KR20070022738A - Use of a pharmaceutical composition comprising calcitriol and clobetasol propionate for the treatment of psoriasis - Google Patents

Abstract

The present invention relates to a pharmaceutical composition intended for the treatment of psoriasis, characterized in that it contains an amount of clobetasol propionate and calcitriol suitable for daily application to the portion (s) of the psoriasis invasive skin.

Description

For the treatment of psoriasis of pharmaceutical compositions containing calcitriol and clobetasol propionate {USE OF A PHARMACEUTICAL COMPOSITION COMPRISING CALCITRIOL AND CLOBETASOL PROPIONATE FOR THE TREATMENT OF PSORIASIS}

The present invention relates to pharmaceutical compositions containing calcitriol and clobetasol propionate in a pharmaceutically acceptable medium and the use of such compositions for the manufacture of a medicament intended for the treatment of psoriasis.

Psoriasis is a chronic inflammatory skin disease that affects about 3% of the French population. The disease manifests itself as a red plaque covered with peeling white squama. Psoriasis plaques are often located on the elbows, knees, scalp and back, but can extend to all other parts of the body, such as the face, hands, feet, anatomical folds, nails and the like. Psoriasis most often occurs first in the tens or twenties, but can occur at any age. As a chronic disease, its development is unpredictable: followed by the remission phase after the relapse phase. The disease rarely endangers human life, but its unpleasant appearance and chronic nature have a great impact on quality of life. In psoriasis, some people have a single psoriasis plaque on a clear part of the body, while others may spread the psoriasis throughout the body.

More specifically, the present invention relates to pharmaceutical compositions containing calcitriol and clobetasol propionate in certain proportions such that a synergistic effect is observed between the two active ingredients in the treatment of psoriasis.

Combinations of two or more active ingredients may be advantageous because it allows to reduce the dosage of the active ingredient administered, thereby reducing the side effects of such active ingredients. However, such combinations are typically not used in the treatment of skin diseases because of problems of chemical stability and interactions between the active ingredients mixed in a single formulation.

Calcitriol is a natural and active form of vitamin D. It is especially used to regulate calcium deficiency and its homeostasis in the body.

Clobetasol propionate, or clobetasol 17-propionate, is a corticosteroid. The mechanism of action of corticosteroids is due to its inflammatory process inhibition (Lange K et al, Skin Pharmacol Appl Skin Physiol 13 (2): 93-103 (2000)). In the detailed description below, clobetasol propionate and clobetasol 17-propionate will be used interchangeably.

US 4,610,978 describes a composition for topical application containing calcitriol in the treatment of skin diseases such as psoriasis. Such compositions may further contain corticosteroids such as, for example, hydrocortisone or dexamethasone.

WO 00/64450 describes pharmaceutical compositions for skin containing vitamin D analogs and corticosteroids. Examples provided relate more particularly to compositions containing calcipotriol (vitamin D analog) and betamethasone (corticosteroid). Comparison of measures of efficacy in patients with psoriasis with compositions containing calcipotriol alone, betamethasone alone, or a combination of the two active ingredients indicates that the effect obtained in combination corresponds to an additive effect. Indicates. Thus, in view of this document, one skilled in the art would have never imagined that a combination of vitamin D analogs and corticosteroids could have a synergistic effect. In addition, this document does not explicitly describe the combination of clobetasol propionate and calcitriol.

In the FR 2 848 454 document, the applicant has found that the combination of calcitriol and clobetasol propionate makes it possible to obtain a synergistic effect in the treatment of certain skin diseases such as psoriasis, atopic dermatitis, contact dermatitis and seborrheic dermatitis. .

Applicants have surprisingly made it possible for certain amounts of clobetasol propionate and calcitriol to obtain a particularly advantageous synergistic effect in the treatment of psoriasis, such that the pharmaceutical composition containing the compound is a part or parts of the skin in which psoriasis is affected. It has now been found to be applied only once per day. This advantageous effect is obtained due to the simultaneous application of two active ingredients to their site of action.

The present invention therefore provides a pharmaceutical composition intended for the treatment of psoriasis, characterized in that it contains clobetasol propionate and calcitriol in an amount suitable for one-time application to a portion or portions of psoriasis invasive skin.

According to one advantageous embodiment of the invention, the composition is more specifically 100 to 700 μg clobetasol propionate per gram composition, more particularly 150 to 500 μg per gram composition, and preferably 1 gram composition And 250 μg of clobetasol propionate per sugar.

According to another advantageous embodiment of the invention, the composition is more specifically 0.5 to 10 μg of calcitriol per gram of composition, more particularly 1.5 to 9 μg per gram of composition, and preferably 3 μg per gram of composition. It is characterized by containing a calcitriol.

Thus, one preferred composition of the present invention contains 3 μg of calcitriol per gram of composition and 250 μg of clobetasol propionate per gram of composition.

The composition of the present invention further contains one or more pharmaceutical excipients suitable for topical application.

According to one advantageous embodiment, the composition of the invention is in the form of a gel, cream, ointment, lotion or solution.

Preferably, the cream may be formulated from a mixture of mineral oil or a mixture of beeswax and water, which undergoes immediate emulsification, to which calcitriol and clobetasol propionate are added in solution in a small amount of oil, such as almond oil. do.

Preferably, the lotion may be prepared by dissolving calcitriol and clobetasol propionate in a high molecular mass alcohol, such as polyethylene glycol.

The ointment can be formulated by mixing a solution of calcitriol and clobetasol propionate in an oil such as almond oil in heated paraffin, and then cooling the mixture.

Gels may preferably be prepared by dispersing or dissolving calcitriol and clobetasol propionate in proportions suitable for the carbomer, poloxamer or cellulosic material type.

Other ingredients, such as preservatives, for example DL-alpha-tocopherol, or perfume, may also be added to the topical composition.

The present invention also relates to the use of a combination of clobetasol propionate and calcitriol for the manufacture of a medicament intended for the treatment of psoriasis, wherein the medicament containing a suitable amount of clobetasol propionate and calcitriol is used to treat psoriasis It is applied once a day to a part or parts.

Each amount of clobetasol propionate and calcitriol is as defined above.

In addition, the medicament contains one or more pharmaceutical excipients which are suitable for topical application and are in the form of gels, creams, ointments, lotions or solutions.

1 and 2 show the mean TSS of the seven compositions tested and described in Example 1 below as a function of time.

3 and 4 show the number of subjects whose lesions were recovered by the seven compositions tested and described in Example 1 below as a function of time.

The following examples illustrate the invention; It does not limit the invention in any way.

Example  One: " Dumas - Scholtz  Experiment: Mini zone  ( minizone ) In psoriasis Treatment "  Evaluation of efficacy of four different compositions of the present invention

The comparative experiments described below, "single center, randomized, shielded investigator intra-individual, active-comparator controlled" experiments, were performed at different concentrations of claws. To evaluate the efficacy and local tolerance of four inventive compositions containing betasol propionate and calcitriol, they were performed in comparison to three non-inventive compositions.

The four inventive compositions are as follows:

A composition containing 250 μg clobetasol propionate and 9 μg calcitriol each per gram of composition, more particularly a cream containing 250 μg / g clobetasol propionate and 9 μg / g calcitriol Containing ointment;

A composition containing 250 μg clobetasol propionate and 3 μg calcitriol each per gram of composition, more particularly a cream containing 250 μg / g clobetasol propionate and 3 μg / g calcitriol Containing ointment (Silkis ^® );

Compositions containing 500 μg of clobetasol propionate and 9 μg of calcitriol, respectively, more particularly cream (Dermoval ^® ) and 9 μg / g of 500 μg / g clobetasol propionate per gram of composition ointments containing g of calcitriol;

Compositions containing 500 μg of clobetasol propionate and 3 μg of calcitriol, respectively, more particularly cream (Dermoval ^® ) and 3 μg / g of 500 μg / g clobetasol propionate per gram of composition ointments containing g of calcitriol (Silkis ^® );

Three non-inventive compositions are as follows:

- a deep betamethasone of 500 ㎍ / g propionate (corticosteroids) and 50 ㎍ / g calcineurin Fort Lee consisting of all combinations ointment containing the active component of, Daivobet ^® is a composition that is commercially available with the name;

A composition containing 250 μg / g clobetasol propionate per gram of composition with a vehicle of Silkis (petrolatum and liquid paraffin mixed ointment);

A composition containing 500 μg / g clobetasol propionate per gram of composition with a vehicle of Silkis (Vaseline / Liquid Paraffin Ointment).

Objective 29 subjects (65.5% men and 34.5% women) suffering from psoriasis of the present invention, after a 21 days treatment applied, Daivobet ^® composition and the claw beta sol propionate concentration of calcitriol exhibit superior potency profile than single-containing composition And for determining and selecting the concentration of clobetasol propionate, wherein the chlor betasol propionate is present at the same concentration as that of the composition containing the combination of clobetasol propionate and calcitriol.

Way:

The seven compositions tested were randomly applied to seven sites on one or more of the same severity psoriasis plaques located on the legs (except the front of the tibia), torso or arm.

Several compositions were applied once a day, except Sunday, for a total of 18 times (ie, 21 days of the experiment) under normal conditions of use, ie without occlusion.

The composition was applied as follows:

Firstly only clobetasol propionate was applied, and when fully penetrated, a vehicle of calcitriol or Silkis was applied under the same conditions without a latent period between the two applications.

Clinical evaluation (score for erythema, infiltration, desquamation and recovery) was performed at the time of patient selection, at its inclusion (baseline) and on days 4, 8, 11, 15, 18 and 22 of the trial. Inappropriate events were also recorded.

The main standard measured is the area under the curve (AUC) calculated from day 1 to day 22 for TSS (total sum score, ie sum of erythema, infiltration and deepithelial).

Statistical analysis was performed by Tukey's test for multiple analysis after analysis of variance including "subject", "zone" and "treatment".

1 and 2 show the average of TSS (total sum score = sum of individual scores for erythema, deepithelial and invasive) as a function of time for the seven different, inventive or non-inventive compositions described in this example. .

The curves linked with black diamonds in FIG. 1 correspond to treatment with the Daivobet ^® composition.

The curves linked by dark gray squares correspond to treatment with a composition containing 250 μg of clobetasol propionate per gram of composition.

The curves connected by the white triangles correspond to treatment with the compositions of the invention containing 250 μg of clobetasol propionate and 3 μg of calcitriol, respectively, per gram of the composition.

The curves linked by the black x table correspond to treatment with the compositions of the invention containing 250 μg of clobetasol propionate and 9 μg of calcitriol, respectively, per gram of composition.

The curve connected by black diamonds in FIG. 2 corresponds to a treatment with Daivobet ^® composition.

The curves linked by dark gray squares correspond to treatment with a composition containing 500 μg of clobetasol propionate per gram of composition.

The curves connected by the white triangles correspond to treatment with the compositions of the invention containing 500 μg of clobetasol propionate and 3 μg of calcitriol, respectively, per gram of the composition.

The curves linked by the black x table correspond to treatment with the compositions of the invention containing 500 μg of clobetasol propionate and 9 μg of calcitriol, respectively, per gram of composition.

3 and 4 show the number of subjects whose lesions were treated as a function of time for the seven different, inventive or non-inventive compositions described in this example.

The curve connected by black diamonds in FIG. 3 corresponds to the processing of a Daivobet ^® composition.

The curves linked by dark gray squares correspond to treatment with a composition containing 250 μg of clobetasol propionate per gram of composition.

The curves connected by the white triangles correspond to treatment with the compositions of the invention containing 250 μg of clobetasol propionate and 3 μg of calcitriol, respectively, per gram of the composition.

The curves linked by the black x table correspond to treatment with the compositions of the invention containing 250 μg of clobetasol propionate and 9 μg of calcitriol, respectively, per gram of composition.

The curves connected with black diamonds in FIG. 4 correspond to treatment with the Daivobet ^® composition.

The curves linked by dark gray squares correspond to treatment with a composition containing 500 μg of clobetasol propionate per gram of composition.

The curves linked by white triangles correspond to treatment with the compositions of the present invention containing 500 μg of clobetasol propionate and 3 μg of calcitriol, respectively, per gram of the composition.

The curves linked by the black x table correspond to treatment with the compositions of the invention containing 500 μg of clobetasol propionate and 9 μg of calcitriol, respectively, per gram of composition.

result:

A total of 29 subjects were randomized and included in the present invention. None of them were excluded from the analysis. Efficacy: The AUC of TSS is shown in Table 1 below.

Table 1:

Composition used Of TSS AUC Clobetasol Propionate 250 μg / g + Calcitriol 3 μg / g 66.96 Clobetasol Propionate 500 μg / g + Calcitriol 3 μg / g 68.98 Clobetasol Propionate 500 μg / g + Calcitriol Vehicle 69.60 Clobetasol Propionate 500 μg / g + Calcitriol 9 μg / g 71.12 Clobetasol Propionate 250 μg / g + Calcitriol 9 μg / g 77.64 Clobetasol Propionate 250 μg / g + Calcitriol Vehicle 82.65 Daivobet ^® 84.20

conclusion:

The results obtained with AUC (major standard) of TSS for a composition containing 250 μg / g clobetasol propionate and 3 μg / g calcitriol (AUC = 66.96) were statistically better than those obtained for Do:

A composition containing 250 μg / g clobetasol propionate and a vehicle (AUC = 82.65) and

Daivobet ^® composition (AUC = 84.20).

The same result was observed for the mean AUC of infiltration. In other standards, the same trend was observed without achieving statistical significance. Non-toxic: 14 inappropriate events were reported; None of them were involved in treatment and did not lead to early withdrawal from the trial.

Under these experimental conditions, the claw beta sol propionate composition containing 250 ㎍ / g calcitriol + 3 ㎍ / g showed a significantly better result than the efficacy claw beta sol propionate 250 ㎍ / g alone and Daivobet ^®. In addition, this combination resulted in similar efficacy as clobetasol propionate 500 μg / g alone (FIGS. 1 and 2).

The combination of clobetasol propionate 500 μg / g and calcitriol (3 μg / g and 9 μg / g) did not show a significant difference in efficacy compared to clobetasol propionate 500 μg / g alone ( 2).

All seven compositions were well tolerated.

Compositions containing 250 μg / g clobetasol propionate and 3 μg / g calcitriol showed better results in terms of treatment compared to the following (see FIGS. 3 and 4):

Clobetasol propionate alone (250 μg / g),

A combination of 250 μg / g clobetasol propionate and 9 μg / g calcitriol, and

- Daivobet ^® (FIG. 3).

To compositions containing a combination of each of which will give a greater result than that obtained by the claw beta sol propionate alone of 500 ㎍ / g as those substantially similar, obtained by Daivobet ^® (FIG. 4):

500 μg / g clobetasol propionate and 3 μg / g calcitriol and

500 μg / g clobetasol propionate and 9 μg / g calcitriol.

Claims (10)

A pharmaceutical composition intended for treating psoriasis, characterized in that it contains an amount of clobetasol propionate and calcitriol suitable for daily application to a portion or portions of psoriasis invasive skin. The method of claim 1, wherein 100-700 μg clobetasol propionate per gram of composition, more particularly 150-500 μg per gram, and preferably 250 μg clobetasol propionate per gram of composition. A composition comprising: 2. The composition according to claim 1, which contains 0.5 to 10 μg of calcitriol per gram of composition, more particularly 1.5 to 9 μg per gram, and preferably 3 μg of calcitriol per gram of composition. 4. A composition according to any one of claims 1 to 3, containing at least one pharmaceutical excipient suitable for topical application. The composition according to any one of claims 1 to 4, which is in the form of a gel, cream, ointment, lotion or solution. Use of a clobetasol propionate and calcitriol combination for the manufacture of a medicament intended for the treatment of psoriasis, wherein the medicament containing an appropriate amount of clobetasol propionate and calcitriol once a day in a psoriasis involvement skin portion or parts Applicable Use. The method according to claim 6, wherein the amount of clobetasol propionate is 100 to 700 μg per gram of the medicament, more particularly 150 to 500 μg per gram, and preferably 250 μg per gram of the medicament Use that is Nate. Use according to claim 6, wherein the amount of calcitriol is 0.5 to 10 μg per gram of the medicament, more particularly 1.5 to 9 μg per gram, and preferably 3 μg of calcitriol per gram of the drug. The use according to any one of claims 6 to 8, wherein the medicament contains one or more pharmaceutical excipients suitable for topical application. Use according to any of claims 6 to 9, wherein the medicament is in the form of a gel, cream, ointment, lotion or solution.

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