HSP for use in treatment for imiquimod related side effects

Abstract

The invention relates to a healthcare product comprising (i) a component selected from the group of heat shock proteins from alfalfa and heat shock protein hydrolysates from alfalfa, the product further comprising imiquimod or a pharmaceutically acceptable salt or derivative thereof. Further, the invention relates to a healthcare product for use in the prophylactic or therapeutic treatment of a skin disorder. Further, the invention relates to HSP for use for use in preventing the occurrence of a negative-side effect of a treatment with imiquimod, or alleviating such side effect. ##STR00001##

Claims

1. A healthcare product comprising an effective amount of at least 0.2 mg/mL of heat shock proteins from alfalfa, and 0.1-10 wt. % of Imiquimod or a pharmaceutically acceptable salt or derivative thereof, wherein the effective amount of heat shock proteins from alfalfa reduces negative side effects of the Imiquimod or the pharmaceutically acceptable salt or derivative thereof, and wherein the negative side effects are erythema, scaling of the skin, thickening of the skin, or other remote site reaction.

2. The healthcare product according to claim 1, wherein the heat shock protein is Hsp70.

3. The healthcare product according to claim 1, wherein the product is a clinical skin-care product.

4. The healthcare product according to claim 1, wherein the healthcare product includes a first container containing a first healthcare composition comprising the heat shock protein and a second container containing a second healthcare composition comprising imiquimod.

5. The healthcare product according to claim 4, wherein the second healthcare composition is a skin-care product selected from the group consisting of moisturizing skin-care compositions, skin-care balms, skin-care oils, skin-care lotions, skin-care salves, skin-care mousses, skin care foams, and skin-care sprays.

6. The healthcare product according to claim 4, wherein the first healthcare product is a composition for administration to the skin selected from the group consisting of moisturizing skin-care compositions, skin-care balms, skin-care oils, skin-care lotions, skin-care salves, skin-care mousses, skin care foams, and skin-care sprays.

7. The healthcare product according to claim 4, wherein the first healthcare product is a composition for administration via the respiratory tract, a composition for oral administration into the respiratory tract, or a composition for parenteral administration.

8. The healthcare product according to claim 1, wherein the product is a skin-care product and wherein the imiqimod and the heat shock protein are present in the same skin-care composition, which composition is selected from the group consisting of moisturizing skin-care compositions, skin-care balms, skin-care oils, skin-care lotions and skin-care sprays.

9. The healthcare product according to claim 1, wherein the heat shock protein is present in a total concentration of at least 0.2 mg/mL to 1 mg/mL of the composition in which it is present.

10. The healthcare product according to claim 1, wherein the concentration of imiquimod is in the range of 1-6 wt. %.

Description

EXAMPLE: TOPICAL ALFALFA-DERIVED HSP70 FOR TREATMENT OF A SKIN DISORDER

(1) Materials

(2) Imiquimod was provided in a commercially available cream (Fougera, a cream comprising 5% Imiquimod).

(3) HSP70 (from alfalfa) was obtained from Alfa Biogene International B.V. It was dispersed in a concentration of 50 or 250 g/ml in a carrier cream from Deutscher Apotheken Index. Said carrier cream contained (per 100 g): 4.0 g Glycerolmonostearate 60 6.0 g Cetylalcohol 7.5. g Medium-chain Triglycerides 25.5 g White Petrolatum 7.0 g Macrogol-20-glycerolmonostearate 10.0 g Propylene-glycol 40.0 g Purified water

(4) Methods

(5) The effect of HSP was tested on mice (BALBc mice, male 10-12 weeks old)

(6) The mice were divided in 5 groups of eight mice each:

(7) Group 1: mice were treated for 6 days on shaved back and right ear with one daily application of imiquimod 5% cream to the skin (3.125 mg daily dose)

(8) Group 2: mice were treated for 6 days as group 1. In addition the part of the skin to which imiquimod was applied was treated twice daily with the cream comprising 50 g/ml HSP (20 g HSP per dose). Each day, the cream comprising HSP70 was applied to the skin in a 1 mm layer, 4 hours before application of the imiquimod, and again 4 hours after treatment with imiquimod.

(9) Group 3: mice were treated for 6 days as group 2, except for the cream comprising 250 g/ml HSP (100 g HSP per dose)

(10) Group 4: mice were treated as group 2 except for the carrier cream comprising no Hsp70. (mice were treated for six days, twice a day, once four hours before treatment with imiquimod, once four hours after treatment with imiquimod.

(11) Group 5: control group, no cream application.

(12) Study Protocol:

(13) Day 1: initial evaluation for visible signs of psoriasis. An visible signs were categorized and scored by a PASI score (PASI: psoriasis area and severity index) from 0-4 (erythema, scales, thickness, cumulative score: maximum of 12 points). Animal backs were shaved and photographs were taken.

(14) Thickness of both ear pinnae were measured. Cream application was performed according to the categorization into above detailed groups.

(15) Day 2-6: Animals in the treatment groups were treated with the according skin creams. An animals were assessed and examined once daily for behavioural changes and adverse effects. Ear pinnae measurements are performed daily. Skin changes were assessed by the PASI score. On day 7, photographs of all animals (backs) were taken to document progression of the disease.

(16) Day 7: The animals were euthanized and skin tissue and blood was processed. Inflammatory markers were measured with Q-PCR (skin samples). Skin samples were histologically examined.

(17) Statistical Methods:

(18) Study groups on ordinal and continuous outcomes were compared using the Kruskal-Wallis test with a Steel-Dwass adjustment for pairwise group comparisons for an overall statistical significance criteria of 0.05 for each outcome.

(19) Results

(20) Ear Pinnae:

(21) Thickness of the right ear remained in the range of 0.20-0.25 mm for each of the groups until day 4. Thereafter, the thickness rose sharply for Group treated with imiquimod (Group 1) only, and to a less extent for the other Groups (2-4). The following table shows ear thickness in mm.

(22) TABLE-US-00001 Group Day 1 Day 5 Day 6 Day 7 1 (imiquimod only) 0.21 0.28 0.37 0.40 2 (20 g HSP) 0.23 0.28 0.33 0.34 3 (100 g HSP) 0.22 0.25 0.28 0.29 4 (carrier cream) 0.22 0.28 0.30 0.33 5 (control) 0.25 0.22 0.19 0.19

(23) The results show that HSP used in co-therapy with imiquimod is effective in reducing or even avoiding the occurrence of a side-effect of imiquimod (swelling).

(24) Epidermal Thickness:

(25) A histology study on the back skin samples taken of the euthanized mice, resulted in the following average epidermal thickness of the treated skin (in m):

(26) TABLE-US-00002 Group epidermal thickness 1 (imiquimod only) 58 2 (20 g HSP) 42 3 (100 g HSP) 40 4 (carrier cream) 53 5 (control) 10

(27) The results show that HSP used in co-therapy with imiquimod is effective in reducing or even avoiding the occurrence of a side-effect of imiquimod (swelling).

(28) PASI-Score:

(29) The results for the cumulative PASI Score on day 7 were as follows:

(30) TABLE-US-00003 Group PASI score 1 (imiquimod only) 6.5 2 (20 g HSP) 1.7 3 (100 g HSP) 3.0 4 (carrier cream) 3.5 5 (control) 0

(31) The results support that HSP can be used to reduce psoriasis area and severity.

(32) Visual Appearance:

(33) FIG. 1 shows the backs of one mouse of each of groups 1-4 after 6 days of treatment. From left to right: Group 2 (20 g HSP), Group 3 (100 g HSP), Group 4 (carrier cream only) and Group 1 (imiquimod only)

(34) As illustrated by FIG. 1, the backs of the mice treated with imiquimod in co-therapy with HSP were still essentially free of scaling, whereas the mice treated with imiquimod only were severely scaled. Increased scaling was also observed in mice treated with carrier cream only, compared to the mice treated in accordance with the invention.