DESCRIPTION

Technical Field of Invention

The object of the present invention is Adelmidrol in the treatment of epithelial dysfunctions.

Background Art

Palmitoylethanolamide (PEA) is an endogenous lipid N-acylamidic substance of which an effect on neuroinflammation and pain has been widely demonstrated [Calignano A. et alEurop. J. Pharmacol.2001; 419:191-198; Skaper S. D. et alMol Neurobiol.2013; 48:340-352; Skaper S. D. et al.Inflammopharmacology.2014; 22:79-94]. On the pharmacological level, the increase in the endogenous levels of PEA is currently considered important to determine the control of the neuroinflammation and pain mechanism due to different etiopathogenetic causes and associated with many diseases both of human beings and animals [Petrosino S. et alWSAVA/FECAVA World Small Animal Congress2008; Richardson D. et al. Arthritis Research & Therapy 2008; 10 (2); R43; Ghafouri N. et alPLoS ONE2011; 6(11); Naccarato M. et alLipids in Health and Disease2010; 9:47]. Two different pharmacological methods have currently been suggested to obtain this increase.

The first method is based on the systemic oral or sublingual administration of PEA: in this case, PEA must be administered in micronized (particle size in the range between 2 and 10 microns) or ultra-micronized (particle size in the range between 0.8 and 6 microns) form due to the high insolubility in water of the lipid molecule [EP 1207870 B1; WO 2011/027373 A1].

On the other hand, the second method is based on the inhibition of the activity of the specific PEA-degrading enzyme activity, i.e. FAAH (Fatty Acid Amide Hydrolase) and NAAA (N-Acylethanolamine Acid Amidase); this inhibition was obtained with the systemic administration of synthetic inhibitors of said hydrolases [Piomelli D. et alCNS Drug Reviews2006; 12:21-38; Fiasella A.Chem Med Chem2014 Epub of Print] able to block the degradation of PEA. However, this method implies a serious problem since blocking the degradation of PEA through the block of specific degradation enzymes corresponds to preventing reuse, which is essential, of the PEA components, ethanolamine and palmitic acid, needed to return the phospholipid from which PEA is biologically synthesized “on demand” to the cell, through the phospholipid synthesis. There is also the problem that, while the systemic oral administration of PEA in micronized or ultramicronized form has been found to be effective and safe [Skaper S. D. et alInflammopharmacol.2014; 22:79-94; Esposito E. et al.,Mini Rev Med Chem.2013; 13:237-55], the topical use, in the form of a cream or solution, is very difficult and poorly effective because of the difficulty of producing, in this manner, pharmacologically effective amounts of PEA as a result of the high hydrophobicity of this important lipid molecule.

Adelmidrol is a synthetic N-acylamidic molecule as well (N,N′-Bis(2-hydroxyethyl)nonandiamide) with a high solubility in water as well as a good solubility in lipids.

SUMMARY OF INVENTION

The inventors of the present patent have surprisingly found that Adelmidrol, when brought in contact with epithelial cells such as keratinocytes, is able to cause an important increase of the endogenous levels of PEA while not interfering with the activity of the PEA-degrading enzymes (FAAH and/or NAAA). This discovery allows an effective pharmacological action on external (skin, mucocutaneous genital tissues, oral mucosa) and/or internal epithelia (bladder urothelium, ureter mucosa, mucous membranes of the seminal vesicles, mucous membranes of the digestive system, endothelial layer of synovial membranes, mucous membranes of the respiratory tract), with suitable pharmaceutical forms for the various uses, on diseases of the epithelia of different organs, both in human beings and in animals.

It may also be useful to enhance the activity of Adelmidrol on increasing the local levels of Palmitoylethanolamide by associating the same Adelmidrol with substances capable of modulating (but not blocking) the activity of PEA-degrading enzymes. In particular, PEA Oxazoline, described in the international application published with number WO 2013/121449 A1, may be used.

Therefore, an object of the present invention therefore is Adelmidrol for use in the treatment of epithelial tissue dysfunctions in a human being or animal.

A further object of the invention is a pharmaceutical formulation for use in the treatment of epithelial tissue dysfunctions in a human being or animal, the formulation containing Adelmidrol, optionally in association with an active ingredient selected from the group consisting of an oxazoline derivative of Palmitoylethanolamide, an anti-microbial agent, trans-traumatic acid, and hyaluronic acid or derivatives thereof.

The invention is defined by the appended claims.

Further features and advantages of the invention will become apparent from the following description of preferred embodiments thereof, provided by way of non-limiting example.

