Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

• This invention relates to topical compositions containing ascomycins for treatment of skin disorders, e.g. subacute and chronic inflammatory and hyperproliferative skin diseases, e.g. atopic dermatitis, vitiligo, psoriasis, lichenified skin diseases, e.g. lichen planus, a lichenified form of atopic dermatitis.
• skin disorders e.g. subacute and chronic inflammatory and hyperproliferative skin diseases, e.g. atopic dermatitis, vitiligo, psoriasis, lichenified skin diseases, e.g. lichen planus, a lichenified form of atopic dermatitis.
• Ascomycins have a variety of useful pharmacological actions, e.g. immunosuppression, and which may be administered topically. However, inter alia because of their physicochemical properties, e.g. high molecular weight and lipophilicity the ascomycins have posed problems for topical administration.
• Skin disorders also present difficulties in treatment, particularly lichenified skin diseases, e.g. psoriasis, where the skin is hyperproliferated and the skin barrier function and skin lipid composition may have changed.
• Topical compositions for use in lichenified skin diseases, e.g. psoriasis, containing an ascomycin present particular difficulties.
• compositions of the present invention serve to enhance penetration of active agent through human skin, e.g. for the treatment of lichenified skin diseases, e.g. psoriasis.
• These compositions show other particularly interesting properties, e.g. they are easily applied to large areas of the skin and are stable.
• this invention provides a composition for topical administration of an ascomycin which composition comprises a carrier vehicle comprising
• (ii) means to hinder water evaporating from the skin.
• the ascomycin is hereafter referred to as active agent.
• active agent is to be understood ascomycin itself or a derivative, antagonist, agonist or analogue thereof, e.g. a compound of the FK 506 class.
• FK506 is a known macrolide antibiotic that is produced by Streptomyces tsukubaensis No 9993. It is also a potent immunosuppressant.
• the structure of FK506 is given in the appendix to the Merck Index, 11 th Edition as item A5. Methods of preparing FK506 are described in EP 184162.
• FK 506 itself or a derivative, antagonist, agonist or analogue thereof, which retain the basic structure and modulate at least one of the biological properties (for example immunological properties) of FK506.
• a large number of compounds of the FK 506 class are known. These compounds are described in for example EP 184162, EP 315978, EP 323042, EP 423714, EP 427680, EP 465426, EP 474126, WO 91/13889, WO 91/19495, EP 484936, EP 532088, EP 532089, EP 569337, EP 626385, WO 93/5059 and the like.
• ascomycin derivatives such as macrolactam compounds of the FK506 class are particularly useful in the topical treatment of inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically-mediated illnesses.
• examples of ascomycin derivatives suitable for use in the present invention include FK506; 33-epi-chloro-33-desoxy-ascomycin as disclosed in Example 66a in EP 427 680 (hereafter referred to as Compound A);
• FK 506, Compounds A, B, C, D, E, and F are preferred ascomycins, particularly preferred are Compounds A, B, and C, especially Compound A.
• the active agent is e.g. present in the compositions of this invention in an amount of from 0.05 to 3% by weight, e.g. from 0.1 to 2% by weight, e.g. from 0.4 to 1% by weight based on the total weight of the composition.
• the active agent may be dissolved, e.g. partially dissolved in the vehicle.
• the active agent may be in suspension, e.g. partially in suspension in the vehicle.
• the active agent is partially dissolved in the vehicle.
• the active agent may be used in a micronized form.
• the suspension may contain particles of ascomycin of from 5, e.g. from 10, to about 90, preferably to about 25 microns in diameter.
• the particles of the ascomycin may be produced in conventional manner, e.g. by grinding or milling.
• the carrier vehicle comprises means to retain water in the outer skin layer, e.g. moisturizers.
• a pharmaceutically acceptable moisturizer capable of e.g. penetrating and residing in the outer skin layer, e.g. the stratum corneum, and e.g. absorbing, holding and retaining moisture to increase the moisture content of the skin.
• Means to retain water in the outer skin layer e.g. moisturizers, e.g. as described in Dermatika, Eds. R. Nieder, J. Ziegenmayer,ticianliche Verlagsgesellschaft Stuttgart 1992, 271-272, may be selected from a group comprising
• a urea e.g. urea and its derivatives, e.g. monoacetyl urea, 1-dodecyl urea, 1,3-didodecyl urea, 1,3 diphenyl urea or cyclic urea derivatives, e.g. 1-methyl-4-imidazolin-2-one-3-methylenedecanoate.
• Urea may be commercially available from e.g. Merck, Germany;
• an inorganic salt e.g. sodium chloride, e.g. as known and commercially available from e.g. Merck, Germany; and
• a carboxylic acid e.g. a mono carboxylic acid or a cyclic carboxylic acid, salts and derivatives thereof.
• Particularly preferred are e.g. lactic acid; glycolic acid; lactic acid sodium and/or ammonium salt, e.g. sodium lactate, e.g. as known and commercially available from e.g. Merck, Germany; glycolic acid sodium and/or ammonium salt; lactamide; lactamidopropyl-triammonium chloride; sodium cocoyl lactylate; 2-pyrrolidone-5-carboxylate; 2-pyrrolidone-5-carboxylate sodium and/or calcium salt, e.g.
• sodium 2-pyrrolidone-5-carboxylate e.g. as known and commercially available under the name Sodium PCA from A+E Connock, UK; 2-pyrrolidone-5-carboxylate derivatives of amino acids, e.g. lysin or arginin; or acyl esters, having e.g. a chain length of C 1 -C 30 , e.g. C 3 -C 18 , branched or unbranched, e.g 2-pyrrolidone-5-carboxylic laurate (Fiedler, H. P.
• the carrier vehicle comprises a urea, e.g. urea itself or derivatives thereof, e.g. monoacetyl urea, 1-dodecyl urea, 1,3-didodecyl urea, 1,3 diphenyl urea or cyclic urea derivatives, e.g. 1-methyl-4-imidazolin-2-one-3-methylenedecanoate. Particularly preferred is urea itself.
• urea e.g. urea itself or derivatives thereof, e.g. monoacetyl urea, 1-dodecyl urea, 1,3-didodecyl urea, 1,3 diphenyl urea or cyclic urea derivatives, e.g. 1-methyl-4-imidazolin-2-one-3-methylenedecanoate.
• urea e.g. urea itself or derivatives thereof, e.g. monoacetyl urea, 1-do
• the means to retain water in the outer skin layer may be present in amount of from 0.1 to about 20%, e.g. from 1 to about 15%, preferably about 5% by weight based on the total weight of the composition.
• the means to retain water in the outer skin layer may be suspended or dispersed in the vehicle. They may be used in a micronized or non micronized form. Particularly preferred is the micronized form.
• the suspension or dispersion may contain particles of, e.g., urea of from 5, e.g. from 10, to about 90, preferably to about 25 microns in diameter.
• the non-micronized particles may have a size of equal to or less than 500 microns.
• the particles of the urea may be produced in conventional manner, e.g. by grinding or milling.
• the ascomycin and the means to retain water in the outer skin layer are present in a weight ratio of 0.05 to 3:0.1 to 20, more preferably in a weight ratio of 0.1 to 2:5 to 15, even more preferably in a weight ratio of 0.4 to 1: about 5.
• the carrier vehicle further comprises means to hinder water evaporating from the skin, e.g. hydrocarbons.
• Hydrocarbons may be selected from a group comprising
• petrolatum e.g. white petrolatum, e.g. as known and commercially available from e.g. Mineral Chemie AG, Germany;
• liquid paraffin e.g. as known and commercially available from e.g. Mobil BP Oiltech, Switzerland;
• a reaction product of a paraffin and a polyethylene e.g. a polyethylene having a molecular weight of from 10000 to about 400000 Daltons, e.g. 21000 Daltons, e.g. as known under the name Hydrophobes Basisgel DAC and commercially available under the trade name Plastibase®, from e.g. Hansen & Rosenthal, Germany (Fiedler, H. P., loc. cit, 2, p. 1198).
• Hydrocarbons may be present in amount of from 70 to about 95%, preferably of from 75 to about 90%, more preferably about 85% by weight based on the total weight of the composition.
• the amount and the type of hydrocarbons in the composition may depend on the desired viscosity of the composition as is conventional.
• the ascomycin and the hydrocarbon are present in a weight ratio of 0.05 to 3:70 to 95, more preferably in a weight ratio of 0.1 to 2 :75 to 90, even more preferably in a weight ratio of 0.4 to 1: about 85.
• composition as defined above which composition comprises a carrier vehicle comprising
• a carboxylic acid is to be understood a mono carboxylic acid or a cyclic carboxylic acid, salts and derivatives thereof, e.g. as defined above.
• a urea is to be understood urea it self or a derivative thereof, e.g. as defined above.
• composition as defined above which composition comprises a carrier vehicle further comprising
• liquid means e.g. lipophilic solvents and/or polar solvents, to solubilize ascomycin.
• the lipophilic solvents may be selected from a group comprising
• liquid waxes e.g. natural-, synthetic-, semisynthetic- or emulsifying-waxes.
• liquid waxes e.g. natural-, synthetic-, semisynthetic- or emulsifying-waxes.
• isopropyl myristate e.g. as known and commercially available from Henkel, Germany
• oleyl erucate e.g. as known and commercially available under the trade name Cetiol® J600 from e.g. Henkel, Germany
• diisopropyl adipate e.g. as known and commercially available under the trade name Isopat® 1794 from e.g. Dargoco, Germany
• oleyl oleate e.g. as known and commercially available under the trade name Cetiol® from e.g. Henkel, Germany
• cetiol® e.g. Henkel, Germany
• oleyl oleate e.g
• liquid fatty alcohols saturated and/or unsaturated, branched and/or unbranched, having e.g. a C 8 to C 24 chain.
• oleyl alcohol e.g. as known and commercially available under the trade name HD Eutanol® from e.g. Henkel, Germany, may be used;
• fatty acids saturated and/or unsaturated, branched and/or unbranched, having e.g. a C 8 to C 24 chain, e.g. oleic acid and/or lauric acid; and
• fatty oils comprising e.g. mono-, di- and tri-glycerides, having e.g. C 8 to C 24 fatty acids, e.g. a medium chain fatty acid triglyceride, e.g. Miglyol®812.
• Miglyol®812 is a fractionated coconut oil comprising caprylic-capric acid triglycerides and having a molecular weight of about 520 daltons.
• Fatty acid composition C 6 max. about 3%, C 8 about 50 to 65%, C 10 about 30 to 45%, C 12 max 5%; acid value about 0.1; saponification value about 330 to 345; iodine value max 1.
• Miglyol® 812 is commercially available from e.g. Huls Chemie AG, Germany.
• the polar solvents may be selected from a group comprising
• glycols e.g. glycerol, propylene glycol, butylene glycol, hexylene glycol.
• Propylene glycol may be commercially available from e.g. Dow Chemical;
• alcohols having e.g. a C 1 to C 7 chain, branched and/or unbranched, e.g. isopropanol;
• dimethyl isosorbide e.g. as known and commercially available under the trade name Arlasolve® DMI from ICI, Germany;
• the liquid means to solubilize the ascomycin may consist of one component or a mixture of components.
• the liquid means may be isopropyl myristate.
• the liquid means may be present in amount of from 1 to 20%, preferably from 2 to 15%, more preferably about 5% by weight based on the total weight of the composition.
• the composition is in the form of an ointment, containing no added water, e.g a water content of less than 5 or 2%.
• the liquid means may serve to dissolve partially the active agent. Typically 1 to 5% of the active agent is dissolved. Preferably a saturated solution of the active agent in the composition is obtained.
• the ascomycin and the liquid means are present in a weight ratio of 0.05 to 3:1 to 15, more preferably in a weight ratio of 0.1 to 2 :2 to 10, even more preferably in a weight ratio of 0.4 to 1: about 5.
• the ascomycin, the urea, the hydrocarbon and the liquid means when present, are present in a weight ratio of 0.05 to 3:0.1 to 20:70 to 95:1 to 15, more preferably in a weight ratio of 0.1 to 2:5 to 15:75 to 90:2 to 10, even more preferably in a weight ratio of 0.4 to 1: about 5: about 85 : about 5.
• the components of the carrier vehicle may be described in Fiedler, H. P., loc. cit., the contents of which are hereby incorporated by reference.
• compositions of this invention may be water-free or substantially water-free.
• the compositions may however comprise water, e.g. in an amount of from 0 to about 10% by weight based on the total weight of the composition, e.g. from 0.5 to 5%, e.g. from 1 to 3%.
• the compositions of this invention may be water-free.
• compositions of the invention are preferably in the form of an ointment.
• stabiliser agents to hinder degradation of urea may be included, e.g. allantoin, acteylglyceride, propionic acid ester, taurin, collagen, collagen hydrolysate, amino acid salts, monoalkylphosphate diethanolamine, triacetin, lactic acid, polysaccharides, chelating agents, e.g. citric acid or EDTA, e.g. as described in Fiedler, H. P. (loc. cit., 1, page 737).
• chelating agents e.g. citric acid or EDTA, e.g. as described in Fiedler, H. P. (loc. cit., 1, page 737).
• Further components e.g. preserving agents, e.g. microorganism growth inhibitors, and antioxidants, such as benzyl alcohol, butyl-hydroxytoluene, ascorbyl palmitate, sodium pyrosulfite, butyl hydroxy anisole, propyl p-hydroxybenzoate, methyl p-hydroxybenzoate, sorbic acid, chlorcresol and tocopherol may be included as appropriate.
• Preserving agents and antioxidants are preferably present in an amount of about 0.01 to about 2.5% by weight based on the total weight of the composition.
• pH modifying agents may be included to bring the pH of the composition to between 4 and 6 or by adding a pharmaceutically acceptable buffer system.
• a pH of between 4 and 6 is desirable to avoid skin irritation.
• compositions of the invention may further comprise thickeners, e.g. to stabilize the compositions, e.g.
• solid alcohols having e.g. a C 12 to C 24 chain, e.g. cetyl alcohol and/or stearyl alcohol.
• Cetyl alcohol and stearyl alcohol may be commercially available e.g. under the trade names Lorol® C16 and Lorol® C18, respectively, from Henkel, Germany;
• solid acids having e.g. a C 12 to C 24 chain, e.g. stearic acid and its salts, e.g. aluminium- or magnesium stearate;
• esters e.g. solid esters, of glycerol, e.g. mono-, di-, or tri-esters, e.g. glycerol monostearate and/or hydrogenated castor oil.
• Glycerol monostearate may be commercially available under the trade name Atmul® 84K from ICI, Germany;
• esters e.g. solid esters, of propylene glycol, e.g. mono- or di-esters, e.g. propylene glycol monooleate;
• inorganic thickening agents e.g. magnesium sulfate, bentonite or silicates including hydrophilic silicon dioxide products, e.g. alkylated, for example methylated, silica gels, in particular colloidal silicon dioxide products as known and commercially available under the trade name Aerosil, e.g. Arosil® 200, Aerosil® R812 or Aerosil® R 972, e.g. from Degussa, Germany (Handbook of Pharmaceutical Excipients, 2nd Edition, Editors A. Wade and P. J. Weller (1994), Joint publication of American Pharmaceutical Association, Washington, USA and The Pharmaceutical Press, London, England, page 424-427);
• inorganic thickening agents e.g. magnesium sulfate, bentonite or silicates including hydrophilic silicon dioxide products, e.g. alkylated, for example methylated, silica gels, in particular colloidal silicon dioxide products as known and commercially available under the trade name Aerosil,
• esterified compounds of fatty acid and fatty alcohols may include esterified compounds of fatty acid having e.g. a C 12 to C 24 chain, saturated or unsaturated, and primary alcohol having e.g. a C 12 to C 24 chain, e.g. cetyl palmitate.
• Thickening agents are preferably present in an amount of from about 1% to about 30%, e.g. from about 2% to about 10%, by weight based on the total weight of the composition.
• compositions of the present invention may further comprise emulsifiers, e.g.
• Especially preferred products of this class are Tween® 60 and Tween® 65.
• Sorbitan fatty acid esters e.g. sorbitan mono C 12-18 fatty acid esters, or sorbitan tri C 12-18 fatty acid esters as known and commercially available under the trade mark Span® or Arlacel®.
• Particularly preferred are the products Arlacel® 83 (Sorbitan sesquioleate) available from ICI, Germany, or Span® 60 (Sorbitan monostearate) (Fiedler, loc. cit., 2, p. 1430; Handbook of Pharmaceutical Excipients, loc. cit., page 473).
• Polyoxyethylene alkyl ethers e.g. polyoxyethylene glycol ethers of C 12 to C 18 alcohols, e.g. Polyoxyl 2-, 10- or 20-cetyl ether or Polyoxyl 4- or 23-lauryl ether, or polyoxyl 2-, 10- or 20-oleyl ether, or Polyoxyl 2-, 10-, 20- or 100-stearyl ether, as known and commercially available under the trade name Brij® from e.g. ICI, Germany.
• An especially preferred product of this class is e.g. Brij® 30 (Polyoxyl 4 lauryl ether) or Brij® 72 (Polyoxyl 2 stearyl ether) (Fiedler, loc. cit., 1, pp. 259; Handbook of Pharmaceutical Excipients, loc. cit., page 367).
• Polyoxyethylene fatty acid esters for example polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj® (Fiedler, loc. cit., 2, p. 1042; Handbook of Pharmaceutical Excipients, loc. cit., page 379).
• Myrj® 52 Polyoxyethylene 40 stearate having a D 25 of about 1.1., a melting point of about 40 to 44° C., an HLB value of about 16.9., an acid value of about 0 to 1 and a saponification no. of about 25 to 35.
• Sucrose esters e.g. sucrose fatty acid esters.
• the fatty acid moiety may comprise saturated or unsaturated fatty acids or mixtures thereof.
• Particularly suitable are C 6-18 -fatty acid saccharide mono- or diesters, in particular water soluble C 6-18 fatty acid saccharide mono- or diesters.
• caproic C 6
• caprylic C 8
• capric C 10
• lauric C 12
• myristic (C 14 ) palmitic
• C 16 oleic
• sucrose distearate e.g. as known and commercially available under the trade name Sucro Ester® 7 from Gattefoss6, France.
• Silicone emulsifiers e.g. laurylmethicone copolyol, e.g. as known and commercially available under the trade name Emulsifier® 10 from Dow Corning or a mixture of cetyidimethicone copolyol, polyglyceryl-4-isostearate and hexyl laurate, e.g. as known and commercially available under the trade name Abil® WE-09 from Goldschmidt.
• Phospholipids in particular lecithins (Fiedler, H. P., “Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre”, Editio Cantor Verlag Aulendorf, Aulendorf, 4th revised and expanded edition (1996), vol 2, p. 910, 1184).
• Lecithins suitable for use in the compositions of the invention include egg lecithins or soybean lecithins, in particular soybean lecithins, e.g. as known and commercially available under the trade name Phospholipon® 80 from Rhone Poulenc Rorer.
• Phospholipon® 80 is a phospholipid fraction with about 76% phosphatidylcholine, about 8% phosphatidic acid, about 4% phosphatidyl ethanolamine, and about 9% other lipids (manufacturer information).
• Lanolin e.g. anhydrous lanolin (Fiedler, H. P., loc.cit., 2, p. 896).
• emulsifiers may be complex mixtures containing side products or unreacted starting products involved in the preparation thereof, e.g. emulsifiers made by polyoxyethylation may contain another side product, e.g. polyethylene glycol.
• compositions additionally comprising emulsifiers may be particularly suitable if it is desirable to easily wash them off the skin.
• compositions of the invention may further include, e.g. perfumes and/or coloring agents, as appropriate.
• compositions according to the invention are useful in the treatment of subacute and chronic inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically-mediated diseases.
• diseases are psoriasis, atopic dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoic dermatitis, Lichen planus, a lichenified form of atopic dermatitis, vitiligo, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematous and Alopecia areata.
• the present invention provides a composition as defined above for use in the treatment of inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically-mediated diseases.
• the present invention provides a method for treating inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically-mediated diseases comprising administering a composition as defined above to the skin of a patient in need thereof.
• the present invention provides the use of a composition as defined above in the preparation of a medicament for administering to the skin of a patient in need thereof.
• the present invention provides the use of a composition as defined above in the preparation of a medicament for the treatment of inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically-mediated diseases.
• the present invention provides the use of a carrier vehicle as defined above to enhance penetration of an ascomycin through human skin.
• the carrier vehicle may be in the form of an ointment.
• compositions of the invention may be prepared in a conventional manner by working up the components into a pharmaceutical composition.
• the composition of the invention may be obtained by suspending the ascomycin and the urea in a mixture of liquid hydrocarbons and the lipophilic or polar solvent. Solid hydrocarbons may be mixed into the suspension in conventional manner.
• the composition of the invention may be obtained by suspending the ascomycin and the urea in a mixture of liquid hydrocarbons, solid hydrocarbons and the solvent as conventional. Other, e.g conventional, excipients may be added at the appropriate time.
• the utility of the compositions according to the invention can be observed in standard clinical tests such as the test set out below.
• a randomised double-blind, vehicle-controlled within-patient study comparing a composition of the invention at a dose of 0.1 to 2% by weight (based on the total weight of the composition) active agent over e.g. 10 cm 2 , corresponding to a dose of about 0.1 to 1 mg/cm 2 , and if desired 0.005% calcipotriol ointment and/or 0.05% clobetasol-17-propionate ointment as positive control is performed in patients with chronic plaque type psoriasis. In total 16 to 26 patients are treated with the composition twice daily for three weeks. The therapeutic effect on erythema, induration and scaling is evaluated for each of three clinical signs. In addition, the time to partial clearance is used for efficacy. Local tolerability of study medications and routine safety parameters, including haematology and clinical chemistry, are recorded.
• compositions of the invention are found to be effective without occlusion by technical means e.g. the Finn chamber technique, e.g. under open application conditions.
• the exact amount of the ascomycin and of the composition to be administered depends on several factors, for example the desired duration of treatment and the rate of release of the ascomycin. Satisfactory results are obtained in larger mammals, e.g. humans, with the local application over the area to be treated of a 0.1 to 2% by weight, preferably 1% by weight, concentration of the ascomycin once or several times a day (for example 2 to 5 times a day).
• the compositions may be applied to areas of skin as small as 1 cm 2 to as large as 1 m 2 . Suitable skin loadings of the ascomycins fall within the range of from 0.001 mg/cm 2 to about 3 mg/cm 2 , e.g. of from 0.1 mg/cm 2 to about 1 mg/cm 2 .
• compositions according to the invention can be observed in standard clinical tests such as the test set out in Example 1 infra using a concentration of 0.1 to 2% by weight (based on the total weight of the composition) active agent.
• the formulation of Example 1 was found to be effective in psoriasis.
• compositions of this invention are well tolerated on skin. Good skin penetration and permeation rates may be achieved using the compositions of the invention.
• compositions of this invention have the advantage of few components, are straightforward to prepare and are well-tolerated on human skin.
• An ointment is prepared having the following composition (amounts in g) Compound A 1 Urea 10 Petrolatum 39 Wax, microcrystalline 10 Paraffin, liquid 35 Isopropyl myristate 5 Total 100
• composition is prepared by suspending Compound A and urea in liquid paraffin and isopropylmyristate and heating to about 70° C.
• White petrolatum and microcrystalline wax are heated to about 85° C., cooled to about 70° C. and slowly added to the ascomycin mixture. The composition is then cooled to room temperature. An ointment is formed.
• Example 1 The formulation of Example 1 was effective. Local tolerability of the study medications tested was good and no systemic side effects were observed.
• An ointment is prepared having the same composition as in Example 1.1.
• the composition is prepared by heating liquid paraffin, microcrystalline wax, white petrolatum and isopropylmyristate to about 85° C., cooling to about 70° C. and suspending Compound A and urea in the mixture obtained. The composition is then cooled to room temperature. An ointment is formed.
• Example 2 3 4 5 6 7 Compound A 1 0.1 1 2 2 1.5 Means to retain water in the outer skin layer Urea 5 0.1 10 7.5 10 2 Means to hinder water evaporating from the skin Petrolatum 44 99.8 84 85.5 86 73 Wax, microcryst.
• Compound A in the compositions described in Example 1 to 13 may be replaced by Compound B, C, D, E, or F or FK 506.
• Compounds A, B, C, D, E or F or FK 506 may be used in micronized or non micronized form.
• Urea may be used in micronized or non micronized form.
• Examples 2 to 13 may be prepared according to Example 1.1 or 1.2.

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