Natural compound Palmitoylethanolamide spares corticosteroids in cream for dermatitis and psoriasis

In a recent patent, titled:

Compositions and methods for treating inflammatory disorders

Inventors described the corticosteroid sparing effects of the natural compound palmitoylethanolamide:

They describe their findings as:

According to one aspect of the present invention there is provided a composition-of-matter comprising an N-acylethanolamine compound and a corticosteroid.

According to further features in preferred embodiments of the invention described below, the N-acylethanolamine compound is N-palmitoylethanolamine.

According to still further features in the described preferred embodiments the corticosteroid is a low potency corticosteroid.

According to still further features in the described preferred embodiments the composition-of-matter of claim 1 and a pharmaceutically acceptable carrier.

According to still further features in the described preferred embodiments the pharmaceutically acceptable carrier is suitable for topical administration.

According to still further features in the described preferred embodiments the pharmaceutically acceptable carrier is suitable for mucosal administration. According to still further features in the described preferred embodiments the pharmaceutically acceptable carrier is suitable for oral administration.

According to still further features in the described preferred embodiments the N-acylethanolamine compound is N-palmitoylethanolamine.

According to still further features in the described preferred embodiments the corticosteroid is hydrocortisone.

According to another aspect of the present invention there is provided a medical device comprising the composition-of-matter described herein.

According to still further features in the described preferred embodiments the composition-of-matter forms a coating of the medical device.

According to still another aspect of the present invention there is provided a method for treating an inflammatory disorder comprising administering to a subject in need thereof a composition comprising an N-acylethanolamine compound and a corticosteroid, thereby treating the inflammatory disorder.

According to still further features in the described preferred embodiments the N-acylethanolamine compound is N-palmitoylethanolamine.

According to still further features in the described preferred embodiments the corticosteroid is a low-potency corticosteroid.

According to still further features in the described preferred embodiments the corticosteroid is hydrocortisone.

According to still further features in the described preferred embodiments the inflammatory disorder is caused by a cutaneous inflammatory disease or disorder and the administering is effected via topical delivery.

According to still further features in the described preferred embodiments the cutaneous inflammatory disease is selected from the group consisting of psoriasis, atopic dermatitis and scleroderma.

According to still further features in the described preferred embodiments the inflammatory disorder is caused by asthma and the administering is effected via inhalation.

According to still further features in the described preferred embodiments the inflammatory disorder is caused by gastrointestinal inflammation.

According to yet another aspect of the present invention there is provided a pharmaceutical composition comprising any of the composition-of-matters described hereinabove and a pharmaceutically acceptable carrier selected for topical delivery.

The present invention successfully addresses the shortcomings of the presently known configurations by providing a composition for treating inflammatory disorder which employs substantially reduced doses of a corticosteroid.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

They also discussed a number of experiments, from which one can clearly deduce the corticosteroid sparing effects of palmitoylethanolamide, such as:

A study was undertaken in order to determine the effect of topical application of a combined preparation of Betamethasone and PEA on ear edema in mice. Ear thickness was measured before croton oil induced ear swelling and 6 and 9 hours post ear edema induction. The preparations were applied topically 1 hour prior to ear edema sensitization.

The difference in ear thickness of the intact ear was subtracted from the ear thickness of the inflamed ear. This value is defined as “ear swelling”.

Materials and Methods

Test systems and procedures are as described above in Example 1, the experimental groups are listed in Table 8 below.

Table 8 – the 4 experimental groups comprising the study

Figure imgf000048_0001
Figure imgf000049_0001

Results

Ear Thickness results are listed in Table 10 and illustrated in Figure 3; Delta Thickness results are listed in Table 11.

A significant ear swelling was measured 6 hours and 9 hours post sensitization in Vehicle treated group (Group IF). Ear thickness increased by 0.9 mm 6 hours post sensitization and increased by 0.13 mm 9 hours post sensitization.

PEA 1% preparation (Group 2F) demonstrated significant activity in inhibiting ear swelling 6 hours post sensitization. (p<0.01 vs. Vehicle) but was not active in inhibiting ear swelling 9 hours post sensitization .

A single mixture prepation of PEA (1 %) + Betamethasone 4μg/25μl per ear calculated (EDmax) (Group 3F) demonstrated significant activity in inhibiting ear swelling 6 hours post sensitization (pO.OOl vs. Vehicle) and maintained significant activity at 9 hours post sensitization (p<0.05 vs. Vehicle).

Betamethasone 4μg/25μl per ear calculated (EDmax) (Group 4F) was active in inhibiting ear swelling 6 hours post sensitization (p<0.001 vs. Vehicle) but was not active at 9 hours post sensitization.

The single mixture prepation of PEA (1 %) + Betamethasone 4μg/25μl per ear calculated (EDmax) (Group 3F) was the only preparation that demonstrated significant activity at 9 hours post sensitization(p<0.05 vs. Vehicle

In view of the above results it can be concluded that a prepation of PEA (1 %) + Betamethasone 4μg/25μl per ear (Group 3F) demonstrated significant activity in inhibiting ear swelling 6 hours post sensitization and continued to demonstrate significant activity 9 hours post sensitization Topical PEA (1%) preparation (Group 2F) demonstrated significant activity in inhibiting ear swelling 6 hours post sensitization (p<0.01 vs. Vehicle) but was not active at 9 hours post sensitization. Betamethasone 4μg/25μl per ear calculated (EDmax) (Group 4F) demonstrated significant activity in inhibiting ear swelling 6 hours post sensitization but was not active at 9 hours post sensitization .

Table 9 – Mean Group Body Weight (g)

Figure imgf000050_0001
Figure imgf000050_0002

*p<0.05 vs. relevant Vehicle; **p<0.01 vs. relevant Vehicle; ***p<0.001 vs. relevant VehicleTable 11 – Mean Left Ear Delta Thickness

Delta +6h VS Delta +9h VS

Treatment/Group # baseline baseline 6h SEM 9h SEM

100% Ethanol (veh.)(lF) 0.098 0.133 0.013 0.016

1% PEA(2F) 0.056* 0.147 0.009 0.024

1% PEA+Beta.EDmax(3F) 0.032** 0.066** 0.005 0.006

Figure imgf000051_0001

# p<0.1 ,*p<0.05 vs Vehicle, **p<0.01 vs Vehicle

Conclusions

• Significant ear swelling was measured 6 hours and 9 hours post sensitization in Vehicle treated group. Ear thickness increased by 0.9 mm 6 hours post sensitization and increased by 0.13 mm 9 hours post sensitization.

• PEA 1% preparation demonstrated significant activity in inhibiting ear swelling 6 hours post sensitization. (p<0.01 vs. Vehicle) but was not active in inhibiting ear swelling 9 hours post sensitization . • Betamethasone 4μg/25μl per ear calculated was active in inhibiting ear swelling 6 hours post sensitization (p<0.001 vs. Vehicle) but was not active at 9 hours post sensitization.

• A single mixture prepation of PEA (1 %) + Betamethasone 4μg/25μl per ear demonstrated significant activity in inhibiting ear swelling 6 hours post sensitization (p<0.001 vs. Vehicle) and maintained significant activity at 9 hours post sensitization (p<0.05 vs. Vehicle).

• Combination of PEA and Betamethasone prolonged anti-inflammatory activity

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Compositions and methods for treating inflammatory disorders
EP 2309858 A1 (tekst uit WO2010013240A1)

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