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.
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.
After exhaustive testing it has now been surprisingly found that the 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.
In one aspect this invention provides a composition for topical administration of an ascomycin which composition comprises a carrier vehicle comprising
The ascomycin is hereafter referred to as active agent. Under “ascomycin” 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, 11th Edition as item A5. Methods of preparing FK506 are described in EP 184162.
Under “compound of the FK 506 class” is to be understood 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.
It is also known (for example from EP 315978 and EP 474126) that 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.
Thus 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);
{[1E-(1R,3R,4R)]1R,4S,5R,6S,9R,10E,13S,15S,16R,17S,19S,20S}-9-ethyl-6,16,20-trihydroxy-4-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methylvinyl]-15,17-dimethoxy-5,11,13,19-tetramethyl-3-oxa-22-aza-tricyclo[18.6.1.0(1,22)]heptacos-10-ene-2,8,21,27-tetraone as disclosed in Examples 6d and 71 in EP 569 337 (hereafter referred to as Compound B); and
{1R,5Z9S,12S-[1E-(1R,3R,4R)],13R,14S,17R,18E,21S,23S,24R,25S,27R}17-ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0(4,9)]octacosa-5,18-diene-2,3,10,16-tetraone, also known as 5,6-dehydro-ascomycin as disclosed in Example 8 in EP 626 385 (hereafter referred to as Compound C);
Imidazolylmethyloxyascomycin, as disclosed in Example 1 and as compound of formula I in WO 97/08182, contents of which are incorporated herein by reference (hereafter referred to as Compound D);
32-O-(1-hydroxyethylindol-5-yl)ascomycin, also known as Indolyl-ASC or L-732 531 as disclosed in Transplantation 65 (1998) 10-18, 18-26, on page 11, FIG. 1 (hereafter referred to as Compound E); and
(32-deoxy-32-epi-N1-tetrazolyl)ascomycin, also known as ABT-281 as disclosed in J. Inv. Derm. 112 (May 1999), 729-738, on page 730, FIG. 1 (hereafter referred to as Compound F).
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. In a further aspect the active agent may be in suspension, e.g. partially in suspension in the vehicle. Preferably the active agent is partially dissolved in the vehicle.
Preferably 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.
If desired further active agents may be present.
The carrier vehicle comprises means to retain water in the outer skin layer, e.g. moisturizers.
Under “means to retain water in the outer skin layer” is to be understood, e.g. a pharmaceutically acceptable moisturizer, capable of e.g. penetrating and residing in the outer skin layer, e.g. the stratum comeum, 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. Zegenmayer, Wissenschaftliche Verlagsgesellschaft Stuttgart 1992, 271-272, may be selected from a group comprising
Preferably 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.
The means to retain water in the outer skin layer, e.g. urea, 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.
Preferably 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
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.
Preferably 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.
In another aspect the present invention provides a composition as defined above which composition comprises a carrier vehicle comprising
Under “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. Under “a urea” is to be understood urea it self or a derivative thereof, e.g. as defined above.
In another aspect the present invention provides a composition as defined above which composition comprises a carrier vehicle further comprising
The lipophilic solvents may be selected from a group comprising
The polar solvents may be selected from a group comprising
The liquid means to solubilize the ascomycin may consist of one component or a mixture of components. Preferably 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.
Preferably 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.
Preferably 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.
Preferably 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.
The 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%. Preferably the compositions of this invention may be water-free.
The compositions of the invention are preferably in the form of an ointment.
If desired, stabiliser agents to hinder degradation of urea may be included, e.g. allantoin, acteylglyceride, propionic acid ester, taurin, collagen, collagen hydrolysate, amino acid salts, monoalkyiphosphate 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).
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.
If desired, 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.
If desired, the compositions of the invention may further comprise thickeners, e.g. to stabilize the compositions, e.g.
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.
The compositions of the present invention may further comprise emulsifiers, e.g.
It is to be appreciated that 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.
The compositions of the invention may further include, e.g. perfumes and/or coloring agents, as appropriate.
The 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. Examples of such 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.
In another aspect 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.
In another aspect 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.
In another aspect 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.
In yet another aspect 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.
In yet another aspect 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.
The compositions of the invention may be prepared in a conventional manner by working up the components into a pharmaceutical composition.
For example, 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. Alternatively, 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 representative clinical trial is carried out as follows:
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 cm2, corresponding to a dose of about 0.1 to 1 mg/cm2, 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.
The 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). In general the compositions may be applied to areas of skin as small as 1 cm2 to as large as 1 m2. Suitable skin loadings of the ascomycins fall within the range of from 0.001 mg/cm2 to about 3 mg/cm2, e.g. of from 0.1 mg/cm2 to about 1 mg/cm2.
In particular the utility of the 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.
The compositions of this invention are well tolerated on skin. Good skin penetration and permeation rates may be achieved using the compositions of the invention.
The compositions of this invention have the advantage of few components, are straightforward to prepare and are well-tolerated on human skin.
The following Examples illustrate the invention.
An ointment is prepared having the following composition (amounts in g)
The 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.
In total 20 patients were treated for three weeks. The therapeutic effect on erythema, induration and scaling was evaluated for each of three clinical signs. In addition, the time to partial clearance was used for efficacy. Local tolerability of study medications and routine safety parameters, including haematology and clinical chemistry, were recorded.
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.
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.
Number | Date | Country | Kind |
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9826656.2 | Dec 1998 | GB | national |
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3666863 | Swanbeck | May 1972 | A |
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4309206 | Michaud et al. | Jan 1982 | A |
4324811 | Eugley | Apr 1982 | A |
4401650 | Salamone | Aug 1983 | A |
4488989 | Lamberti | Dec 1984 | A |
4612331 | Barratt et al. | Sep 1986 | A |
4672078 | Sakai et al. | Jun 1987 | A |
4690774 | Vishnupad et al. | Sep 1987 | A |
4826677 | Mueller et al. | May 1989 | A |
4963555 | Jones et al. | Oct 1990 | A |
5002760 | Katzev | Mar 1991 | A |
5143918 | Bochls et al. | Sep 1992 | A |
5225403 | Treiber et al. | Jul 1993 | A |
5352671 | Baumann et al. | Oct 1994 | A |
5385907 | Asakura et al. | Jan 1995 | A |
5385938 | Yu et al. | Jan 1995 | A |
5559098 | Wohlrab et al. | Sep 1996 | A |
5912238 | Baumann et al. | Jun 1999 | A |
5925649 | Hersperger et al. | Jul 1999 | A |
5939427 | Kagayama et al. | Aug 1999 | A |
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Number | Date | Country |
---|---|---|
195 49 243 | Jun 1997 | DE |
196 06 355 | Aug 1997 | DE |
0 069 512 | Jun 1986 | EP |
0 184 162 | Jun 1986 | EP |
0 315 978 | May 1989 | EP |
0 323 042 | Jul 1989 | EP |
0 364 211 | Apr 1990 | EP |
0 423 714 | Apr 1991 | EP |
0 427 680 | May 1991 | EP |
0 465 426 | Jan 1992 | EP |
0 474 126 | Mar 1992 | EP |
0 484 936 | May 1992 | EP |
0 532 088 | Mar 1993 | EP |
0 532 089 | Mar 1993 | EP |
0 569 337 | Nov 1993 | EP |
0 626 385 | Nov 1994 | EP |
0 512 109 | Nov 1995 | EP |
0 780 129 | Jun 1997 | EP |
937453 | Aug 1999 | EP |
1 074 255 | Feb 2001 | EP |
2 142 238 | Jan 1985 | GB |
60-228423 | Nov 1985 | JP |
62-223163 | Oct 1987 | JP |
4-182429 | Jun 1992 | JP |
5-25046 | Feb 1993 | JP |
5-43457 | Feb 1993 | JP |
7-252150 | Oct 1995 | JP |
8-34731 | Feb 1996 | JP |
8-133979 | May 1996 | JP |
8-143458 | Jun 1996 | JP |
8-231369 | Sep 1996 | JP |
9-315954 | Dec 1997 | JP |
10-231248 | Sep 1998 | JP |
10-251137 | Sep 1998 | JP |
WO 9113889 | Sep 1991 | WO |
WO 9113899 | Sep 1991 | WO |
WO 9119495 | Dec 1991 | WO |
WO 9211860 | Jul 1992 | WO |
WO 9305059 | Mar 1993 | WO |
WO 9428894 | Dec 1994 | WO |
WO 9519162 | Jul 1995 | WO |
WO 9613249 | May 1996 | WO |
WO 9613273 | May 1996 | WO |
WO 9631514 | Oct 1996 | WO |
WO 9638135 | Dec 1996 | WO |
WO 9708182 | Mar 1997 | WO |
WO 9723242 | Jul 1997 | WO |
WO 9901458 | Jan 1999 | WO |
WO 9920261 | Apr 1999 | WO |
WO 9924036 | May 1999 | WO |
WO 0001385 | Jan 2000 | WO |
Entry |
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Number | Date | Country | |
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20120202841 A1 | Aug 2012 | US |
Number | Date | Country | |
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Parent | 11266639 | Nov 2005 | US |
Child | 13204489 | US | |
Parent | 09871367 | May 2001 | US |
Child | 11266639 | US | |
Parent | PCT/EP99/09351 | Dec 1999 | US |
Child | 09871367 | US |