MXPA97002699A - Pharmaceutical compositions that comprise a unsaturated fatty alcohol and use of a fatty alcohol unsaturated in the mis - Google Patents

Abstract

This invention provides a topical composition, in the form of an emulsion, comprising a compound of the FK506 class, an alkanediol, ether diol or diether alcohol containing up to 8 carbon atoms, physiologically acceptable, as a solvent for the compound of the invention. class of FK506, a fatty alcohol unsaturated in water. In another aspect, this invention provides a topical pharmaceutical composition comprising a macrolide in suspension. In a traditional aspect, this invention provides the use of an unsaturated fatty alcohol to stabilize a macrolide in a pharmaceutical composition.

Description

PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to topical pharmaceutical compositions comprising a macrolide, and in particular to formulations comprising a macrolide such as an ascomycin, a rapamycin or a compound of the class of FK506.

BACKGROUND OF THE INVENTION FK506 is a known macrolide antibiotic, which is produced by S trept myces tsukubaensis No. 9993. It is also a potent immunosuppressant. The structure of FK506 is listed in the appendix found in Merck ndex, lia. Edition as subsection A5. The method of preparation of FK506 is described in EP 184,162. A large number of derivatives, antagonists, agonists and analogues of FK506 are known, which contain the basic structure and at least one of the biological properties (for example, REF: 24360 base oil and do not contain water. Lag compositions containing water have been reported in the literature and the compounds of FK506 have also been formulated as fine suspensions (EP 484,936).

DESCRIPTION OF THE INVENTION It has now been found, surprisingly, that the compounds of FK506 can be formulated in stable emulsions. The emulsions, since they contain an aqueous phase, are much less occlusive than the oil-based compositions and hence are better tolerated in many situations. Accordingly, in one aspect, this invention provides a topical composition, in the form of an emulsion, comprising a composition of the class of FK506; an alkanediol; physiologically acceptable diethyl ether or jiol alcohol, containing up to 8 carbon atoms, as a solvent for the compound of the class FK506; an unsaturated fatty alcohol and water Est; topical composition is effective, well R? Erj independently (a) is a pair of H atoms but R2 can also be alkyl or (b) forms a second bond between the carbonp atoms to which they are attached; R7 is H, OH, a protected OH group, a formyl group xi or an alkoxy group, or R7, together with Ri, forms an oxo group; Re and R9 are, independently, H or OH; R? Is H, an alkyl group, an alkyl group substituted by one or more OH groups, 1 group or alken, an alkenyl group substituted by one OH groups, or an alkyl group substituted by oxo group; is H or OH; it's H; or and X2, together, are an oxo group or and Y2 together are an oxo group, N-NRnRi2 O N-OR13; Rii and 12 independently, are H, an alkyl group, an aryl group or a tosyl group; R 13 i4 / Ri5 Rie i7 ißf R19, R22 and R23 are independently H, or an alkyl group; R20 and] 2if together, form an oxygen atom in an epoxide ring, or (c) a 5- or 6-membered cycloalkyl group, which may be optionally substituted. For example R24 may be a cyclopentyl group substituted by methoxymethyl ilo, optionally protected hydroxymethyl, acyloxymethyl, (wherein the acyl moiety contains either a dimethylamino group which may be in the quaternary form, or a carboxy group which may be is teri fied), or one or more amino and / or hydroxy groups that may be protected, or aminooxalyloxymethyl. A preferred example is a 2-formyl-cyclopentyl group. Suitable alkyl groups, alkenyl groups, aryl groups, protecting groups and acyl groups are defined in EP 484,936. The macrolide used in the compositions of the present invention preferably has immunosuppressive properties. The macrolide can be rapamycin or an O-subs tu derivative in which the hydroxy which is at position 40 of formula A, illustrated on page 1 of WO 95/16691, incorporated herein by reference, is find replaced by -OR? wherein Ri is hydroxyalkyl, hydroalkoxyalkyl, acylaminalkyl and aminoalkyl; for example 40-0- (2-hydroxy) ethyl-rapamycin, 40-0- (3-hydroxy) propi 1-rapamycin, 40-0- [2- (2-hydroxy) ethoxy] eti 1-rapamicinia and 40-0- (2- (ace toaminoe ti 1) -rapamycin These 0-substi-uidos derivatives can be produced by reacting Rapamycin (or dihydro or deoxorapamycin) with an organic radical attached to a leaving group (for example RX wherein R is the organic radical that is desired as the 0 -subthi ": uder, such as an alkyl, allyl, or benzyl moiety, and X is a leaving group such as CC13C (NH) 0 or CF3SO3) under suitable reaction conditions Conditions may be acidic or neutral conditions, for example in the presence of an acid such as trifluoromethanesulfonic acid, camphor sulfonic acid, p-acid phonyl toluensul or their respective pyridinium or substituted pyridinium salts when X is CCl3C (NH) 0, or in the presence of a base such as pyridine, a substituted pyridine, diisopropylethylamine, or pentamethoxypiperidine when X is CF3SO3. is 40-0- (2-hydroxy) et ilrapamycin (from here hereinafter the component A) as described in WO 94/09010. A preferred component of class FK 506 is describede in EP 427,680, for example, in the E] empl > 66a (also called 33-epi-chloro-33-deoxy iscomycin), hereinafter com- pound B. Other preferred compounds of the class FK 506 are described in EP 465,426, EP 569, 337 and in EP 626,385, for example the compound of Example 6d in EP 569,337, hereinafter compound C, or the compound of Example 8 of EP 626,385, hereinafter the compound D. Exemplary impurity of solvents of alkanediol, which are able to dissolve compounds of the class of FK506, are propylene glycol (1,2-propanediol), butylene glycol, 2-yl-l, 3-hexanediol, hexylene glycol (2-met il-2) , -pentanediol) and the like. Examples of ether diol solvents are propylene glycol, diethylene glycol and the like. Examples of diether alcohol solvents are diethylene glycol monomethyl ether. Preferably the solvent is hexylene glycol. Solvent is present, preferably, in an amount from about 5 hast to about 50% w / w, more preferably from 5 to 20% w / w and even more preferably from 5 to 20%. 10% w / w of the emulsion. The oil phase of the emulsion may comprise from about 20 to about 80% w / w, more preferably from 25 to 75 and even more preferably from 35 to 75%. 65 by weight of the composition. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. The oil-in-water emulsion can be in the form of an emulsion gel (in which case the aqueous phase can still be thickened using a polymeric thickener) or in the form of a cream. The unsaturated fatty alcohol forms part of the oil phase, of the emulsion, and is preferably a lanolin alcohol a fatty alcohol of 16 to 18 carbon atoms; more preferably oleyl alcohol, or alcohol elaidype, although the alcohol is particularly preferred. oleic The composition preferably contains sufficient amounts of the unsaturated fatty alcohol to promote the absorption of the compound of the FK506 class, in the skin, more preferably from about 2 to about 10% w / w, and even more preferably from 5 to about Approximately 10% p / p. The oil phase may also contain other liquid oils, thickening agents and fatty bases that are usually used in topical compositions. Suitable liquid oils include medium chain triglycerides, obtained from fractionated vegetable oils, such as the triglycerides of capric / caprinic acid. An example of one of these triglycerides is one that is commercially available under the trade name Miglyol 812 (which has an ileal weight of about 520, a value of nD20 from about 1,448 to 1,450 and a viscosity from 0.28 to 0.32 Pa.s). The liquid oil may comprise from about 5 to about 60% w / w of the emulsion and preferably from 5 to 15% w / w.

Suitable thickening agents include thickened, conventional teas such as alcohol cetyl, cetostearyl alcohol, tear alcohol, hydrogenated castor oil (Cutina HR), Yellow wax, White wax, cetyl ester wax, wax emulsifier, microcrystalline talin wax, and the like. Preferably the thickening agent forms from about 2 to about 30% w / w of the emulsion and more preferably from 2 to 10% w / w. Suitable fatty bases include bases such as natural wax, Vaseline (petroleum in the form of a gel, also commercially available as an ether), coarse paraffin, wool wax alcohols (such as those sold under the trademarks Eucerinum or Eucerin). , wool wax derivatives, triglyceride waxes (such as those commercially available under the trade names Softisan 378) and the like. The composition may also include suitable emulsifiers as is usual in emulsion compositions. These emulsifiers are described in standard texts such as Fiedler, H. P .; 1989; Lexikon der Hilfsstoffe für Pharma ie, Kosmetic und angrenzende Gebiete, Edit io Cantor, D-7960 Aulendorf, Germany and in the Handboq > k of Pharmaceutical Excipients a Joint publication of the Association American Pharmaceutical, Washington DC, United States of America and the Pharmaceutical Society of Great Britain, London, United Kingdom; 1986. Examples of suitable emulsifiers include: (a) esters of mono-fatty acids and propylene glycol digesters, such as propylene glycol di capitol (which is commercially available under the trademark of Miglyol 840) , propylene glycol dilaurate, hydroxypropyl glycol, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, and propylene glycol stearate; (b) fatty acid esters of polyoxylenesorbitan, such as the monolauryl and trilauryl, palmityl, tear, and oleyl esters. Examples of commercially available esters are those that are available under the trade name of T een (see Fiedler, pages from 1,300 to 1,30) and particularly the Tween 60 (polyexyethylene (20) sorbitan monoether); (c) esters of polyoxyethylene fatty acids, for example esters of polyoxyethylene stearic acid of the type known and commercially available under the trade name of Myrj (see Fiedler, pages 834 and 835) and in particular Myrj 52 (which has an O¿ of about 1.1, a melting point of about 40 to 44 ° C, and a Hydro-lipo-Lipo fí 1 ico (HLB) value of about 16.9) ); (b) copolymers and block copolymers, of polyoxyethylene-polyoxypropylene, such as those known and commercially available under the 1> names of Pluronic, Emkalyx and Polaxamex (see Fiedler, page 959) and in particular the Pluron c F68 (which has a melting point of approximately 52 ° C and a molecular weight of approximately 6,800 to 8,975) and the Poloxamer 188; the dioctyl sulfosuccinate or the di- [2-ethylhe il] succinate; (f phospholipids and in particular lecithins (see F edler, pages 943 and 944); (g) salts of fatty alcohol sulphates such as sodium lauryl sulfate and cetyl are sodium tearl sulfate (esters of sorbitan fatty acids such as sorbitan monostearate and sorbitan monolose which are commercially available). are available under the trademarks Arlacel 60 (which has an HLB of approximately 4.7 and a melting point of approximately 53 ° C) and Span 80 (which has a D25 is approximately 1, an HLB of approximately 4.3 and a viscosity of approximately 950 to 1100 cP); (i) monos: glycerin earate which is commercially available under the trade name of Imwitor (see Fiedler, page 645) and par ticularly the Imwitor 960; (j) glycerol esters of polyethylene glycol, having at least one free hydroxyl group, and aliphatic carboxylic acids of 6 to 22 carbon atoms. examples include glycerin monostearate of PEG-20; (k) reaction products of a castor oil, natural or hydrogenated, and of ethylene oxide and of which examples are available under the trade name of Cremophor as the Cremophor RH 40 (which has a Do not . of saponification of about 50 to 60, and an acid number < 1, a nD of approximately 1,453 to 1,457 and a value of HLB 224 and 284); (p) glycerin sorbitan fatty acid esters such as those which are available under the tradename Arlacel 481 (which has a molecular weight of about 630 and an HLB value of about 4.5) and (q) mixtures of the same. Preferably the emulsifier is selected from polyethylene glycol monostearate. (20) glycerin, sorbitan monostearate (Arlacel 60), sorbitan monooleate (Span 60), Tween 60, Tween 80, glycerin monostearate (Inwitor 960), stearic acid, cetyl alcohol, wool wax derivatives and alcohols and the Labrafil M2130 CS and mixtures thereof. If the emulsion is a water-in-oil emulsion, the selected emulsifier preferably has a HLB value of 10 to 15. If the emulsion is an oil-in-water emulsion, the selected emulsifier preferably has an HLB value of 4. to 8. Preferably the emulsifiers are present in an amount of about 1 to about 30% w / w and preferably 10 to 25% w / w.

It is also possible to add gelling agents to provide a gelled emulsion. Suitable gelling agents are carbomers (polyacrylic acid derivatives); such as those commercially available under the trade name of Carbopol (see Fiedler, pages 254 to 256). Carbopol 974 and Carbopol 1342 are preferred. The gelling agents are preferably present in an amount of 0. 2 w / w; more preferably less than about 1% w / w. The emulsion may also include preservatives and antioxidants such as benzyl alcohol, butyl hydroxy toluene, ascorbyl palote, sodium pyrosulfite, butyl idroxianisole, propyl p-hydroxybenzoate. (commercially available, for example, under the name of Paraben), methyl p-hydroxybenzoate (commercially available, for example as Paraben), sorbic acid and tocopherol. The preservatives and antioxidants serve to prevent bacterial growth, and are preferably present in a c ant i d d from about 0.01 to about 2.5% w / w. The pH modifying agents may be included to bring the pH of the emulsion to values that are between 4 and 6 or by the addition of a pharmaceutically acceptable buffer system. To avoid skin irritation a pH between 4 and 6 is desirable. The aqueous phase of the emulsion may comprise from about 20 to about 80% w / w, more preferably from 25 to 75% and in the form even more preferred from 35 to 65% of the emulsion. The aqueous phase is preferably in the form of sterilized water. The compound of the FK506 class is preferably present in the emulsion in an amount from about 0.01 to about 10% w / w and most preferably in an amount from 0.1 to 1% w / w. Preferably, the compound of the FK506 class and the unsaturated fatty alcohol are present in a weight ratio of from 1: 1,000 to 5: 1; preferably from 1: 100 to 1: 5. It has now been found in a surprising manner, that the macrolides can be formulated into stable pharmaceutical compositions, when the compounds are in suspensions. Accordingly, in another aspect, this invention provides a topical pharmaceutical composition comprising a macrolide in suspension. The term macrolide has the meaning described above. The pharmaceutical composition may be in the solid form, but is preferably in the semisolid form suitable for topical administration. These compositions in suspension, of this? invention, are effective, well tolerated on the skin, and stable from a reasonable degree to a large or extreme. The suspension contains macrolide particles from about 5, for example from 10, to about 90 microns in diameter. The particles of the macrolide can be produced in a conventional manner, as for example by empl < by crushing or grinding. The suspension can be prepared as a cream, a water-free ointment, a water-in-oil emulsion, an oil-in-water emulsion, an emulsion gel or a gel. In another aspect, this invention provides a topical taxation which is in the form of an oil in water emulsion gel, which comprises a) a macrolide in an amount of up to 5% in weight b) a thickener found in a quantity of up to 20% by weight, c) a hydrophilic component which is present in an amount of up to 40% by weight, d) one or more organic acids which are present in a total amount of up to 5% by weight , e) one or more stabilizers, which are in a total amount of up to 5% by weight, f) water that is in an amount of up to 90% by weight. Thickening agents are as defined above and may include paraffin, waxes and petrol ato. Suitable hydrophilic components include in propylene glycol, alcohols such as the cetyl hollic ale, the stearyl alcohol and the oleyl alcohol. Examples of suitable organic acids, containing sides for use in this invention, include sorbic acid. The acid functions as a preservative and serves to substantially prevent bacterial growth. In another aspect the invention provides a topical composition, in the form of an emulsion or suspension, as defined above., For e. use in the treatment of diseases of the foot L, inflammatory and hyperproliferative diseases, and of cutaneous manifestations of immune-mediated diseases. In another aspect, the invention provides a method for the treatment of skin diseases, inflammatory or hyperproliferative, or cutaneous manifestations of immunologically mediated diseases, which comprises administering a topical composition, as defined above. previously, to the skin of a patient who ne esite of the same. In still another aspect, the invention provides the use of a compound of the class of FK506; anodiol, ether diol, or diethyl alcohol, p-gically acceptable, which contains up to 8 carbon atoms, as the solvent for the compound of the class of FK506; an unsaturated fatty alcohol and water in the preparation of a medicament, in the form of an emulsion, for the treatment of skin diseases, inflammatory and hyperproliferative diseases, and skin infections of immune-mediated diseases. Emulsion compositions can be obtained by dissolving the compound of the FK class! 06, in the solvent and the unsaturated fatty alcohol, to provide the oil phase. If desired, in the oil phase, liquid oils, fatty bases * and thickening agents can be mixed. The oil phase is then emulsified with the aqueous phase and, if necessary, suitable emulsifiers. Other excipients may be added, at the appropriate time, to the proper phase, as is conventional. Applicants have found that the macrolides may be unsightly in topical compositions. It is believed that this instability is caused by gradation or rearrangement routes which are not fully understood. After extensive experimental work the applicants have found that unsaturated fatty alcohol can be used to stabilize macrolide compositions. In a further aspect, this invention provides the use of an unsaturated fatty alcohol to stabilize a macrolide in a pharmaceutical composition. In another aspect, this invention provides a method for stabilizing a macrolide in a pharmaceutical composition, a method comprising mixing: an unsaturated fatty alcohol with the macrolide. The unsaturated fatty alcohol can be an alcohol having 8 to 22 carbon atoms, or it can comprise a mixture of alcohols. Unsaturated fatty alcohol may have one, two or three weak bonds. Preferably the unsaturated fatty alcohol has a double bond, and a cis-configuration. Oleyl alcohol is preferred. An effect can be observed when the weight ratio of the unsaturated fatty alcohol to the active agent is at least about 1: 5, for example from 1: 2 to 1: 1 f higher, for example about 5: 1. . It has been found herein that the unsaturated fatty alcohol, for example the oleyl alcohol, is suitable for stabilizing a macrolide in a topical pharmaceutical composition. Examples of topical compositions are as described herein. The unsaturated fatty alcohol can be used, for example oleyl alcohol, to stabilize a macfolide having at least a portion as the following In the present application it has been found that oleyl alcohol is useful for slizing ascomynes and compounds of the FK506 class, for example FK506, ascomycin and 33-epi-chloro-3-deoxyscomycin. The topically defined topical compositions are useful in the treatment of skin diseases, inflammatory and hyperp. oli eratives, and cutaneous manifestations of immunologically mediated diseases, s. Examples of these diseases are psoriasis, atopic dermatitis, contagious dermatitis and other eczematous dermatitis, seborrhoeic dermatitis, Lichen planus, Pénfigi, Bullous pemphigoid, Epidermolisis bulosa, urtica, angioedemas, vasculi tidos, erythema, eosinolias Cutaneous, Lupus erythematosus and Alopec a areata. The usefulness of the topical compositions can be observed in standard clinical tests such as 1 to the test described in Example 12 using a concentration of 0.01 to 10% w / w (preferably 0.1 to 1% w / w). of the compound of the FK506 class. Utility can also be observed using models of animal models as described in EP 315,978. The exact amount of the compound of the FK506 class and the composition to be administered depends on several factors, eg, the desired duration of treatment and the release rate of the compound of the FK506 class. . Smaller mammalian results are obtained by (2-pro enyl) -15, 19-epoxy-3H-pyrido [2, 1-c] [1,4] oxaazacycloticosin-1, 7, 20, 21 (4H, 23H) -tet rum (i) [3S- [3R * [E (1S *, 3S *, 4S *)], 4S *, - 5R, -8S *, 9E, 12R *, 14R *, 15S *, 16R *, 18S *, - 19S *, 26aR *]] - 5,6,8, 1,12, 13, 14, 15, 16, 17, 18, 19, 24, 25, 26, 26a-hexade ahydro-5,19-dihydroxy-3- [2- (4-hydroxy-3-methoxy-cyclohexyl) -1-methylethenyl) 1-14,16-dimethoX i-4,10,12,18 -tetramethyl-8 -ethyl-15, 19-epoxy-H-pyridy [2, 1-c 1 [1,] oxaazacyclics in-1, 1, 2 0 21 (4H, 23H) -tetrone, and (ii) [3S - [3R * [E (1S *, 3S *, 4S *) 1.4S *, 5R *, 8S *, 9E, -12R *, - 4R *, 15S *, 16R *, 18S *, 19S *, 26aR *]] - 5, 6, 8, 1.12, 13, 14, 15, 16, -17, 18, 19, 24, 25, 26, 26a-hexade ahydro-5,19-dihydroxy-3- (3 -hydrox methylcyclopentyl) -1-methylethenyl)] -14, 16-dimethoX i-4,10,12,18, -tetramethyl-8-ethyl-15, 19-epoxy- $ H -pyrido [2, 1-c ] [1, 4] oxaazacycloticosin-1, 7, 20 21 (H, 23H) -tetrone, the topical application of with: 0.01 to 1% w / w, a once a day, in the treatment of psoriasis, chronic plaque, in humans. In these applications, the compositions are as effective as the ultra-potent composition of Clobetasol (0.05%). It > Examples below describe compounds 14,15, [L6,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3- [2- (4-hydroxy-3-methoxy-cyclohexyl)] -1-methylethhenyl)] -14, 16-dimethoxy-4, 10, lp, 18, -tetramethyl-8-ethyl-15, 19-epoxy-3H-pyrido [2, 1-c] [1,4] oxaazacyclotrichosin -1, 7, 20L 21 (4H, 23H) -tetron. This compound is known as Ascomycin. "Compound A, Compound B, Compound Compound D have the respective meanings as described above. The se term, as used in the following Examples, means that no separation of the components is observed. of the respective composition when stored at ambient temperature for a period of four months or longer Chemical analysis of the active agent is carried out using reverse phase HPLC with UV detection; λ = 210 nm The limit of quantification is 0.1 % by weight The tolerability of the compositions is carried out, in vivo, in pig skin and in human skin, and a visual evaluation is carried out at 0.5, 1, 2 and 4 hours after the application.

Benzyl alcohol 1.00 Arlacel 481 7.00 White oil 15.00 Coarse paraffin 5.00 Water 58.4 MgS04.7H20 0.5 The emulsion is se Example 4 An oil-in-water emulsion is prepared in one m; similar to that of Example 1, and which contains the following ingredients (in parts by weight): Compound 2 0.10 Oleyl alcohol 7.50 PEG glycerin monostearate 7.00 Propylene glycol 10.00 Cetyl alcohol 6.00 Glycerin monostearate 4.00 Paraffin 10.00 (coarse) Example 8 to 11 The following emulsions are prepared in a manner analogous to that of Example 1.

Example 10 11 Compound 3 0.10 0.10 0.10 0.10 Hexylene glycol 5 00 10.00 10.00 5.00 Cetyl Palmitate 2 00. Oleyl Alcohol 10.00 10.00 Lanolin Alcohols 1.50 T :: MC glycerides * 10.00 10.00 5.00 Isopropyl Myristate 8.00 - Cetyl Alcohol 4.00 5.00 5.00 2.00 Stearyl alcohol 4.00 5.00 2.00 Benzyl alcohol 1.00 1.00 1.00 1.00 Sorbitan monostearate 1.90 2.00 3.00 Sorbitan monooleate - 4.00 Glycerin monostearate - 3.00 10.00 - Tween 80 6.10 - Petrolatum, white 23.50 Water 67.90 49.90 53.90 56.40 Magnesium sulfate, heptahydrate 0.50 MO medium chain, for example Miglyol 812 The compositions of Examples 4 to 11 are straight.

Example 12 A double-blind, single-center, double-blind, controlled trial or test is carried out to determine the efficacy of the compositions of Examples 4 to 7 in rheological plaque psoriasis. Ten patients over 18 years of age who have plaque psoriasis are chosen; and who have not received systemic or topical therapy for chronic plaque psoriasis, in 1 month and: week, respectively. On day -1, the scales were removed with a topical composition containing 10% salicylic acid in Vasel iha. On day 0, the compositions of Examples 4 to 7, a composition of Clobetasol at 0.05%, available under 1, are applied. Trademark Dermovate and a placebo, to the desquamated plates under semi-active conditions and left for 24 hours. The patient is allowed to bathe and the lesions are gently dried. The lesions were evaluated visually (erythema) and by no adverse events were observed with the compositions of Examples 4 and 7, but skin atrophy was observed in the 2 patients who received Dermovate. However, the compositions of Examples 4 through 7 are at least as effective as Dermovate. The active agent used in the compositions described in Examples 1 to 11 can be replaced by Compound A, B, C or D.

Examples from 13 to 16 Oil-in-water emulsions are prepared in a manner analogous to that of Example 1 and having the following compositions.

Example 13 14 15 16 Oleyl alcohol 10 10 10 10 Mi fcrlyol 812 15 15 15 15 Cetyl alcohol Stearyl alcohol Glycerol moho stearate Sorbitan sorbitan Polysorbate 20 The degradation product increases up to 0.5%. No separation of the compounds is observed when stored at room temperature for four months.

Examples from 17 to 19 Oil-in-water compositions containing 1% by weight of the active ingredient are prepared.

Example 17 18 19 Oleyl alcohol 2.5 10 Miglyol 812 22.5 20 15 Cetyl alcohol Stearyl monomer Glycerol monostearate Sorbitan monostearate Polysorbate 60 Methylparaben 0.07 0.07 0.07 Propi lparaben 0.03 0.03 0.03 Citric acid 0.05 0.05 0.05 NaOH 1M p.abs./lOO g 0.02 0.02 0.02 Propylene glycol Compound B Up to up to Water des in 100 100 100 Lab emulsions of Examples 17, 18 and 19 are stable and no separation of the components is observed. It is found that the compositions are well tolerated in human skin. The compositions are stored at 40 ° C for eight weeks and the chemical analysis is carried out using HPLC. The analysis of the main degreasing product for compositions 17, 18 and 19 is .1%, 0.8% and 0.4%, respectively. In the compositions of Examples 13 to 19, the active agent of compound B may be Plied by compound A, by compound C, by compound D, by compound 1, by compound 2 or by compound 3.

Example 20 An oil-in-water emulsion composition, such as a cream, is prepared using Compound C as the active agent: Component Quantity weight-% Compound C 0.3 Hexylene glycol 10 Alcohol oleic 1 ico 10 Miglyol 812 10 Methylparaben 0.07 Propylparaben 0.03 Cetyl alcohol 5 Glycerol monostearate Water up to 100 to reduce the efficacy of the compositions of Example 21 in the psoriasis of chronic plaque. It is igen 10 patients who are over 18 years of age, who have chronic plaque psoriasis and who have not received systemic or topical therapy for chronic plaque psoriasis, in 1 month and 1 week respectively. On day 1, n scales are removed with a topical composition containing 10% salicylic acid in Vaseline. On day 0, the compositions of Example 21, a Clobetasol composition at 0.05%, available under the trademark Dermovate, and a glass, are applied to the desquamated plates, under semi-occlusive conditions, and left for 24 hours. . The patient is allowed to bathe and the lesions dry gently. The lesions are evaluated visually (erythema) and by palpation (inflmation) with scores ranging from 0 (aus €; ntes) up to 3 (severe). The procedure is repeated daily until 10/11; the separation of psoriasis is observed.

Example 24 Quantity (g / 100 g) Compound B 0.1 Paraf i .na, coarse 48 Glycerol monoestrate 8 Petro > lato, white 43.9 Example 25 Amount (g / 100 g) Compound B 0.1 Parafiha, thin 20 Petrolatum, white 71.9 Wax, crystalline beginning 8 E j p e 26 Amount (g / 100 g) Paraf iha, thick 30 Cetyl alcohol 5 Stearyl alcohol 5 Monoes sorbitan epoxide 2 Pol iso bato 80 (polyhydroxyethylenesorbitan monooleate) 4 Monoes glycerol monostea 3 Ascorbyl acetate 0.05 Compound B 0.1 Orbital acid 0.1 Propi 1: ngl icol 5 Water 45.75 Example 27 Quantity (g / 100 g) Propylene glycol 10 Paraffin. thick 15 Compound B 0.1 Carbopol 1342 (polyacrylic acid, partially long chain alkyl alkyl ester) 1 Methylparabens 0.07 Propylparabens 0.03 Aqueous solution of NaOH 2.5 to 5 < Water 71.30 Example 28 Amount (g / 100 g) Compue to B 0.1 Carbop 1 947 1 Aqueous solution IN of NaOH 2.5 Water 96.4 Example 29 Quantity (g / 100 g) Compue to B 0.1 Cetilestearyl alcohol 0.5 Alcoho is of wool wax 6 Petrol to, white 93.4 Ej empl 30 Amount (g / 100 g Compue s to B 0.1 To the coho 1 cetiles tearí 1 ico 0.25 Alcohols of wool wax 3 Petrol ato, white 46.65 Water 50 Good to very good stability is observed for the suspension compositions of Examples 24 through 30. The suspensions are applied to healthy volunteers and are found to be well tolerated. Compound B can be replaced by compound 1, 2, 3, A, C or D in any of the compositions described in Examples 23 to 30. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as antecedent property is claimed as contained in the following:

Claims (1)

1. A pharmaceutical composition, topical, characterized in that it comprises a macrolide in ion suspensions. A composition according to claim 5, characterized in that the macrolide is an ascomycin, a rapamycin or a compound of the class of FK506. A composition according to claim 6, characterized in that the macrolide is ascomycin, 33-epi-chloro-33-deoxy ascomycin or FK506. 8. A method for the treatment of skin diseases, inflammatory or hyperproliferative, skin manifestations or immunologically mediated diseases, characterized in that it comprises administering a topical composition according to any of claims 1 to 7, to the skin of a patient who needs it. The use of an unsaturated fatty alcohol to ablate a macrolide, in a pharmaceutical composition A method for stabilizing a macrolide in a pharmaceutical composition, characterized in that it comprises mixing unsaturated fatty alcohol with macrolide.