MXPA00009949A - Medicinal compositions - Google Patents

Abstract

Medicinal compositions having a high stability, an excellent absorbability and/or little irritativeness which contain as the active ingredient macrolide compounds typified by tricyclo compounds (I) or pharmaceutically acceptable salts thereof, dissolution promoters, sorbefacients and bases optionally together with compatibility enhancingagents and/or thickeners.

Description

MEDICINAL COMPOSITIONS Technical Field This invention relates to a pharmaceutical composition containing a macrolide compound; said composition is stable and, in addition, exhibits a very satisfactory absorption kinetics and / or a low potential for irritation. This composition finds application in the therapy and in the prophylaxis of various skin diseases.

Prior Art It is known that the tricyclic compound and its pharmaceutically acceptable salt which is a representative of the macrolide compound for use in accordance with this invention have excellent immunosuppressive activity, antimicrobial activity and other pharmacological activities and, as such , is valuable in the treatment or in the prevention of rejection reactions produced by tissue organ transplants, graft versus disease. host, autoimmune diseases, and infectious diseases [EP-A-0184162, EP-A-0323042, etc.].

In particular, among the mentioned tricyclic compounds (1) is Substance FK506 which, as has been demonstrated, is useful in therapy and in the prevention of rejection of grafts in organ transplants, as a consequence of its immunosuppressive activity practically excellent. EP-A-0315978 mentions that an ethanol solution of Substance FK506 is effective in stopping the advance of inflammatory reactions and that Substance FK506 can be provided in the form of a lotion, a gel or a cream. However, there is no disclosure regarding such dosage forms. Meanwhile, EP-A-0474126 presents an ointment comprising Substance FK506 and analogs thereof, with the addition of a digestion promoter / ab s or in a sufficient amount to dissolve the active compound and an ointment base. Also, W094 / 28894 presents a lotion comprising Substance FK506 and its analogues, a dissolution / absorption promoter, a liquid base and, optionally, an emulsifier or thickener.

In the treatment of diseases of the skin, an ointment constitutes t r ans i c i n lme n t the cardinal regime. However, a variety of administration forms are needed, in fact, for the purpose of treating different symptoms or injuries in different places.

Presentation of the Invention The inventors of this invention conducted an exhaustive investigation to obtain a pharmaceutical composition suitable for the administration of a macrolide compound a representative of which is Substance FK506- and discovered a dosage form having very satisfactory characteristics, such as : stability, good percutaneous absorption and / or a low potential for skin irritation. In this manner, the present invention specifically relates to the preparation of a gel comprising the macrolide compound for external application. According to this invention, there is provided a pharmaceutical composition comprising said macrolide compound, a d i s or luc i on / ab s or c i on promoter and a pharmaceutical base, such as so also, optionally, a buffer agent and / or a thickener. The term "macrolide compound" to be used according to the invention is the generic name of the compounds with 12 or more members, which belong to the lactones ma c r oc i c a s. The abundant macrolide compounds generated by the microorganisms of the genotype S t rep tomy and such as rapamycin, tacrolimus (FK506) and ascomycin, as well as the analogues and derivatives thereof, are included in the; compound expression of macrolide. As a particular example of a macrolide compound, there may be mentioned the tricyclic compound of the following formula (I): In which each of the adjacent pairs of R1 and R2, R3 and R4 and R5 and R6, independently (a) is represented by two adjacent hydrogen atoms, although R2 may also be an alkyl group, or (b) may form another bond that is formed between the carbon atoms to which it is 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-NRllR12 or N-OR13; R and R are, independently, a hydrogen atom, an alkyl group, an aryl group or a tosyl group; independently a hydrogen atom or an alkyl group; R24 is a closed chain system or substituted chain, which may contain one or more heteroatoms; n is an integer of 1 or 2; and in addition to the previously mentioned definitions, Y, R and R, together with the carbon atoms to which they are attached, may represent a closed chain with an oxygen, sulfur and / or nitrogen content. , of 5 or 6 members, saturated or more saturated, 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. Preferably R 4 can be a group c i c 1 or 1 to 1 qu 11 or (C5_7) and as examples can be cited the following: (a) a 3,4-d? -oxo-c? Clohexyl group; (b) a group 3-R2-4-R21-cic 1 ohe x 11 o, wherein R20 is hydroxy, an alkoxy group, an oxo group or a group -OCH2OCH2CH2OCH3, and R21 is hydroxy, -OCN, an alkoxy group, a heteroprotein 11 ox 1, which may be substituted by its 111 suitable atoms, a group -OC H2OCH2C H2OCH 3, a protected hydroxy group, chlorine, bromine, iodine, amynooxa 111 ox 1, an azido group, p - where R is opc 1 ona lme nte protected hydroxy or protected arrimo and R2d is hydrogen or methyl or R20 and R21 together form an oxygen atom in a closed epoxide chain; or (c) a cyclopentyl group substituted by meto 111 or, optionally 1 or oxime 111 or protected, by 11 oxime 111 or (in which the acyl part contains, optionally, a group dimethylamino which may be quaternized or a carboxy group which may be esterified), one or more hydroxy and / or hydroxy groups, which may be protected or aminooxa 111 oxime 111 or.

An example that is preferred is the 2-formyl-cyclopentyl group. The definitions used in the previous general formula (I) and the specific examples and Preferred thereof are now explained and described in detail. The term "lower" means, unless otherwise indicated, a group having between 1 and 6 carbon atoms. The preferred examples of "alkyl groups" and an alkyl part of the "alkoxy group" include: a straight or branched chain aliphatic hydrocarbon residue, for example, a lower alkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl. Preferred examples of "alkenyl groups" include a straight or branched chain aliphatic hydrocarbon residue, having a double bond, for example, a lower alkenyl group, such as, for example, vinyl, propenyl (eg, aillo group), butenyl, me 111 pr op in 11 o, pentenyl and hexenyl. Preferred examples of "aplo groups" include phenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl. The preferred protective groups in the "Protected hydroxy groups" and "protected auno" are the l- (lower alkyl) alkyl group (lower) as for example a group at 1 qu 1111 ome 111 or lower (for example me 11111 ome 111 o, e 11111 ome 111 o, pr op 1111 ome 111 o, is op r op 1111 ome 111 or but 1111 ome 111 or, isobutyl-thiomethyl, hexylthiomethyl, etc.), more preferably a group at 1 qu 1111 ome 111 or C1-C4, still more preferably, a methylthiomethyl group; a silyl group tr 1 sust 1 t ui do, such as tr 1 - a 1 qui 1 s 111 lo (1 nfer 1 or) (for example, tr íme 111 s 1111 o, tr 1 e 111 s 1111 o, tr 1 bu 111 s 1111 o, tert -bu 11 ldime 111 s 1111 otr 1 - tert -bu 111 s 1111 o, etc.) or alkyl (1 nfer 1 or) - d 1 ar 11 s 1111 o (for example metildifen lysilyl, ethyldifenylsilyl, propyldiphenylsilyl, tert-butyldiphenyl-silyl etc), more preferably, a tp-alkylsilyl group (C 1 -C 4) and a group at 1 qui 1 di f 1 i 1111 or C, -C? , optimally a group t e r t -bu 111 dime 111 s 1111 o and a tert-butyldiphenylsilyl group; and an acyl group, such as, for example, an aliphatic group, an aromatic acyl 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, having 1 or more optics in one or more suitable groups, such as carboxy, for example, fodder, acetyl, propionyl. butyl, isobutyryl, valeplo, isovaleryl, pivaloyl, hexanoyl, ca bbo x i a ce 111 or c a b or x i p r op i o n 11 o, carboxybuterol, carboxy-hexanoyl, etc .; a lower (lower) cycloalkoxy (lower) alkoxy group having one or more substitutes in suitable tetras, such as: lower alkyl, eg, cyc 1 or op 11 oxyace 111 or, cyclo 1 ob or 111 oxipr op i on 11 o, cic 1 ohep 111 ox iobu 11 r 11 o, me 111 o xi o e 111 o men 11 loxip r op i oni 1, ment loxi-butylo, me n 111 ox ipente 11 or, I n 111 oxi hexane 11 o, etc .; a group. camphorsulfonyl; or a group at 1 to 11 with an 11 or lower, having one or more suitable substituents, such as carboxy or protected carboxy, for example a carboxy (lower) group - at 1 qui 1 ca rbamo 11 o (for example carboxymethylcarbamoyl) , carboxyethylcarbamoyl, carooxypropylcarbamoyl carboxybutylcarbamoyl, caprobox ipen 111 ca bamoi lo, ca ox ox i x 11 ca bamo 11 o, etc.), a tp-alkylsilyl group (lower) to 1 c oxic rbon 11 o ( lower than 1 qu 11 ca r bamoi 1 or (lower) group, (eg, tpmethylsilylmethoxycarbonylethylcarbamoyl, tpmethylsilylethoxycarbonylpropylcarbamoyl triethylalleytoxycarbonylpropylcarbamoyl, tert-butyldimethylsilyltoxycarbonylpropylcarbamoyl, tri-methylallylpropoxycarbonylbutylcarbamoyl, etc. ) and else. Examples of the aromatic acyl groups include an aroyl group which has optionally one or more substitutes and is suitable, such as nitro, for example: benzoyl, toluolyl, xyloyl, naphthoyl, n 11 r oben zo 11 or di n 11 r oben zo 11 o, nitro-naphthoyl, etc.; and an arenesulfonyl group having, optionally, one or more suitable substitutes, such as halogen, for example, benzene 1 fon 11 or, to 1 which nsu 1 fon 11 o, x 11 ensu 1 fon 11 or, naphtha 1 in its 1 f on 11 o, f 1 uobence nsu 1 f oni 1 o, cioroben-c in its 1 f oni 1, b omobence ns ul f on 11 o, iodobenzenesulfonyl, etc. Examples of aliphatic acyl groups substituted by an aromatic group include: an ar-alkanoyl group (lower), having optionally one or more suitable substitutes, such as lower alkoxy otriha 1 o- to 1 qu 11 or lower, for example, fen 11 to ce 111 or, phenylpro-pionyl, f in i Ib 11 lo, 2-trif 1 or ome 111-2 -me toi-2-phenylacetyl, 2-etl-2 -tr? fluomet? l-2-fen? lacet? lo, 2-trif 1 uome 111 - 2 -pr opox i -2 - f eni 1 to ce 111 o, etc.

More preferably, the acyl groups, among the acyl groups mentioned above are: a C 1 -C 4 alkanoyl group, having optionally carboxy, a cyclo (C 5 -C 6) alkoxy-alkanoyl group (C 1 -C 4) ), which optionally has two alkyls (C1-C4) in the part of c 1 c 1 or 1 qu 11 o, a group a 1 can forsu 1 f oni 1 o, a group caboxy - a 1 qu 11 car bamo 11 o (Cj-Ci), a group tr 1 to 1 qui 1 s 1111 o (C 1 - C) - a 1 co 1 car bon 11 or (C1-C4) -a 1 qu 11 ca r bamo 11 or (C1-C4), a benzoyl group, optionally having one or two nitro groups, a benzene 1 fon 11 group or having a halogen or a 11-a1-cano or 11 (C 1 -C 4) phen group have alkoxy (C1-C4) and a group tr 1 ha 1 o- a 1 qui 1 o (C1-C4) Among these, the most preferred are: acetyl, carboxypropionyl, menthyloxyacetyl a 1 canforsu 1 fon 11 o, benzoyl, n 11 r obzo 11 o, di n 11 r obe n zo 11 o and odobenc in its 1 f on 11 o and 2-tr? t? l-2-methox? -2-fen? lacet? lo. Preferred examples of the "closed chain he t o r c 1 c 11 ca with oxygen, sulfur and / or nitrogen content, with 5 or 6 members" include a pyrrolyl group and a group t e t r there dr o f u r 11 o. A part of "an heteropole" which may be substituted by suitable substituents "of the "heteroaryloxy which may be substituted by suitable substituents" may be represented by those which are cited as examples for R of the compound of the formula of E P-A-532,088, preference being given to the 1-hi-ox i e t i 1-l-5-yl, the disclosure of which is incorporated herein by reference. The tricyclic compounds (I) and their pharmaceutically acceptable salt for use in accordance with this invention are widely known to have immunosuppressive activity, antimicrobial activity and other pharmacological actions and, as such, may prove valuable in the treatment or prevention of the rejection reactions by transplantation of organs or tissues, of graft vs. host, 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, W089 / 05303, 093/05058, W096 / 31514, W091 / 13889, W091 / 19495, W093 / 5059, etc.], whose disclosures are incorporated herein by reference. Particularly, the compounds that receive the designations of FR900506 (= FK506), FR900520 (ascomicma), FR900523 and FR900525 are products coming from the microorganisms of the genus Str ep t omy ce s, such as? treptomyces tsu ubaensis No. 9993 [deposited in the Agency of the National Institute of Bioscience and Human Technology of Technology and Industrial Science (formerly, Agency of Instigations on Fermentation of Technology and Industry Science), appointment at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, deposit date: October 5 1984, accession number FERM BP-92] or Streptomyces hygroscopicus subsp. vakushimaensis N o .7238 [deposited in the National Institute of the Agency of Bioscience and Human Technology of Technology and Industrial Science (before, Agency of the Research Institute on the Fermentation of Technology and Science of Industry), appointment in 1-3, Higashi 1-chome , Tsukuba-shi, Ibaraki, Japan, deposit date: 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 - to 111 - 1, 14 -dihi dr ox i - 12 - [2- (4-hydrox? -3-methox? Cyclohexyl) -1-met? Lvm? L] -23 , 25-d? Methox? -13, 19, 21, 27-tetramet? L-ll, 28-d? Oxa-4-azat r? Cycle [22.3.1. O4 9] or c t a c o s - 18 - e n - 2, 3, 1 O, 16 -tetraone. Preferred examples of the cyclic compounds (I) are those in which each of the adjacent pairs of R3 and R4 or R5 and R °, independently, form another bond formed between the carbon atoms to which they are added.; R8 and R'1, each of them, are independently a hydrogen atom; R ° 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; And it's an oxo group; each of the following: R14, R15, R16, R17, R18, R19 and R22 is a methyl group; R24 is a group 3-R20-4-R21-cyclohexyl; where R 'is hydroxy, an alkoxy group, an oxo group or a group or -OC H 20C H 2C H 2OC H 3 and R 21 is hydroxy, -OCN, an alkoxy group, a heter o or a 1 or x i which may be substituted by suitable substitutes, a group - OCH2OC H2CH2OCH3, a protected hydroxyl group, chlorine, bromine, iodine, ami or -oxa 111 ox1, an azido group, pt ol i1 oxy t lo rboni loxi or R25R2 dC HCOO-, wherein R25 is optionally protected hydroxy or protected amino and R2S is hydrogen or methyl or R20 and R21 together form an oxygen atom in a closed epoxide chain; and n is an integer of 1 or 2. The most preferred tricyclic compounds (I) are, in addition to FK506, the ascomycin derivatives, such as halogenated ascomycin, example, 33 - and i-c 1 or o-33 -of s ox i a s ea a), which is presented in EP 427,680, example 66a. As the other preferred example of macrolides as immunosuppressants, rapamycin [THE MERCK INDEX (12th edition), No. 8288] and its derivatives can be cited. The preferred example of the derivatives is a derivative 0 - its 111 ui do, in which the hydroxy, at position 40 of formula A illustrated on page 1 of WO 95/16691, incorporated herein by reference, is it is replaced by -ORi, where Ri is hi dr oxy to 1 qu 11 o, hydroalkoxyalkyl, acylammoalkyl and ammoalkyl; for example 40-O- (2-hi dr oxy) and 111-r ap ami cin, 40-O- (3-h? drox?) -propyl-rapamicma, 40-0- [2- (2-h? drox?) -et ox i] e 111 - r apami ci na and 40 - 0 - (2 - a ce t ami noe 111) -rapamycin. These O-sus 111 ui do derivatives can be produced by reacting rapamycin (or dihydro or deoxo-rapami ci na) with an organic radical attached to an exit group (for example RX, in which R is the organic radical that is as an O substituent, such as, for example, an alkyl, ayl or benzyl moiety and X is an outlet group, such as, for example, CCl3C (NH) 0 or CF3SO3, under suitable reaction conditions.The conditions may be acidic or neutral. , for example, in the presence of a acid as acid trif luome tansu 1 phonics, acid to 1 canforsu 1 f oni co, acid p-to 1 uens u 1 f oni co or their respective pyridmium or substituted pipdmium salts, where X is CC13C (NH) O, or in the presence of a base such as pipdma, a substituted pyridine, di i sopropí le ti lamina or pentametil-pipepdma when X is CF3SO3. Most preferred is the 40-0- (-h 1 dr ox 1) and 111 rapamic a, which is presented in W094 / 09010, the disclosure of which is incorporated herein by reference. The tricyclic compounds (I) and the rapamicma and their derivatives have a similar basic structure, ie a structure of ticclic macrolides and at least one of the similar biological properties (e.g., immunosuppressive activity). The t-cyclic compounds (I) and rapamicma and their derivatives may be in the form of a salt thereof, which includes conventional non-toxic and pharmaceutically acceptable salts, such as the salt with organic and inorganic bases, specifically, a salt of alkali metal, such as the sodium salt and the potassium salt, a non-terrestrial metal salt at 1 to 11, such as, for example, the salt of calcium and salt of magnesium, an ammonium salt and an amine salt, such as a triethylamine salt and the salt of N -be nc i 1 -me t i 1 amine. With respect to the macrolide compound used in the present invention, it should be understood that there may be conformers and one or more stereoisomers, such as optical isomers and geometric isomers, whether or not to the carbon atoms or at or the double bonds and those mentioned Formers and isomers are also included in the scope of a macrolide compound in the present invention. In addition, the macrolide compounds may be in the form of a solvate, which is included in the scope of the present invention. The solvate preferably includes a hydrate and an ethanolate.

The dissolution / absorption promoter for use in this invention has no particular restriction, as long as it is capable of dissolving therein a macrolide compound, such as a tricyclic compound (I) or its pharmaceutically acceptable salt, and / or promoting its percutaneous absorption. For example, the fatty acid esters of α 1 coho 1 -mon or hydride, the acid diesters can be advantageously employed. dibasic and the lower alkylene carbonates listed below: * Severe acid esters of monohydric alcohol: (isopropyl myristate, ethyl miptate, butyl myristate, isocetyl miptate, oc 111 dodec 11 miptate, isopropyl palmitate , isostearyl palmitate, isopropyl isostearate, isocetyl isostearate, butyl stearate, isocetyl stearate, cetyl isolate, ethyl linoleate, isopropyl lmoleate, hexyl laurate, ethyl oleate, decyl oleate, oleate of oleyl, oc 1 1 dode c 11 -miristate, hexyldecyl-dimethyloctanoate, oc 111 dode c 11 - ne ode ca no t to, etc) * D? esters of dibasic acid (adipate di is op r opi 1 i co, adipate dimethyl, adipate diethyl, adipate d 11 s op r op 111 co, sebacate diethyl, sebacato di op op 1, ico, dipropyl sebacate, diethyl phthalate, diethyl pimelate, etc.). * Lower alkylene carbonates (propylene carbonate, ethylene carbonate, etc.).

In this invention, each of the di or 1 uc i on / abs or r promoters that have been listed above can be used independently or in a suitable combination. In particular, dietary sebacate is the quintessential dissolution / absorption promoter in case the stability and / or solubility of the active ingredient and / or the aroma, color and texture of the composition is considered. The amount of the said promoter of the dissolution / absorption in the composition is not restricted in any particular way, although it must be large enough to dissolve the macrolide compound and / or to promote its percutaneous absorption. example, its amount is preferably 0.1-50% (w / w), more preferably 0.5- 30% (w / w), more preferably still, 1-20% (w / w) • The pharmaceutical base to use in this invention it has no particular restriction, as long as it is compatible with the other ingredients that are in the composition and, even, that it is capable of dissolving the thickener. Particularly, hydrophilics capable of dissolving both the macrolide compound are preferred. as the mentioned thickener. As such, hydrophilic glycols, such as the lower alkanediols, are particularly preferred, for example, e t i 1 eng 11 co 1, p r opi 1 e ngl i co 1 and bu 111 e ng 1 i col. The amount of the pharmaceutical base in the composition of this invention can be selected according to its need. On the other hand, it is possible to control the percutaneous absorption of the macrolide compound, by mixing a suitable amount of the hydrophilic polymers such as polyethylene glycol with the base f a rma céu t i c a. The buffering agent for use in optional form in this invention is a substance that improves the compatibility of the drug / ab sorption promoter with the pharmaceutical base and, as such, includes, but is not limited to them. , the following: ^ Alcohols: (isopropyl alcohol, ethanol, oleyl alcohol, cetanol, stearyl alcohol, 2-octi 1 dodeca no 1, etc.). * Mono- to Iqui lo (i n f e r i o r) - e t e rs of diethylene glycol (diethylene glycol monoe ti 1 ether, diethylene glycol monobute 1 ether, etc.) Among them, the most preferred are monoalkyl (lower) diethylene glycol ethers, among which are higher preference to diethylene glycol monoethyl ether. And in the case where diethylene glycol monoethyl ether is used, good percutaneous retention of the macrolide compound can be expected. The amount of formulation of the above mentioned carrier agent does not have any particular restriction, as long as it is added in an amount sufficient to improve the compatibility of the dissolution / absorption promoter with the pharmaceutical base and, as such may be for example from 1-30% (w / w), more preferably 2-20% (w / w) optimally from 5-15% (w / w). The thickener that is optionally employed in this invention does not present any particular restriction, provided that it is pharmaceutically acceptable and capable of imparting viscosity to the pharmaceutical base, including in this manner, the following water-soluble organic and inorganic macromolecular substances, among others. (1) Organic substances Native polymers: Arabica gum, guar gum, carrageenan, tragacanth gum, pectin, starch, xanthan gum, gelatin, casein, dextrin, cellulose. In vitro polymer polymers: cellulose polymer (methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, etc.), carboxymethyl starch, sodium alginate, propylene glycol alginate. Synthetic polymers: carboxyvinyl polymer (Carbopol), polyvinyl alcohol, polyvinyl alcohol, polyethylene glycol, poly (vinyl methyl ether), sodium polyacrylate. (2) Inorganic substances Bentonite, synthetic magnesium silicate, magnesium dioxide, magnesium dioxide, e t c. The pharmaceutical composition of this invention, preferably, contains a thickener and the amount of thickener in the pharmaceutical composition can be selected c r i t e r i t e n t in accordance with the viscosity to which it is intended arrive in the pharmaceutical composition. For example, the thickener is used in a proportion of preferably 0.1-10% (w / w), more preferably 0.5-5% (w / w). Among the specific examples mentioned above, the polymer of cellulose - such as, for example, hydr oxy-pr opi 1 ce lu 1 osa - and the polymer of cavbox i vi n or are the most preferred and when changing them, it is possible to change the texture of the pharmaceutical composition. In addition to the aforementioned ingredients, the pharmaceutical composition of this invention may contain the conventional excipient (eg, lactose, sucrose, starch, mannitol, etc.), an anti oxidant stabilizer (eg, ascorbyl palmitate, tocopherol). , etc.)], a coloring agent, a sweetener, perfume, a diluent and a preservative, as well as other substances with medicinal action. Particularly, the stability of the present pharmaceutical composition can be improved if an amount of 0.01-1% (w / w), more preferably 0.05-0.1% (w / w) of ascorbyl palmitate as stabilizer is used. . The pharmaceutical composition of this invention can be used by applying it to the site affected, in particular to the skin lesion, once to 4 times per day. The appropriate amount of said macrolide compounds in the pharmaceutical composition depends on the particular species that is used, the age of the patient, the type of disease, the severity and other factors. Normally, the recommended amount with respect to the total composition is 0.001-20% (w / w), more preferably 0.01-10% (w / w), more preferably 0.03-3% (w / p). p) The composition may also contain one or more other drugs that are indicated in skin diseases. Also, the pharmaceutical composition of this invention may be produced in the same manner as described in the following Examples EXAMPLES The following examples are intended to illustrate this invention in greater detail and, in no way, should be construed as a definition of the scope of the invention. In the examples that follow, FK506 is mixed as its monohydrate when preparing the compositions that contain it, although its amount it is expressed as the weight of FK506, not its monohydrate. Example 1 [Composition 1] The monoethylether of d i e 111 engl i co 1 was dissolved in a mixture of opi 1 ngl i co 1 and diethyl sebacate, and then, the FK506 and the hydroxyl opium were dissolved in the resulting solution. Then, stirring was carried out in order to obtain a gel preparation for external application.

Example 2 In accordance with a manner similar to Example 1, the following pharmaceutical compositions were prepared.

[Composition 2] [Composition 3J [Composition 4] [Composition 5] [Composition 6] [Composition 7] [Composition 8] Example 3 In a manner similar to Example 1, the following pharmaceutical compositions 9, 10 and 11 were prepared.

Example 4 In a manner similar to Example 1, the following pharmaceutical compositions 12, 13 and 14 were prepared.

EXAMPLE 5 The experiments on percutaneous absorption and skin retention performed by using the pharmaceutical composition of the invention are described below. By using composition 1 of Example 1, an experiment of the percutaneous absorption in vivo and a skin retention experiment (residue on the skin). As experimental animals, three 7-week-old male SD rats were used. With each animal immobilizing in a dorsal decubitus position on an e e t t i x i c o device, the hair layer was removed with an electric razor to cut the hair and a depilatory cream (Eva Cream, manufactured by Tokyo Tanabe Co.) was applied to the shaved area. After the application of the cream, the local skin was washed with water for 10 minutes to remove the hairs; the animal returned to the cage and remained intact for 24 hours. After immobilizing the animal once more in the dorsal decubitus position in the stereotactic device, an area of 2.5 cmx4 cm was marked on the depilated abdominal skin of the rat and 50 mg of the test drug was applied to said animal. marked area. At predetermined intervals after the medication, 0.3 ml of blood was removed from the vena s ubc 1 to vi cu 1 ar in a syringe containing EDTA and, after mixing well with the EDTA, the blood sample was kept frozen. to submit it to the analysis. The concentration in the whole blood of Substance FK506 was determined by submitting ours to the test to an enzyme immunoassay using a peroxidase [the analysis system described, for example, in the Japanese Kokai Tokkyo Koho Hl-92659). On the other hand, after taking a blood sample at 24 hours, the surface of the medicated skin was washed with water and the skin tissue was extracted from the marked area that was mentioned previously. After removing the subcutaneous adipose tissue from the isolated skin, the skin tissue was homogenized in 0.1 N-HCl / ethanol (1/1) to prepare a homogenate of skin tissue at 1% (w / w) . The amount of Substance FK506 in this homogenate was determined by the enzyme and enzyme described above. The parameters of percutaneous absorption of the test drug were determined. The results are presented in Table 1. In Table 1, AUC [0-24 hr] denotes the ba area or the blood concentration curve - time from 0-24 hs. Table 1 Effect of the Invention In accordance with this invention there is provided a pharmaceutical composition containing a macrolide compound, particularly the t-cyclic compound (I) or its pharmaceutically acceptable salt, which is very satisfactory from the standpoint of stability, its ability to work it, user acceptance, irritation potential and / or efficiency for dermal penetration. In particular, a gel preparation for external application could be obtained which ensures an improved penetration of the macrolide compound, particularly the said cyclic compound (I) or its pharmaceutically acceptable salt, through the keratoidal layer, which constitutes a barrier against absorption, as well as good skin retention (particularly, in the dermis) of the macrolide compound. On the other hand, the pharmaceutical composition of this invention has a suitable action of emollient (humectant) and does not present risks for dermatrophy and the so-called rebound phenomenon.

The pharmaceutical composition of the present invention is useful for the treatment or prevention of inflammatory or hypersensitskin diseases. Cutaneous conditions of non-oily and medically mediated diseases (eg, psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, li ch enplanus (lichen piano or Wilson's), pemphigus, bullous pemphigoid, epidermo 1 isis bulosa, urticaria, angioedema, vasculitis, erythema, dermal eosinophilia, lupus eptematosus, acne and alopecia areata), due to the pharmacological activities of the macrolide compound. In particular, the gel preparation for external use of the present invention is useful for the treatment or prophylaxis of psoriasis, such as: arthropathic psoriasis, circinid psoriasis, diffuse psoriasis, discoid psoriasis, psoriasis. generalized pustular of Zumbusch, geographic psoriasis, psoriasis gutata, psoriasis gyrata, psoriasis mveterata, nummular psoriasis, 1. orbicular psoriasis, osteacea psoriasis, psoriasis punctata, Pustular psoriasis, psoriasis e s p ond i i i t i c a, psoriasis unsalis and others. Likewise, the pharmaceutical composition of the present invention is useful in the therapy or prophylaxis of the following diseases Autoimmune eye diseases (for example, which are associated with Behcet's disease, keratitis keratitis herpetica, conical keratitis, epithelial dystrophy of the cornea that lasts 1 eucoma, ocular pemphigoid, Mooren's ulcer, escleptis, Graves' ophthalmopathy, Vog syndrome t - Koy anag i -Harada, which rat ocon j a 11 vi 11 s sicca ( ocular dryness), flictenula, iri doc ic 1111 s, sarcoidosis, endocrine ophthalmopathy, etc.); Diseases of the skin (eg rma t or os 111 s, leukoderma vulgaps, ichthyosis vulgaps, photosensitivity and cutaneous T-cell lymphoma, hypertrophic or keloid scar due to trauma, burns or surgery. Patent applications and the references cited in the present application are included in the description of the present specification.

Claims (10)

1. CLAIMS 1. A pharmaceutical composition, characterized in that it comprises a macrolide compound, a dissolution / absorption promoter, a pharmaceutical base and, optionally, a comparative agent and / or a thickener.
2. 2. The pharmaceutical composition according to claim 1, characterized in that the macrolide compound is a tricyclic compound of the f or rmul a (I): where each of the adjacent paras of R1 and R2, R3 and R4 and R5 and R6 independently (a) is represented by two adjacent hydrogen atoms, although R2 can also be a alkyl group, or (b) can form another bond that is formed between the carbon atoms to which it is 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 -CH2O-; 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-NR1XR12 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, R11, R18, R19, R22 and R23 are, independently, a hydrogen atom or an alkyl group; R24 is a closed chain system or substituted cyclism, which may contain one or more heteroatoms; n is an integer of 1 or 2; Y In addition to the previously mentioned definitions, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a closed chain with a content of oxygen, sulfur and / or nitrogen. , of 5 or 6 members, saturated or restored, or is replaced 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.
3. 3. The pharmaceutical composition according to claim 2, characterized in that the tricyclic compound (I) is that in which each of the adjacent paras of R3 and R4 or R5 and R6, independently, form another bond formed between the atoms of carbon to which they are attached; R and R are, each 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; And it's an oxo group; each of the following R, < Í ^ fau £ a £ a. hydroxy, an alkoxy group, an oxo group or a group -OCH2OCH2CH2OCH3 and R21 is hydroxy, -OCN, an alkoxy group, a heteroary group which may be substituted by a suitable substitution, a group -OCH2OCH2CH2OCH3, a protected hydroxy group, chlorine, bromine, iodine, amino-oxa 11 lox 1, an azido group, xi t -localbonoloxy or 1 or R'5R26CHCO is opc 1 ona protected hydroxy or protected ammo and R26 is hydrogen or methyl or R20 and R21 together form an oxygen atom in a closed epoxide chain; and n is an integer of 1 or 2
4. 4. The pharmaceutical composition according to claim 3, characterized in that said tricyclic compound (I) is 17- to 111-1,14-d? H? Drox? -12- [2- (4-h? Drox? -3 -methoxy? c? clohex ??) -1-methylvinyl] -23,25-d? methox? -13, 19, 21, 27- tetramethyl-11,28-d? oxa-4-azatr? c? clo [ 22.3.1 O49] octacos-18-en-2,3,10,16-tetraone or its hydrate.
5. 5. The pharmaceutical composition according to claim 1, characterized in that the promoter of d 1 s olucí on / ab s or r c 1 on is a member selected from the group consisting of. diesters of dibasic acids and esters of severe acid of monohydric alcohol.
6. 6. The pharmaceutical composition according to claim 5, characterized in that the promoter of the di sion / ab s or r c i on is isopropyl miptate, adipate di i s op r opi 1 i c o or dietary sebacate.
7. 7. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical base is represented by hydrophilic glycols.
8. 8. The pharmaceutical composition according to claim 1, characterized in that it comprises monoethylether of di e 111 e ngl i col as a compatibilizing agent.
9. 9. The pharmaceutical composition according to claim 1, characterized in that it comprises cellulose polymer or polymer of carboxy or vi as a thickener.
10. 10. The pharmaceutical composition according to claim 1, characterized in that it is in the form of a gel.