The composition for local application

 

(57) Abstract:

The invention relates to a composition for topical application in the form of an emulsion for the treatment of inflammatory and hyperproliferative diseases of the skin and cutaneous manifestations of immunologically mediated diseases. The composition includes a compound of the FK506 class in the amount of from 0.01 to 10% by weight, the physiologically acceptable alcander, ether diol or fluids alcohol containing up to 8 carbon atoms as a solvent for the compound of the FK506 class in an amount of 5 to 50% by weight, of an unsaturated fatty alcohol WITH8-C22as a stabilizer in a weight ratio between the compound of the FK506 class and unsaturated fatty alcohol is from 1:1000 to 1:5 and water. A method for treating inflammatory or hyperproliferative skin diseases consists in the application of the composition to the skin of the patient. The composition for local application has a stable, well tolerated by the skin and penetrates the skin with high speed, efficient in use. 4 C. and 4 h.p. f-crystals, 6 PL.

The present invention relates to pharmaceutical compositions for topical application, including the macrolides, and in particular compositions comprising such macrolide, as ascomycin, rapamycin Il the nsis 9993. He also is a potent immunosuppressive drug. The structure of FK506 in the Annex to the 11th Edition of Merchindise in paragraph A5 (Merck Index, 11th Edition). Methods of obtaining FK506 described in EP 184162.

There are a large number of derivatives, antagonists, agonists and analogs of FK506, retaining the basic structure and at least one of the biological properties (e.g immunological properties) FK506. These compounds are described in many publications, for example in 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. In General, these compounds are called compounds of the FK506 class.

Known (EP 484936) compounds containing water, in addition, it is known (EP 484936) that compounds of the FK506 class was included in the pharmaceutical compositions representing a fine suspension.

It was unexpectedly found that the compound of the FK506 class can be entered into pharmaceutical compositions, which represents a stable emulsion. The emulsion due to the fact that they contain the aqueous phase, much less occlusal compared with formulations based on oil and thus better tolerated in many cases.

In accordance with this, in one of his is the Association class FK506; physiologically acceptable alcander, Egirdir or dietary alcohol containing up to 8 carbon atoms as a solvent for the compound of the FK506 class; unsaturated fatty alcohol and water.

These compositions for topical application of an effective, well tolerated by the skin and have stability from moderate to very high.

In this description "the connection of the FK506 class" is a compound which has a similar to FK506 basic structure and at least one of the biological properties of FK506 (for example immunosuppressive properties). The connection may be in free base form or in the form of pharmaceutically acceptable salts are obtained by adding acid. Examples of compounds of the FK506 class are the compounds of formula I:

< / BR>
in which each of the neighboring pairs of residues R1and R2, R3and R4and R5and R6independently (a) is a pair of hydrogen atoms, but R2in addition, it can be alkyl, or (b) forms a second bond between the carbon atoms to which they are attached;

R7represents H, HE, HE protected group, formyloxy or alkoxygroup, or R7together with R1forms oxoprop;

R8and R9NUU one or multiple IT groups, alkenylphenol group, alkenylphenol group, substituted by one or more HE-groups, or alkyl group substituted by oxopropoxy;

X1is H or HE;

X2is H; or

X1and X2together represent oxoprop or-CH2O-;

Y1is H or HE;

Y2is H; or

Y1and Y2together represent oxoprop, N-NR11R12or-N OR13;

R11and R12independently are H, alkyl group, aryl group or toiley group;

R13, R14, R15, R16, R17, R18, R19, R22and R23independently are H or alkyl group;

R24represents a possibly substituted cyclic structure which may contain one or more heteroatoms;

n is 1, 2 or 3; or

Y1, Y2, R10or R23together with the carbon atoms to which they are attached, represent a saturated or unsaturated 5 - or 6-membered heterocyclic ring containing nitrogen atoms, sulfur or oxygen, and possibly substituted by one or more groups selected from alkyl, HE, alkoxygroup, benzyl,

-CH who or salt, obtained by adding acid.

Preferably, when R24choose from (a) 3,4-dioxocyclohexa group; (b) 3-R20-4-R21-tsiklogeksilnogo group, in which R20is a HE, alkoxygroup or group-OCH2OCH2CH2OCH3, a R21is HE, -OCN, alkoxygroup, group-OCH2OCH2CH2OCH3protected hydroxyl group, chlorine-, bromine-, iodine-, methylthiomethyl, isobutyryloxy, aminoacylase, sidegroups, p-tolylenediisocyanate or group25R26CHCOO-, in which R25is possible protected hydroxy - or perhaps protected amino group, a R26represents H or methyl, or R20and R21together form an oxygen atom in an epoxide ring; or (C) a 5 - or 6-membered cycloalkyl group which may be substituted. For example, R24can be cyclopentyloxy group, substituted methoxymethyl possibly protected hydroxymethyl, acyloxymethyl (in which the acyl component may contain ether or dimethylaminopropyl, which can be quaternion or carboxyl group which may be etherification), or of one or more is determined as being an example is 2-formultimedia group.

The appropriate alkyl groups, alkeline group, aryl group, the protective group and acyl group is defined in the EP 484936.

Used in the compositions according to the present invention macrolide preferably has immunosuppressive properties. This macrolide may be rapamycin or O-substituted derivative in which the hydroxyl group in position 40 of the formula As shown on page 1 publication WO 95/16691, shown here as a reference, replaced by a group-OR1in which R1is hydroxyalkyl, hydroalkoxylation, acylaminoalkyl and aminoalkyl; for example 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)-ethoxy]ethyl-rapamycin and 40-O-(2-acetamidomethyl)rapamycin. These O-substituted derivatives can be obtained by the interaction of rapamycin (or a dihydro - or desoxypeganine) with an organic radical attached to tsepliaeva group (e.g. RX, where R is an organic radical of the type alkyl, allyl or benzyl component that you want as the O-substituent, and X represents tsepliaeva group, such as CCL3C(NH)O or CF3SO3in appropriate circumstances reuterslenovo acid, camphorsulfonic acid, p-toluensulfonate acid, or their corresponding salts, pyridinium or substituted pyridinium, if X is a CCL3C(NH)O or in the presence of a base such as pyridine, substituted for the pyridine, diisopropylethylamine or pentamethylpiperidine, if X is CF3SO3.

The preferred compound is 40-O-(2-hydroxy) ethyl-rapamycin (hereinafter compound A), which is described in WO 94/09010.

The preferred compound of the FK506 class described in EP 427680, in particular in Example 66A (also called the 33-epichloro-33-desoxycortisol), in further connection C. Other preferred compound of the FK506 class described in EP 465426, EP 569337 and EP 626385, for example the compound of Example 6d in EP 569337 in further connection With, or compound from Example 8 in EP 626385, further connection D.

Examples arcangioli solvents capable of dissolving the compound of the FK506 class are propylene glycol (1,2-propandiol), butyleneglycol, 2-ethyl-1,3-hexanediol, hexyleneglycol (2-methyl-2,4-pentanediol and the like. Examples of essential diodes as solvents are dipropyleneglycol, diethylene glycol and the like. Examples diapiric alcohols to what is hexyleneglycol. The preferred solvent content in the emulsion is from about 5 to 50%, more preferred from 5 to 20% and most preferred from 5 to 10% by weight.

The oil phase of the emulsion may range from 20 to 80% by weight, more preferably from 25 to 75% and most preferably from 35 to 65% by weight of the composition. The emulsion may be either an emulsion of oil in water, emulsion water in oil. The oil-water emulsion can be in the form of an emulsion gel (in this case a continuous aqueous phase can be condensed using polymeric thickener) or in the form of cream.

Unsaturated fatty alcohols form part of the oil phase of the emulsion and the preferred ones are lanolin alcohol, or C16-C18fatty alcohol; more preferred is alerby alcohol or laidlawii alcohol, the most preferred alerby alcohol. The composition preferably contains sufficient for improving the adsorption on the skin of the connection class FK506 amount of unsaturated fatty alcohol, more preferably from about 2 to 10% by weight and most preferably from 5 to 10% by weight.

The oil phase, in addition, may contain other liquid oils, thickening agents iasla include triglycerides with a chain of medium length, derived from fractionated vegetable oils, such as triglycerides of Caprylic/capric acids. One example of such triglyceride is a commercially available product with the trade name Miglyol 812 (molecular weight of approximately 520, nD20approximately 1,448 up to 1,450, and a viscosity of from 0.28 to 0.32 Pas). Liquid oils can be approximately from 5 to 60% by weight of the emulsion and preferably ranges from 5 to 15% by weight.

Appropriate thickening agents include conventional thickeners, such as cetyl alcohol, cetosteatil alcohol, stearyl alcohol, hydrogenated castor oil (Cutina HR), yellow wax, white wax, wax-based cetyl ether, emulsifying wax, microcrystalline wax and the like. Preferably the thickening agent is from about 2 to 30% by weight of the emulsion, and more preferably from 2 to 10% by weight.

The corresponding fatty bases include such basics as natural wax, petroleum jelly (vaseline jelly, also commercially available under the name Petrolatum), thick paraffin, alcohols fiber-based wax (for example, commercially available under the trade names Eucerinum or Eucerin), producing the similar.

The composition may also contain appropriate emulsifiers, customary for emulsion compositions. Such emulsifiers are described in the literature (Fiedler, H. P.; 1989; Lexikon der Hilfsstoffe fur Pharmazie, Kosmetic und angrenzende Gebiete, Editio Cantor, D-7960 Aulendorf, Germany and Handbook of Pharmaceutical Excipients, A Joint Publication of the American Pharmaceutical Association, Washington DC, USA and the Pharmaceutical Society of Great Britain, London, UK; 1986). Examples of appropriate emulsifiers include:

a) mono - and diesters of fatty acids and propylene glycol, such as propilenglikolstearat (commercially available under the trade name Miglyol 840), propilenglikolstearat, propilenglikolmonostearata, propilenglikolstearat, propilenglikolstearat, propilenglikolstearat and propilenglikolstearat;

b) esters of polyoxyethylenesorbitan and fatty acids, namely mono - and trilaurylamine, Piletilevi, stearyl and aerovee esters. Are commercially available, for example, esters under the trade names Tween (see Fiedler, S. 1300-1304), in particular Tween 60 (polyoxyethylene(20)servicemonitor) and Tween 80 (polyoxyethylene(20)servicemanual);

C) esters of fatty acids and polyoxyethylene, for example esters of stearic acid and polyoxyethylene type commercially available under the trade name Myrj (see Fiedler, S. 834 and 835) and, in particular, Myrj 52 (available who athelny balance), approximately equal to 16.9);

d) copolymers of polyoxyethylene-polyoxypropylene and copolymers of the type known and commercially available under the trade names Pluronic, Emkalyx and Poloxamer (see Fiedler, S. 959), particularly Pluronic F68 (having a melting point of about 52oAnd the value of molecular weight from about 6800 to 8975) and Poloxamer 188;

e) dioctylsulfosuccinate or di[2-ethylhexyl]-succinate;

e) phospholipids, and in particular lecithins (see Fiedler, S. 943 and 944);

g) salts of sulfates of fatty alcohols, namely sodium lauryl sulfate and cetylstearyl sodium;

C) esters sorbitan and fatty acids, namely servicemonitor and servicemanual, commercially available under the trade names Arlacel 60 (having an HLB value of about 4.7 and a melting point of approximately 53oC) and Span 80 (having a value of D25approximately 1, HLB about 4.3 and a viscosity of from about 950 to 1100 SP);

and) glycerylmonostearate, commercially available under the trade name Imwitor (see Fiedler, S. 645) and, in particular, Imwitor 960;

C) esters of aliphatic C6-C22carboxylic acids and ethers of polyethylene glycol and of glycerol with at least one free hydroxyl group. Examples vclog oil and ethylene oxide, commercially available under the trade name Cremophor, namely Cremophor RH 40 (the number of saponification of which is approximately 50 to 60, an acid number of <1, the value of nD60approximately 1,453 up to 1,457, and HLB is approximately 14 to 16), Cremophor RH 60 (the number of saponification of which is approximately from 40 to 50, an acid number of <1, the values of nD25approximately 1,453 up to 1,457 and HLB from about 15 to 17) and Cremophor EL (saponification number which is approximately 65 to 70, an acid number of about 2, the value of nD25approximately 1,471 and a molecular weight of approximately 1630). Suitable are also various surfactants, commercially available under the trade names Niccol, Emulgin, Mapeg and Incrocas (see Fiedler).

m) stearic acid;

n) emulsifiers on the basis of oil or wax, as for example, cetyl alcohol and emulsifying wax;

on polyoxyethyleneglycol, as, for example, commercially available under the trade names Labrafil M2130 CS (see Fiedler, S. 707);

p) polyoxyalkylene esters, as, for example, polyoxyethyleneglycol ether, polyoxyethyleneglycol ether and polyoxyethyleneglycol ether, commercially available under the series trade name Brij and Cetomacrog the new name Arlacel 481 (the value of the molecular weight of which is approximately 630, and HLB of approximately 4.5) and

(C) mixtures thereof.

Preferably the emulsifier is selected from polyethylene glycol(20)glycerylmonostearate, servicemonitoring (Arlacel 60), sorbitanoleat (Span 60), Tween 60, Tween 80, glycerylmonostearate (Imwitor 960), stearic acid, cetyl alcohol, derivatives and alcohols fiber-based wax, Labrafil M2130 CS and mixtures thereof. In the case when the emulsion is an emulsion of water in oil emulsifier selected preferably has a value of HBL from 10 to 15. In the case when the emulsion is an oil-water emulsion, the preferred HLB value of the selected emulsifier is from 4 to 8. The preferred content of the emulsifier in the emulsion is from about 1 to 30% by weight, preferably from 10 to 25% by weight.

To obtain a gel-like emulsion in its composition, in addition, can be entered thickeners. Appropriate thickeners are carbomer (derivatives of poly (acrylic acid), for example commercially available under the trade names Carbopol (see Fiedler, S. 254-256). Preferred are Carbopol 974 and Carbopol 1342. The preferred content of the thickening agent is from 0.2 to 2% by weight, more preferably less than 1% by weight.

The aqueous phase of the emulsion may range from 20 to 80% by weight, more preferably from 25 to 75%, even more preferably from 35 to 65% by weight of the emulsion. The preferred form of the aqueous phase is sterilized water.

The compound of the FK506 class preferably present in the emulsion in amounts of from about 0.01 to 10% by weight and more preferably from 0.1 to 1% by weight.

The preferred weight ratio between the compound of the FK506 class and unsaturated fatty alcohol is from 1:1000 to 5:1, prefer the governmental funds in the form of a suspension.

In accordance with this other aspect of the present invention encompasses pharmaceutical compositions for topical application, including macrolides in suspension.

The term "macrolide" shall have the same meaning as described earlier.

The pharmaceutical composition may be in solid form, but it is preferable to semi-solid form suitable for topical application.

These compositions according to the invention in the form of suspensions effective, well tolerated by the skin and have stability from moderate to very high.

The suspension contains particles of the macrolide from about 5, for example from 10 to 90 microns in diameter. Particles of the macrolide can be obtained in the usual way, for example by grinding or crushing.

The slurry may be prepared in the form of a cream, not containing water ointment, emulsion of water in oil, oil emulsions in water, emulsion, gel or gel.

Another aspect of the present invention encompasses a composition for topical application in the form of oil-in-water emulsion gel, including:

and macrolides in an amount up to 5% by weight,

b) a thickener in an amount up to 20% by weight,

b) hydrophilic component kolichestvennaia stabilizers in the total amount up to 5% by weight,

e) water in an amount up to 90% by weight.

Appropriate thickeners defined above and may include paraffin waxes and petroleum jelly.

Appropriate hydrophilic components include propylene glycol, alcohols type of cetyl, stearyl and olejowego alcohol.

Examples of appropriate organic acids, provided for use in this invention include sorbic acid. The acid acts as a preservative and is used primarily to prevent bacterial growth.

In another aspect, the present invention encompasses compositions for topical application in the form of emulsion or suspension, as defined above, used for the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases.

In his next aspect of the present invention encompasses a method of treating inflammatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically mediated diseases, including assigning a higher composition for local application needs it for the patient.

In another of its aspects this invention is about alcohol, containing up to 8 carbon atoms as a solvent for the compound class F506; unsaturated fatty alcohol and water to prepare drugs in the form of an emulsion for treating inflammatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically mediated diseases.

Compositions in the form of emulsions can be obtained by dissolving the compound of the FK506 class in the solvent and the unsaturated fatty alcohol with obtaining oil phase. If desired, the oil phase can be mixed liquid oils, fatty bases and thickeners. After this oil emulsify phase with the aqueous phase and, if necessary, with appropriate emulsifiers. At the right time to the correct phase of the emulsion may be added in accordance with the usual rules of other excipients.

The authors of this application it was found that macrolides can be unstable in compositions for topical application. It is assumed that this instability is not due until the end of intuitive decomposition reactions and rearrangements. As a result of enormous research work the authors found that, for the stabilization of compositions containing macrolides, mo is ativam the use of an unsaturated fatty alcohol to stabilize the macrolide in the pharmaceutical composition.

In another aspect, the invention covers a method of stabilization of the macrolide in the pharmaceutical composition, which consists in mixing an unsaturated fatty alcohol with a macrolide.

Unsaturated fatty alcohol can be a C8-C22alcohol or may include a mixture of alcohols. Unsaturated fatty alcohol may contain one, two or three double bonds. Preferably unsaturated fatty alcohol contains one double bond and has the CIS-configuration. It is preferable alerby alcohol. The stabilizing effect can be observed when the weight ratio between unsaturated fatty alcohol and an active agent comprising at least about 1: 5, for example at a ratio of from 1:2 to 1:1 or greater, such as 5:1.

The authors of this application have found that unsaturated fatty alcohol, for example alerby alcohol, suitable for stabilization of the macrolide in the pharmaceutical composition for local application. Examples of such pharmaceutical compositions for local application described in the application.

Unsaturated fatty alcohol, for example alerby, can be used to stabilize the macrolide having at least one structure represented neither is in and of compounds of the FK506 class, for example, FK506, ascomycin and 33-epichloro-33-detoxicating.

Compositions for topical application, as defined above, useful in the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases. Examples of such diseases are psoriasis, atopic dermatitis, contact dermatitis, and other eczematous dermatitises, seborrhoeic dermatitis, red flat zoster, disease, bullous pemphigoid, congenital bullous bullosa, urticaria, angioedema, vasculitis, erythema, dermal eosinophilia, lupus and alopecia areata.

The efficacy of compositions for topical application may be demonstrated in standard clinical tests in, for example in the test are given below in Example 12, in which the compound of the FK506 class is used in a concentration of from 0.01 to 10% by weight (preferably from 0.1 to 1% by weight). In addition, it is shown (EP 315978) the effectiveness of these compounds in the standard model experiments with animals.

The exact amount required for the introduction of the connection class FK506 and composition depends on several factors, such as the required duration of treatment, and the speed of removing soedinenii connection class FK506 on the workpiece surface at a concentration of from 0.01 to 10% by weight, preferably from 0.1 to 3% by weight of one (for example, from 2 to 5 times a day). In General, such a composition may be applied to the surface of the skin ranging in size from 1 cm2up to 1 m2. Acceptable load connection class FK506 on the skin are in the range from 0.1 mg/cm2up to 1 mg/cm2.

The compositions of this invention are well tolerated by the skin. When using the compositions according to the present invention can be achieved with good skin penetration and high speed injection.

The compositions described below in Examples 13, 14 and 19, are the preferred emulsion compositions intended for use in mammals, such as humans.

For compounds

(i) [3S-[3R*{E(1S*,3S*,4S*)],4S*,-5R*,8S*, 9E, 12R*,14R*,15S*,16R*,18S*, 19S*, 26aR*] ] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26 and hexadecagon-5, 19-dihydroxy-3-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methylethenyl)] -14, 16-dimethoxy-4,10,12,18, -tetramethyl-8-(2-propenyl)-15,19-amoxin-pyrido[2,1-C][1,4]oxathiazin-1,7,20,21(4H, M)-tetron;

(ii) [3S-[3R*{E(1S*,3S*,4S*)],4S*,-5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*, 19S*, 26aR*] ] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26 and hexadecagon-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methylethenyl)] -14,16-dimethoxy-4,10,12,18,-tetramethyl-8-ethyl-15,19-epoxy-3H-pyrido[2,1-C] [1,4]oxathiazin the-hexadecagon-5,19-dihydroxy-3-(3-hydroxymethylglutaryl)-1-methylethenyl)] -14,16-dimethoxy-4,10,12,18, -tetramethyl-8-ethyl-15,19-epoxy-3H-pyrido[2,1-C] [1,4] oxathiazin-1,7,20,21(4H, M)-tetron

effective in the treatment of chronic plaque-like psoriasis in humans when applied topically once daily concentrations are from 0.01 to 1% by weight. In such applications of these compounds as effective as a potent composition of Clobetasol (0.05 per cent).

The following examples describe compositions according to this invention.

Examples:

"Connection 1" is a combination of [3S-[3R*[E(1S*,3S*,4S*)],

4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,

19S*, 26aR*] ] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26 and hexadecagon-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methylethenyl)] -14,16-dimethoxy-4,10,12,18, -tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-C] [1,4] oxathiazin-1,7,20,21(4H,M)-tetron. This connection is more commonly known as FK506.

"Connection 2" is a combination of [3S-[3R*[E(1 S*,3S*,4S*)],

4S*,5R*,8S*,9E,12R*,-14R*,15S*,16R*,18S*,

19S*, 26aR*] ] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26 and hexadecagon-5,19-dihydroxy-3-(3-hydroxymethylglutaryl)-1-methylethenyl)] -14,16-dimethoxy-4,10,12,18, -tetramethyl-8-ethyl-15,19-epoxy-3H-pyrido[2,1-C] [1,4] oxathiazin-1,7,20,21(4H,M)-tetron. This compound and its production method described in EP 465426.

Compound A, compound B, compound C and compound D as described above.

The term "stable", as used in the following examples, it should be understood in the sense that the relevant structures were not observed separation of the components during storage at room temperature over a period of time of four months or more.

Chemical analysis of the active agent is carried out using a reversed-phase HPLC with UV-detection; =210 nm. The limit of detection is 0.1% by weight.

Data portability compounds tested in vivo in the pig skin and human skin. Visual assessment is made after 0.5, 1, 2 and 4 hours after application.

Example 1

Prepare the oil-water emulsion containing the following ingredients (in parts by weight):

Connection 2 - 0,10

Alerby alcohol - 10,00

Miglyol 812 - 10,00

Hexyleneglycol - 10,00

Cetyl alcohol - 5,00

Steadily alcohol - 5,00

Benzyl alcohol - 1,00

Servicemonitor - 2,00

Tween 80 - 4,00

Glycerylmonostearate - 3,00

Water - 49,90

The composition is prepared by mixing and heating to 65oWith up to complete dissolution of all components. Then the oil phase is added rlacel 60, Tween 80 (polyoxyethylene(20)servicemanual) and glycerylmonostearate and stirred until complete dissolution of all components. Then in a vessel equipped with a stirrer and homogenizer, heated water. Then add benzyl alcohol. After this, slowly add the oil phase under stirring and homogenizing to obtain a homogeneous emulsion with droplet size less than 20 microns. The emulsion was then cooled to room temperature. This emulsion is stable.

Example 2

The oil-water emulsion is prepared analogously to Example 1 and contains the following ingredients (in parts by weight):

Connection 1 - 0,10

Alerby alcohol - 10,00

Miglyol 812 - 10,00

Hexyleneglycol - 10,00

Cetyl alcohol - 5,00

Stearyl alcohol - 5,00

Benzyl alcohol - 1,00

Servicemonitor - 2,00

Tween 80 - 4,00

Glycerylmonostearate - 3,00

Water - 49,90

This emulsion is stable. Component separation is not observed.

Example 3

The emulsion of water in oil is prepared analogously to Example 1 except that the water is added slowly to the oil phase. The composition contains the following ingredient the wax - 3,00

Benzyl alcohol - 1,00

Arlacel 481 - 7,00

White oil - 15,00

Thick paraffin - 5,00

Water - 58,4

MgSO47H2O - 0,5

The emulsion is stable.

Example 4

The oil-water emulsion is prepared analogously to Example 1 and contains the following ingredients (in parts by weight):

Connection 2 - 0,10

Alerby alcohol - 7,50

PEG-glycerylmonostearate - 7,00

Propylene glycol - 10,00

Cetyl alcohol - 6,00

Glycerylmonostearate - 4,00

Paraffin (thick) - 10,00

White oil - 15,50

Sorbic acid - 0,01

Water - 39,89

Examples 5, 6 and 7

Emulsion of oil in water are prepared analogously to Example 1 and contain ingredients (in parts by weight), shown in Table 1 (see end of description)

Examples 8-11

The emulsion is prepared analogously to Example 1 (see Table 2 at the end of the description).

The compositions of Examples 4-11 stable.

Example 12

To determine the effectiveness of the compositions of Examples 4-7 for chronic plaque-like psoriasis spend a single center, double-blind and controlled with placebo study. Select the 10 patients older than 18 years with chronic plaque-like psoriasis and not receiving General or MNI number -1 in patients using the composition for local application, containing 10% salicylic acid in vaseline, and remove the scales. Day number 0 on scaly plaques impose, poluprikryla them, the compositions of Examples 4-7, 0.05% composition lbestasol, commercially available under the trade name Dermovate, and placebo, and leave in this state for 24 hours.

To allow patients to take a bath, and affected areas gently dried. Defeat assessed visually (erythema) and by palpation (infiltration) by assigning points in the interval from 0 (absence) to 30 (severe condition). The procedure is repeated daily until 10-11 days.

Total scores are presented in Tables 3 and 4.

As a result of action of the compositions of Examples 4-7, there was no side effects, and two patients receiving Dermovate observed atrophy of the skin. While the compositions of Examples 4-7 were at least as effective as and Dermovate.

The active agent used in the compositions described in Examples 1-11 can be replaced with Connection a, b, C or D.

Examples 13-16

Emulsion of oil in water are prepared analogously to Example 1 and containing components shown in Table 5 (see the end of the description).

The compositions of Examples 13-16 are well tolerated by the skin of the pig is s incubation at 70oWith a was 0.1% (limit of quantitation); replacing olejowego alcohol on Miglyol 812 result of the analysis of the main product of degradation increased up to 0.5%. When stored at room temperature for four months there was no separation of components.

Examples 17-19

The compositions constituting the emulsion oil in water, prepared with 1% weight concentration of active agent (see Table 6 at the end of the description).

The emulsions of Examples 17, 18 and 19 stable separation of the components of the emulsions is not observed. It is established that the compounds are well tolerated by human skin. After storage of the composition at 40oWith over eight weeks was produced by chemical analysis using HPLC. The result of the analysis of the main product of degradation of compounds 17, 18 and 19 was 1.1, 0.8 and 0.4%, respectively.

In the compositions of Examples 13-19 active agent connection may be replaced by compound a, compound C, compound D, compound 1, compound 2 or compound 3.

Example 20

Composition based emulsion of oil in water is prepared in the form of a cream by using as the active agent connection:

Connection - the Amount in weight %

With>Propylparaben - 0,03

Cetyl alcohol - 5

Glycerylmonostearate - 10

Water Up to 100

The cream is stable, component separation is not observed.

Examples 21-30

In Examples 21-30 describes the preparation of compounds in the form of suspensions.

Example 21

Prepare the composition in the form of suspension for topical application, containing the following ingredients (in parts by weight):

Connection 1, 2, 3, a, b, C or D - 0,10

Vaseline is 99.9

The composition is prepared by mixing compound and other excipients.

Example 22

To determine the effectiveness of the compositions of Example 21 for chronic plaque-like psoriasis spend a single center, double-blind and controlled with placebo study. Were selected 10 patients older than 18 years with chronic plaque-like psoriasis and not receiving General or local treatment against chronic plaque-like psoriasis within 1 month and 1 week, respectively. Per day number -1 in patients with composition for topical use containing 10% salicylic acid in vaseline, and remove the scales. Day number 0 on scaly plaques impose, poluprikryla them, the composition of Example 21, 0.05% composition lS="ptx2">

To allow patients to take a bath, affected areas gently dried. Defeat assessed visually (erythema) and by palpation (infiltration) by assigning points in the interval from 0 (absence) to 30 (severe condition). The procedure is repeated daily until 10-11 days; there is a cure for psoriasis.

Example 23

Prepare the composition in the form of suspension for topical application in the form of an emulsion gel type oil-in-water containing the following ingredients (in parts by weight):

Connection - 0,3

Paraffin, thick - 15

Glycerylmonostearate - 0,3

Propylene glycol - 10

Carbopol R - 0,5

Carbopol 1342 - 0,5

NaOH 5% to 2.5

Sorbic acid - 0,1

Water - 70,8

The composition is prepared by mixing compound and other ingredients. The structure is subjected to loads in the centrifuge within 24 hours at temperatures up to 95oC. no degradation of the active agent according to HPLC is not observed.

Compositions in the form of suspensions prepared in Examples 24-30.

Example 24

Quantity (g/100 g)

The connection IN the 0.1

Paraffin, thick - 48

Glycerylmonostearate - 8

Vaseline, white - 43,9

Example 25

Quantity (g/100 g)

The connection IN the 0.1

P is (g/100 g)

Paraffin, thick - 30

Cetyl alcohol - 5

Stearyl alcohol - 5

Servicemonitor - 2

Polysorbate 80 (polyhydroxy etilendiaminmonoatsetat) - 4

Glycerylmonostearate - 3

Ascorbyl palmitate - a 0,05

The connection IN the 0.1

Sorbic acid - 0,1

Propylene glycol - 5

Water - 45,75

Example 27

Quantity (g/100 g)

Propylene glycol - 10

Paraffin, thick - 15

The connection IN the 0.1

Carbopol 1342 (Polyacrylic acid, partially dlinnozerny alkyl ether) - 1

Methylparaben - 0,07

Propylparaben - 0,03

NaOH, 5% aqueous solution of 2.5

Water - 71,30

Example 28

Quantity (g/100 g)

The connection IN the 0.1

Carbopol 947 - 1

NaOH, 1N aqueous solution of 2.5

Water - 96,4

Example 29

Quantity (g/100 g)

The connection IN the 0.1

Cetylstearyl alcohol - 0,5

Alcohols fibrous wax - 6

Vaseline, white - 93,4

Example 30

Quantity (g/100 g)

The connection IN the 0.1

Cetylstearyl alcohol - 0,25

Alcohols fibrous wax - 3

Vaseline, white - 46,65

Water - 50

For compositions in the form of suspensions of Examples 24-30 observed stability from good to very good. Test suspensions in healthy volunteers show is written in the Examples 23-30.

1. The composition for topical application in the form of an emulsion for the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases, characterized in that it comprises a compound of the FK506 class in the amount of from 0.01 to 10% by weight, the physiologically acceptable alcander, ether diol or fluids alcohol containing up to 8 carbon atoms as a solvent for the compound of the FK506 class in an amount of 5 to 50% by weight, of an unsaturated fatty alcohol WITH8-C22as a stabilizer in a weight ratio between the compound of the FK506 class and unsaturated fatty alcohol is from 1: 1000 to 1: 5 and water.

2. The composition for local application on p. 1, characterized in that the compound of the FK506 class represents ascomycin, 33-epichloro-33-desoxycortisol or FK506.

3. The composition for topical application under item 1 or 2, characterized in that the solvent is hexyleneglycol or propylene glycol.

4. The composition for topical use according to any one of paragraphs. 1-3, characterized in that the unsaturated fatty alcohol is alerby alcohol.

5. A method for treating inflammatory or hyperproliferative skin diseases and cutaneous manifestations and the means according to any one of paragraphs. 1-4 on the skin in need of it the patient.

6. The use of an unsaturated fatty alcohol WITH8-C22to stabilize the connection of the FK506 class from degradation in the pharmaceutical composition.

7. Method of stabilizing compounds of the FK506 class from degradation in the pharmaceutical composition in which the unsaturated fatty alcohol WITH8-C22mix with the specified connection.

8. The method according to p. 7, characterized in that the unsaturated fatty alcohol is alerby alcohol.

Priority points:

04.11.1994 on PP. 1-5;

26.10.1995 on PP. 6-8.

 

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