Amino acid derivative of glucosamine stimulating extracellular matrix synthesis and pharmaceutical composition comprising the same

Abstract

The present patent application relates to the use of an innovative amino acid derivative of glucosamine having the Formula 1 of the general structure which follows, or of a pharmaceutical composition which contains it as a single active ingredient or in association with one or more further active ingredients for the preparation of a medicament for the treatment or prophylaxis of diseases involved mainly with the regulation of the turnover of macromolecules that make up the ECM of connective tissue in general and more specifically of the cartilage. ##STR00001##

Claims

1. A pharmaceutical composition suitable for parenteral administration route comprising an amino acid derivative of glucosamine having the following Formula 1 of general structure: ##STR00004## or the pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein the group R represents an amino acid, an N-acyl derivative of an amino acid or an N-acyl derivative of a peptide and wherein the amine group of glucosamine is bound by amide bond to the carboxyl side chain of said amino acid; wherein the pharmaceutical composition comprises the amino acid derivative of glucosamine at a concentration of between 0.5% by weight and 4.5% by weight, together with carriers suitable for said administration route.

2. The pharmaceutical composition according to claim 1, wherein the parenteral administration route is selected from the intra-articular route and the trans-dermal route.

3. The pharmaceutical composition of claim 1, further comprising glucosamine and/or hyaluronic acid, wherein glucosamine and/or hyaluronic acid each have a concentration ranging from 0.1% by weight to 0.4% by weight.

4. The pharmaceutical composition of claim 3, wherein glucosamine and/or hyaluronic acid each have a concentration of 0.25% by weight.

5. A pharmaceutical composition according to claim 1, wherein the amino acid derivative of glucosamine consists of an N-acetyl-phenylalanine derivative of glucosamine having the following structural Formula 2: ##STR00005## or the pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.

6. The pharmaceutical composition of claim 1, comprising the amino acid derivative of glucosamine at a concentration of between 1% by weight and the 3% by weight, together with carriers suitable for said administration route.

7. A method for therapeutic regeneration of connective tissue, comprising applying an effective amount of the pharmaceutical composition of claim 1 to a patient in need thereof.

8. A method according to claim 7 wherein the method is a method for therapeutic regeneration of connective tissue-following degenerative processes of the articular cartilage of an osteoarthritic nature, in a human being, following degenerative processes due to a hyper-stressing of the articular cartilage.

9. A method according to claim 7 wherein the method is a method for therapeutic regeneration of connective tissue in the treatment of skin aging.

10. The method of claim 7, wherein the pharmaceutical composition is administered by topical administration.

11. A pharmaceutical composition suitable for topical administration route, comprising an amino acid derivative of glucosamine having the following Formula 1 of general structure: ##STR00006## or the pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein the group R represents an amino acid, an N-acyl derivative of an amino acid or an N-acyl derivative of a peptide and wherein the amine group of glucosamine is bound by amide bond to the carboxyl side chain of said amino acid; wherein the pharmaceutical composition comprises the amino acid derivative of glucosamine at a concentration of between 0.1% by weight and 2% by weight.

12. The pharmaceutical composition of claim 11, comprising the amino acid derivative of glucosamine in a cream.

13. A pharmaceutical composition according to claim 11, wherein the amino acid derivative of glucosamine consists of an N-acetyl-phenylalanine derivative of glucosamine having the following structural Formula 2: ##STR00007## or the pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.

14. The pharmaceutical composition of claim 11, comprising the amino acid derivative of glucosamine at a concentration of 1% by weight.

15. A method for therapeutic regeneration of connective tissue, comprising applying an effective amount of the pharmaceutical composition of claim 11 to a patient in need thereof.

16. A method according to claim 15 wherein the method is a method for therapeutic regeneration of connective tissue in the treatment of skin aging.

17. The method of claim 15, wherein the pharmaceutical composition is administered by topical administration.

18. The method of claim 16, wherein the pharmaceutical composition is administered by topical administration.

19. The method of claim 9, wherein the pharmaceutical composition is administered by topical administration.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) It should be noted that hereinafter, only some of the possible embodiments of the present invention will be illustrated, by way of non-limiting example, it being possible to describe many others thereof on the basis of the particular technical solutions identified.

(2) The present patent application relates to the use of an innovative amino acid derivative of glucosamine, or of a pharmaceutical composition which contains it as a single active ingredient or in association with one or more further active ingredients for the preparation of a medicament for the treatment or prophylaxis of diseases involved mainly with the regulation of the turnover of macromolecules that make up the ECM of connective tissue and more specifically of the cartilage tissue.

(3) Accordingly, the general aim of the present invention is to provide a new pharmacological method capable of stopping the evolutionary pathway of osteoarthritis and thus of preventing the possible debilitating damage that may derive therefrom.

(4) A further object according to the present invention is to provide a drug capable of stimulating the endogenous synthesis of a new extracellular matrix.

(5) An even more particular object is to make the cartilage reacquire a structure very similar to the healthy one, that is, deprived of degeneration due to the osteoarthritic process or in any case of degeneration due to other causes including that due to hyper-stress from an intense sporting activity, appropriately stimulating the cells to produce the components of the matrix, as well as the collagens, the proteoglycans, the glycosaminoglycans and the aggrecan.

(6) A further object relates to the aforementioned ability of this class of products to restore the synthesis of type I and type II collagen due to the activity of fibroblasts, intervening in the remodeling of the cutaneous ECM and therefore to be used appropriately in the treatment of skin aging by counteracting skin atrophy, and in some cases preventing and suggesting new therapeutic strategies for the treatment of skin cancers.

(7) Said inventive compounds generally consist of amino acid derivatives of glucosamine having the following Formula 1 of general structure:

(8) ##STR00002##
wherein the group R represents an amino acid, an N-acyl derivative of an amino acid or an N-acyl derivative of a peptide and wherein the amine group of glucosamine is bound by carbamide bond to the carboxyl side chain of said amino acid.

(9) A particularly preferred embodiment of the present invention provides that said inventive compounds are preferably represented by an N-acetyl-phenylalanine derived from glucosamine having the following Formula 2 of structure:

(10) ##STR00003##

(11) The compound having the Formula 1 according to the present invention or the one having the Formula 2 can exist as a pharmaceutical composition which contains it alone or in association with one or more active ingredients, together with one or more excipients or carriers suitable for the route of administration chosen and prepared according to the well-known standards of good manufacturing technology and pharmaceutical legislation.

(12) In the light of the above experimental evidence, a preferred embodiment of the present invention contemplates to provide a pharmaceutical composition suitable for the parenteral administration route and more specifically for the intra-articular or trans-dermal route, by implementing an injection solution for intra-articular or intra-dermal use consisting of a compound having Formula 1 or of a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof at a concentration comprised between 0.5% by weight and 4.5% by weight and more preferably between 1% by weight and 3% by weight, together with suitable and known carriers for said administration route.

(13) A further preferred embodiment provides that the aforementioned pharmaceutical composition consists of an association of active ingredients consisting of the inventive amino acid derivative of glucosamine having Formula 1 or of a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof at a concentration of between 0.5% by weight and 4.5% by weight and more preferably between 1% by weight and 3% by weight and even more preferably by 2.5% by weight and by glucosamine and/or hyaluronic acid, each at a concentration ranging from 0.1% by weight to 0.4% by weight and more preferably equal to 0.25%. In particular, the aforementioned pharmacological association arose from experimental evidence that demonstrated that the addition of glucosamine has a synergistic effect on the pharmacological activity of the drug, and that the addition of hyaluronic acid is suggested precisely by the properties of this molecule capable of providing greater viscosity to the preparation, with consequent lubricating effect when administered in the joints. In particular, it should be noted that although all human skeletal joints can be subject to and therefore benefit from the aforementioned administration, preferably the knee is the preferred one.

(14) A further embodiment according to the present invention for the purpose of the therapeutic and prophylactic effect referred to above, has the object of providing a pharmaceutical composition suitable for the topical administration route by making a cream consisting of a compound having Formula 1 or of a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof at a concentration comprised between 0.1% by weight and 2% by weight and more preferably equal by 1% by weight in the base cream.

(15) The present invention has been described for illustrative but non-limiting purposes, according to some preferred embodiments thereof, but it is to be understood that any variations and/or modifications may be made by the man skilled in the art without thereby departing from the relative scope of protection as defined by the following dependent claims.