREATMENT OF RHEUMATOID ARTHRITIS

TECHNICAL FIELD

This invention relates to a new use of interleukin 2 inhibitor (hereinafter, referred to IL-2 inhibitor). More specifically, this invention relates to a new use of IL-2 inhibitor for preventing or treating rheumatoid arthritis by topical administration. BACKGROUND ART

Various IL-2 inhibitors have already been known. For example, it is well known that cyclosporins and tacrolimus (FK506), and their derivatives, possess an inhibitory activity on IL-2 production, which was shown in, for example, USP4, 929, 611, and so on. DISCLOSURE OF INVENTION

The inventors of this invention have surprisingly found that the IL-2 inhibitor mentioned herein below has a preventing or treating effect on rheumatoid arthritis by topical administration.

Accordingly, this invention provides a new use of the IL-2 inhibitor for preventing or treating rheumatoid arthritis by topical administration.

Further, this invention provides a pharmaceutical composition for preventing or treating rheumatoid arthritis by topical administration, which comprises the IL-2 inhibitor.

Still further, this invention provides a method for preventing or treating rheumatoid arthritis, which comprises administering said IL-2 inhibitor to mammals topically. The "IL-2 inhibitor" used in the present invention should not be limited and be considered to mean any ones possessing IL-2 inhibitory activity. The particular example is the one possessing an inhibitory activity on IL-2 production. And the other is the one that inhibits the transmission of IL-2 signal.

One example of the inhibitor of IL-2 production is macrolides of the following formula (I).

(wherein each of adjacent pairs of R¹ and R^:, R³ and R⁴ , and R⁵ and R⁶ independently

(a) is two adjacent hydrogen atoms, but R² may also be an alkyl group or

(b) may form another bond formed between the carbon atoms to which they are attached;

R⁷ is a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkoxy group, or an oxo group together with

R¹;

R⁸ and R⁹ are independently a hydrogen atom or a hydroxy group;

R¹⁰ is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group; X is an oxo group, (a hydrogen atom and a hydroxy group) , (a hydrogen atom and a hydrogen atom) , or a group represented by the formula -CH₂0-; Y is an oxo group, (a hydrogen atom and a hydroxy group) ,

(a hydrogen atom and a hydrogen atom) , or a group represented by the formula N-NRⁿR¹² or N-OR¹³; R¹¹ and R¹² are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group; R¹³, R^:\ R¹⁵, R¹⁶, R¹⁷, R^:\ R¹⁹, R²² and R²³ are independently a hydrogen atom or an alkyl group; R²⁴ is an optionally substituted ring system which may contain one or more heteroatoms; n is an integer of 1 or 2; and in addition to the above definitions, Y, R¹⁰ and R²³, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkoxy, a benzyl, a group of the formula -CH₂Se (C₆H₅) , and an alkyl substituted by one or more hydroxy groups.

Preferable R²⁴ may be cyclo (C₅_₇) alkyl group, and the following ones can be exemplified.

(a) a 3, 4-di-oxo-cyclohexyl group;

(b) a 3-R²⁰-4-R¹-cyclohexyl group, in which R²⁰ is hydroxy, an alkoxy group, an oxo group, or a -OCH₂OCH₂CH₂OCH₃ group, and R²¹ is hydroxy, -OCN, an alkoxy group, a heteroaryloxy which may be substituted by suitable substituents, a

-OCH₂OCH₂CH₂OCH₃ group, a protected hydroxy group, chloro, bromo, iodo, aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy, or R²⁵R²⁶CHCOO-, in which R²⁵ is optionally protected hydroxy or protected amino, and R²⁶ is hydrogen or methyl, or R²⁰ and R²¹ together form an oxygen atom in an epoxide ring; or (c) cyclopentyl group substituted by methoxymethyl, optionally protected hydroxymethyl, acyloxymethyl

(in which the acyl moiety optionally contains either a dimethylamino group which may be quaternized, or a carboxy group which may be esterified) , one or more amino and/or hydroxy groups which may be protected, or aminooxalyloxymethyl . A preferred example is a 2- formyl-cyclopentyl group.

The definitions used in the above general formula (I) and the specific and preferred examples thereof are now explained and set forth in detail.

The term "lower" means, unless otherwise indicated, a group having 1 to 6 carbon atoms.

Preferable examples of the "alkyl groups" and an alkyl moiety of the "alkoxy group" include a straight or branched chain aliphatic hydrocarbon residue, for example, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl .

Preferable examples of the "alkenyl groups" include a straight or branched chain aliphatic hydrocarbon residue having one double-bond, for example, a lower alkenyl group such as vinyl, propenyl (e.g., allyl group) , butenyl, methylpropenyl, pentenyl and hexenyl .

Preferable examples of the "aryl groups" include phenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl .

Preferable protective groups in the "protected hydroxy groups" and the "protected amino" are 1- (lower alkylthio)- (lower) alkyl group such as a lower alkylthiomethyl group (e.g., methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl , etc.), more preferably Cj -C₄ alkylthiomethyl group, most preferably methylthiomethyl group; trisubstituted silyl group such as a tri (lower) alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert- butyldimethylsilyl, tri-tert-butylsilyl , etc.) or lower alkyl-diarylsilyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenyl- silyl, etc.), more preferably tri (C_j-C alkylsilyl group and C^C,, alkyldiphenylsilyl group, most preferably tert- butyldimethylsilyl group and tert-butyldiphenylsilyl group; and an acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group substituted by an aromatic group, which are derived from a carboxylic acid, sulfonic acid or carbamic acid . Examples of the aliphatic acyl groups include a lower alkanoyl group optionally having one or more suitable substituents such as carboxy, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl , carboxyhexanoyl, etc.; a cyclo (lower) alkoxy (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl , menthyloxyhexanoyl, etc.; a camphorsulfonyl group; or a lower alkylcarbamoyl group having one or more suitable substituents such as carboxy or protected carboxy, for example, carboxy (lower) alkylcarbamoyl group (e.g., carboxymethylcarbamoyl , carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl , carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), tri- (lower) alkylsilyl (lower) alkoxycarbonyl (lower) alkylcarbamoyl group (e.g., trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl , tri- methylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on.

Examples of the aromatic acyl groups include an aroyl group optionally having one or more suitable substituents such as nitro, e.g., benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc.; and an arenesulfonyl group optionally having one or more suitable substituents such as halogen, e.g., benzenesulfonyl , toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.

Examples of the aliphatic acyl groups substituted by an aromatic group include ar (lower ) alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo (lower) alkyl, e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl- 2-propoxy-2-phenylacetyl, etc.

More preferable acyl groups among the aforesaid acyl groups are C_j-C,, alkanoyl group optionally having carboxy, cyclo (C₅-C₆) alkoxy (Cj-C,,) alkanoyl group having two (C-,-C₄) alkyls at the cycloalkyl moiety, camphorsulfonyl group, carboxy- (C₃-C₄) alkylcarbamoyl group, tri (C_j-C alkylsilyl (C_j-C₄) alkoxycarbonyl (C_j-C - alkylcarbamoyl group, benzoyl group optionally having one or two nitro groups, benzenesulfonyl group having halogen, or phenyl (C₁-C₄) alkanoyl group having C_j-C₄ alkoxy and trihalo (C_j-C₄) alkyl group. Among these, the most preferable ones are acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2- phenylacetyl .

Preferable examples of the "5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring" include a pyrrolyl group and a tetrahydrofuryl group.

"A heteroaryl which may be substituted by suitable substituents" moiety of the "heteroaryloxy which may be substituted by suitable substituents" may be the ones exemplified for R¹ of the compound of the formula of EP-A-532, 088, with preference given to l-hydroxyethylindol-5-yl, the disclosure of which is incorporated herein by reference.

The macrolides for use in accordance with this invention are well known to have excellent immunosuppressive activity, antimicrobial activity and other pharmacological activities and, as such, be of value for the treatment or prevention of rejection reactions by transplantation of organs or tissues, graft-vs- host diseases, autoimmune diseases, and infectious diseases [EP-A-0184162, EP-A-0323042 , EP-A-423714, EP-A-427680, EP-A- 465426, EP-A-480623, EP-A-532088, EP-A-532089, EP-A-569337, EP-A-626385, O89/05303, WO93/05058, W096/31514, W091/13889, 091/19495, O93/5059, etc.], the disclosures of which are incorporated herein by reference.

Particularly, the compounds which are designated as FR900506 (=FK506), FR900520 (ascomycin) , FR900523, and FR900525 are products produced by microorganisms of the genus Streptomyces , such as Streptomyces tsukubaensis No. 9993 [deposited with National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology (formerly Fermentation Research Institute Agency of Industrial Science and Technology ) , at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, date of deposit October 5, 1984, accession number FERM BP-927] or Streptomyces hy roscopicus subsp. yakushimaensis No. 7238 [deposited with National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology (formerly Fermentation Research Institute Agency of Industrial Science and Technology ), at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, date of deposit January 12, 1985, accession number FERM BP-928] [EP-A-0184162] . The FK506 (general name: tacrolimus) of the following chemical formula, in particular, is a representative compound.

Chemical name: 17-allyl-l, 14-dihydroxy-12- [2- (4-hydroxy-3- methoxycyclohexyl) -1-methylvinyl] -23, 25- dimethoxy-13, 19,21, 27-tetramethyl-ll , 28-dioxa- 4-azatricyclo [22.3.1.0^4,9]octacos-18-ene- 2,3,10, 16-tetraone

The preferred examples of the macrolides (I) are the ones, wherein each of adjacent pairs of R³ and R⁴ or R⁵ and R⁶ independently form another bond formed between the carbon atoms to which they are attached; each of R⁸ and R²³ is independently a hydrogen atom; R⁹ is a hydroxy group; R¹⁰ is a methyl group, an ethyl group, a propyl group or an allyl group; X is (a hydrogen atom and a hydrogen atom) or an oxo group; Y is an oxo group; each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²² is a methyl group; R²⁴ is a 3-R²⁰-4-R²¹-cyclohexyl group, in which R²⁰ is hydroxy, an alkoxy group, an oxo group, or a -OCH₂OCH₂CH₂OCH₃ group, and R²¹ is hydroxy, -OCN, an alkoxy group, a heteroaryloxy which may be substituted by suitable substituents, a -OCH₂OCH₂CH₂OCH₃ group, a protected hydroxy group, chloro, bromo, iodo, aminooxalyloxy, an azido group, p- tolyloxythiocarbonyloxy, or R²⁵R²⁶CHCOO-, in which R²⁵ is optionally protected hydroxy or protected amino, and R²⁶ is hydrogen or methyl, or R²⁰ and R²¹ together form an oxygen atom in an epoxide ring; and n is an integer of 1 or 2.

The preferable macrolides (I) is tacrolimus, ascomycin or its derivatives such as 33-epi-chloro-33-desoxyascomycin, which is disclosed in EP 427,680, example 66a. Other preferable compounds (I) are, for example, the compound of example 6d in EP569337, and the compound of example 8, EP626385.

The compounds shown in EP-0184162, EP323042, EP424714, EP427680, EP465426, EP474126, EP480623, EP484936, EP532088, EP532089, EP569337, EP626385, O89/05303, WO93/05058, W096/31514, W091/13889, 091/19495, WO93/5059, W096/31514 and so on, are also exemplified as the preferable examples of the macrolides (I) , the disclosures of which are incorporated herein by reference. Further example of the inhibitor of IL-2 production is cyclosporins, such as cyclosporin A, B, D, etc, which are shown in THE MERCK INDEX (12th edition), No. 2821, the disclosure of which is incorporated herein by reference.

The example of the inhibitor of transmission of IL-2 signal is an another type of macrolide which is called as rapamycin [THE MERCK INDEX (12th edition), No. 8288] and its derivatives. Preferable example of the derivatives is an O-substituted derivative in which the hydroxy in position 40 of formula A illustrated at page 1 of WO 95/16691, incorporated herein by reference, is replaced by -OR_j in which R_x is hydroxyalkyl, hydroalkoxyalkyl, acylaminoalkyl and aminoalkyl; for example 40-O- (2-hydroxy) ethyl-rapamycin, 40-O- (3-hydroxy) propyl- rapamycin, 40-O- [2- (2-hydroxy) ethoxy] ethyl-rapamycin and 40- 0- (2-acetaminoethyl ) -rapamycin . These O-substituted derivatives may be produced by reacting rapamycin (or dihydro or deoxo-rapamycin) with an organic radical attached to a leaving group (for example RX where R is the organic radical which is desired as the O-substituent , such as an alkyl, allyl, or benzyl moiety, and X is a leaving group such as CC1₃C(NH)0 or CF₃S0₃) under suitable reaction conditions. The conditions may be acidic or neutral conditions, for example in the presence of an acid like trifluoromethanesulfonic acid, camphorsulfonic acid, p- toluenesulfonic acid or their respective pyridinium or substituted pyridinium salts when X is CC1₃C(NH)0 or in the presence of a base like pyridine, a substituted pyridine, diisopropylethylamine or pentamethylpiperidine when X is CF₃S0₃. The most preferable one is 40-0- (2-hydroxy) ethyl rapamycin, which is disclosed in WO94/09010, the disclosure of which is incorporated herein by reference.

The macrolides (I), and rapamycin and its derivatives, have a similar basic structure, i.e., tricyclic macrolide structure, and at least one of the biological properties (for example, immunological properties) .

The IL-2 inhibitor may be in a form of its salt, which includes conventional non-toxic and pharmaceutically acceptable salt such as the salt with inorganic or organic bases, specifically, an alkali metal salt such as sodium salt and potassium salt, an alkali earth metal salt such as calcium salt and magnesium salt, an ammonium salt and an amine salt such as triethylamine salt and N-benzyl-N-methylamine salt.

With respect to the IL-2 inhibitor such as the macrolides (I) , it is to be understood that there may be conformers and one or more stereoisomers such as optical and geometrical isomers due to asymmetric carbon atom(s) or double bond(s), and such conformers and isomers are also included within the scope of the present invention.

The IL-2 inhibitors, particularly the macrolides (I) or its pharmaceutically acceptable salt, can be in the form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate .

And further, the IL-2 inhibitor can be in the form of pro-drugs, suitable derivatives, and so on.

Tacrolimus is the most preferable compound belonging to the IL-2 inhibitor. Other preferable compounds are listed herein below.

17-Ethyl-l, 14-dihydroxy-12- [2- (4-hydroxy-3- methoxycyclohexyl) -1-methylvinyl] -23, 25-dimethoxy-

13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.0

^ ' °] octacos-18-ene-2, 3, 10, 16-tetraone (= ascomycin) :

33-epi-chloro-33-desoxyascomycin (EP-A-427680, example 66a): and 40-O- (2-hydroxy) ethyl rapamycin (WO94/0910) .

The IL-2 inhibitor of the present invention may be administered as pure compounds or mixtures of compounds or preferably, in a pharmaceutical vehicle or carrier.

The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the IL-2 inhibitor, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for topical application, particularly external application. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for solutions (saline, for example), emulsion, suspensions (olive oil, for example), ointment, aerosol sprays, lotion, cream, gel, skin plasters, patches and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active object compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the disease.

Mammals which may be treated using the method of the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans.

For applying to a human, it is preferable to apply it by topical, especially by external, administration, particularly in the form of ointment , gel, lotion, aerosol sprays, cream, skin plasters or patches.

While the dosage of therapeutically effective amount of the IL-2 inhibitor varies from and also depends upon the age and condition of each individual patient to be treated, a daily dose of about 0.0001-1000 mg, preferably 0.001-500 mg and more preferably 0.01-100 mg . of the active ingredient is generally given for treating diseases, and an average single dose of about 0.001-0. Olmg, 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered. Daily doses for chronic administration in humans will be in the range of about 0.1-0.3 mg/kg/day .

Especially, when applying externally, the recommended proportion of IL-2 inhibitors in the pharmaceutical composition is 0.001~20% (w/w) , preferably 0.01~10% (w/w) , of the total composition.

Preferable pharmaceutical composition usable in the present invention is an ointment consisting essentially of the IL-2 inhibitors, a solubilizing and/or absorption-promoting agent selected from the group consisting of a lower alkanediol, a lower alkylene carbonate, an alkane dicarboxylic ester, a higher alkane carboxylic glycerin ester, a higher alkene carboxylic glycerin ester, a higher alkane carboxylic alkyl ester, a higher unsaturated alcohol and an azacycloalkane, and an ointment base selected from the group consisting of oil and fat bases; in which the IL-2 inhibitors are contained therein in an amount of about 0.01 to 10% (w/w) , and the solubilizing and/or absorption-promoting agent is contained therein in an amount of about 1 to 30% (w/w) , where optionally is present one or more of the following ingredients selected from the group consisting of colorants, preservatives, and higher alkene carboxylic acids. The above ointment is described in USP 5,385,907, the disclosure of which is incorporated herein by reference.

The other examples of the pharmaceutical composition usable in the present invention are lotions described in EP- Al-753297, creams described in PCT/JP98/00665, gels decribed in PCT/JP99/02237 and so on, the disclosures of which are incorporated herein by reference.

Rheumatoid arthritis is characterized as a chronic systemic diseases primarily of the joints, usually polyarticular, marked by inflammatory changes in the synovial membranes and articular structures and muscle atrophy and rarefaction of the bones. The present invention is useful for topical prevention or treatment of rheumatoid arthritis, particularly the manifestation caused by and/or accompanied with rheumatoid arthritis, such as articular inflammation, articular pain, expansion of the joints, arthritic atrophy, muscle atrophy, and so on .

The following examples illustrate the present invention in further detail. It should be understood that those examples are not intended to limit the scope of the invention. Example 1 tacrolimus (FK506) 0.1 g propylene carbonate 5.00 g liquid paraffin 11.0 g solid paraffin 3.0 g white bees wax 3.5 g white petrolatum q.s. (to 100.0 g)

The ointment composed of the above ingredients was prepared in a similar manner to that of the Example 1 described in USP 5,385, 907.

Example 2

Similar ointments are prepared by using 33-epi-chloro- 33-desoxyascomycin and 40-O-2-hydroxy) ethylrapa ycin, as an active ingredient, respectively according to a similar manner to that of Example 1.

Example 3

FK506 0.3 mg

Diethyl sebacate 10 mg Diethylene glycol monoethyl ether 10 mg

Propylene glycol q.s. Hydroxypropylcellulose 2.5 mg

Total 100 mg Diethylene glycol monoethyl ether was dissolved in a mixture of propylene glycol and diethyl sebacate and FK506 and hydroxypropylcellulose were then dissolved in the resultant solution, followed by stirring, to provide a gel preparation for external application.

Example 4

According to a similar manner to Example 3, the following pharmaceutical compositions 1, 2, and 3 were prepared.

Composition No.

1 2 3 (% w/w) (% w/w) (% w/w)

FK506 1.00 0.30 0.10

Diethyl sebacate 10.00 10.00 10.00

Diethylene glycol monoethyl 10.00 10.00 10.00 ether

Propylene glycol 76.48 77.18 77.38

Ascorbyl palmitate 0.02 0.02 0.02

Hydroxypropylcellulose 2.5 2.5 2.5

Example 5

Effect of FK506 on rat adjuvant-induced arthritis

Test compositions

1% Gel : Composition 1 prepared in Example 4. Placebo : Placebo prepared in a similar manner to Composition 1 shown in Example 4 excepting FK506.

Methods

Arthritis was induced by injecting adjuvant (suspension of heat killed Mycobacterium tuberculosis) into the right hind paw of female Lewis rats (8 weeks old) according to a conventional manner. After the onset of arthritis, lOOmg of 1% Gel or Placebo was topically applied to the left paw once a day from day 15 to day 24 for 10 days (n=6) . Edema of drug-applied paw was measured with aqueous plethysmometer as change in paw volume.

Results

1% Gel suppressed the edema of the drug-applied hind paw in rat adjuvant-induced arthritis, which is shown in the following Figure 1.

Figure 1

The patents, patent applications and publications cited herein are incorporated by reference.

Claims

1. A use of IL-2 inhibitor for preventing or treating rheumatoid arthritis by topical administration.

2. The use of Claim 1, in which the topical administration is an external administration.

3. The use of Claim 1, in which IL-2 inhibitor is macrolides of the following formula (I).

(wherein each of adjacent pairs of R¹ and R², R and R⁴ , and R⁵ and R⁶ independently

(a) is two adjacent hydrogen atoms, but R" may also be an alkyl group or

R⁷ is a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkoxy group, or an oxo group together with R¹;

R⁸ and R⁹ are independently a hydrogen atom or a hydroxy group;

(a hydrogen atom and a hydrogen atom) , or a group represented by the formula N-NR R¹² or N-OR¹³; R¹¹ and R¹² are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group; R¹³, R¹⁴, R¹⁵, R¹⁶, R³⁷, R¹⁸, R¹⁹, R²² and R²³ are independently a hydrogen atom or an alkyl group; R²⁴ is an optionally substituted ring system which may contain one or more heteroatoms; n is an integer of 1 or 2; and in addition to the above definitions, Y, R¹⁰ and R²³, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkoxy, a benzyl, a group of the formula -CH₂Se(C₆H₅) ) , and an alkyl substituted by one or more hydroxy groups, or a pharmaceutically acceptable salt thereof.

4. A method for preventing or treating rheumatoid arthritis , which comprises administering IL-2 inhibitor to mammals by topical administration.

5. A use of IL-2 inhibitor for manufacturing a medicament for preventing or treating rheumatoid arthritis by topical administration.

6. A pharmaceutical composition for preventing or treating rheumatoid arthritis topically, which comprises IL-2 inhibitor in admixture with a carrier or excipient.

7. A process for preparing the pharmaceutical composition of Claim 6, which is characterized by admixing IL-2 inhibitor with a carrier or excipient.

8. The IL-2 Inhibitor used in Claims 1 to 7 is tacrolimus or its hydrate.

9. A use, prophylactic or therapeutic agent, method, pharmaceutical composition or process substantially as hereinbefore described as being in accordance with the present invention.