Injectable device

Abstract

The present invention regards a composition comprising hyaluronic acid and at least one collagen component. Preferably, the invention relates to a crosslinked hyaluronic acid hydrogel with at least one collagen component or derivative. The invention further regards a process for preparing the composition, and the medical uses and non-therapeutic uses of the composition.

Description

[0001] Injectable device

[0002] DESCRIPTION

[0003] The present invention relates to a composition comprising hyaluronic acid and at least one collagen component.

[0004] STATE OF THE ART

[0005] Hyaluronic acid (HA) is a member of a vast family of glycosaminoglycans (GAGs) which are the main components of the extracellular matrix. The unique characteristics distinguishing it from other GAGs are its simple structure and large molecular size. The HA molecule is made up of D- glucuronic acid and N-acetyl-D-glucosamine linked with [3-glycosidic bonds. Its peculiar properties and its role in important biological functions have made it the subject of innumerable biochemical and medical studies. The numerous uses this molecule has found, in both the medical and cosmetic fields, have obviously contributed to the extraordinary interest surrounding HA. Since it became possible to source it for industrial applications, the properties of gelling and retaining a large amount of water have made it an ideal component for cosmetic moisturising preparations, so much so that it has today become the ingredient par excellence of mid to high-end cosmetics, and also the subject of particularly effective communication. But it is the properties of HA in different fields of application that make it most interesting from a scientific viewpoint, and for which applications have been developed that have in any case made it very popular and widely used for a vast range of medical applications. Firstly, HA is administered by injection to compensate for its loss due to aging, diseases or surgical procedures. Clinical uses include dermal filling, viscosupplementation in deteriorated joints, as ophthalmic surgical aids and as a tear replacement. For such applications, HA has the advantage of being biocompatible and safe and induces a minimum reaction as a foreign body. Because of its important physiological role in tissue repair, as mentioned above, HA is also used for wound healing.

[0006] Many of the applications mentioned above are not obtained using HA in its native form: in fact, “crosslinked” molecules are often used. Crosslinking of a polymer is a process whereby linkages are created between independent chains which make the structure of the polymer stiffer. In the case of HA, crosslinking not only maintains the physiological function of HA, but also imparts the skeletal function of a hydrogel, which further expands the possible applications, starting from the possibility of modulating the rheological properties of the gel. For hyaluronic acid, moreover, crosslinking also has another considerable effect: crosslinked structures are less subject to attack by degrading enzymes (hyaluronidase), and this is why they remain for a longer time at the application site.

[0007] Another compound that is very useful in maintaining the physiological conditions of numerous body structures is collagen. In fact, collagen is one of the body’s most important structural and biological components; it is a structural protein with minimal immunoreactivity which plays structural roles in the main connective tissues, such as the skin, cornea, ligaments, tendons, joint capsules, and in cartilage in general. Many different uses of collagen are described in the literature, particularly for the treatment of diseases affecting the skin and joints. Collagen has shown to be very effective and safe; its side effects are wholly negligible. However, the halflife of collagen, when administered by injection, is very brief. In fact, it is rapidly attacked by enzymes present in body tissues, such as, for example, collagenases, which very quickly degrade collagen.

[0008] Therefore, there is a greatly felt need to provide a system that can transfer collagen in a controlled manner, thus providing an availability and effectiveness that are prolonged over time.

[0009] SUMMARY OF THE INVENTION A first aspect of the present invention relates to a composition comprising crosslinked hyaluronic acid with at least one collagen component or derivative, wherein the at least one collagen component is chosen from: hydrolysed collagen, at least one collagen peptide or at least one portion of said collagen peptide or at least one amino acid of the collagen component and combinations thereof. Preferably, the hydrolysed collagen comprises at least one peptide with a molecular weight between 0.5 and 12 kDa, more preferably between 0.5 and 8 kDa.

[0010] Preferably, the hydrolysed collagen is obtained by enzymatic hydrolysis.

[0011] Preferably, the at least one collagen component comprises at least three, preferably four, even more preferably at least five amino acids chosen from: glycine, proline, alanine, hydroxyproline, glutamic acid, arginine, aspartic acid, serine, lysine, leucine, valine, and threonine.

[0012] Preferably, the composition is a gel or a hydrogel or an oil-in-water or water-in-oil emulsion; more preferably, it is a hydrogel.

[0013] A second aspect of the present invention relates to a process for preparing the composition described above, comprising the steps of:

[0014] I) making available a composition comprising at least one collagen component or derivative;

[0015] II) adding hyaluronic acid to the composition of step I);

[0016] III) adding to the composition obtained in step II) at least one crosslinker to obtain a crosslinking composition; and

[0017] IV) keeping the crosslinking composition at a temperature between 10 and 40°C for between 1 hour and 10 days, wherein the at least one collagen component is chosen from: hydrolysed collagen, at least one collagen peptide, at least one portion of said collagen peptide and combinations thereof.

[0018] Preferably, said at least one collagen component is present in the crosslinking composition in a concentration between 0.01 and 2% weight / weight (w / w). Preferably, the hyaluronic acid is present in the crosslinking composition in a concentration between 0.5 and 15% w / w.

[0019] Preferably, the at least one crosslinker is present in the crosslinking composition in a concentration between 0.02 and 2% w / w.

[0020] A third aspect of the present invention relates to a non-medical, non- surgical cosmetic use of the composition described above. Preferably, said use is chosen from: aesthetic improvement of the skin, for reducing wrinkles, improving skin elasticity, increasing skin resilience, increasing skin moisture content, reducing cellulite and / or reducing stretch marks, accelerating nail growth and / or reducing nail fragility.

[0021] A fourth aspect of the present invention relates to the composition described above for use as a medicament.

[0022] A fifth aspect of the present invention relates to the composition described above for use in the treatment or prevention of a joint disease and / or discopathy in an individual. Preferably, the composition is administered by intra-articular or intradiscal injection.

[0023] A sixth aspect of the present invention relates to the composition described above for use in the treatment or prevention of a skin or oral cavity lesion or a cavity wound or an eye disease.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] A first aspect of the present invention regards a composition comprising hyaluronic acid and at least one collagen component.

[0026] In one embodiment, the composition comprises crosslinked hyaluronic acid with at least one collagen component. In other words, the invention relates to a crosslinked hyaluronic acid composition comprising at least one collagen component.

[0027] In fact, the invention preferably relates to a composition for the extended and / or delayed release of the at least one collagen component or derivative. In one embodiment, the collagen, i.e. the collagen from which the derivative or component is obtained, is chosen from collagen type I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, preferably type I, II or III, preferably type I, preferably type II, preferably type III.

[0028] In a preferred embodiment, the collagen is collagen from vertebrates, in particular fish, amphibians, reptiles, birds and mammals, more preferably fish, bovine, porcine, equine or avian collagen, from invertebrates such as cnidarians or coelenterates, or human collagen.

[0029] Preferably, the collagen is fish or bovine or porcine or equine collagen, more preferably it is fish collagen.

[0030] Preferably, said collagen is chosen from: collagen type I, collagen type III, collagen type IV, collagen type VI or a combination thereof. The collagen is preferably derived from cell cultures, animal tissues or by recombinant means and may be derived from human, porcine or bovine sources. Alternatively, the collagen is preferably derived from cultures of human fibroblasts.

[0031] Preferably, the collagen is type I, type I, II or III, more preferably type I or type III or else type II.

[0032] Preferably, the at least one collagen component is hydrolysed collagen or at least one collagen peptide or else at least one collagen amino acid.

[0033] The hydrolysed collagen may be obtained by hydrolysis of the collagen described above, preferably by hydrolysis of fish collagen.

[0034] In a preferred embodiment, the at least one collagen component is hydrolysed collagen. Preferably, the hydrolysed collagen is obtained by enzymatic hydrolysis of the collagen, for example by using enzymes such as alcalase, papain, or pepsin, or with other methods of enzymatic hydrolysis known to the person skilled in the art.

[0035] Preferably, the hydrolysed collagen comprises low molecular weight peptides, preferably with a molecular weight between 0.5 and 12 kDa, more preferably between 1 and 8 kDa, even more preferably between 0.5 and 6 kDa.

[0036] In a preferred embodiment of the invention, the at least one collagen peptide is a natural peptide, i.e. which has not undergone modifications, substitutions or other alterations from a physicochemical and biological viewpoint. In other words, the at least one collagen peptide has been obtained and / or isolated from the collagen by partial or total hydrolysis of the collagen, preferably by enzymatic hydrolysis.

[0037] Preferably, the at least one collagen peptide is a synthetic or recombinant peptide, in particular a collagen peptide produced synthetically or in a recombinant manner.

[0038] Preferably, the at least one collagen peptide is a non-hydroxylated collagen peptide.

[0039] In a further embodiment, the at least one collagen peptide is a hydroxylated collagen peptide.

[0040] Preferably, the at least one collagen peptide, in particular a synthetic or recombinant peptide, comprises at least one hydroxylated proline and / or hydroxylated lysine.

[0041] In one embodiment, the at least one collagen peptide is produced synthetically, preferably by chemical synthesis, in particular solid-phase synthesis, preferably Merrifield synthesis, Bailey peptide synthesis, or chemoenzymatic synthesis.

[0042] In a further embodiment, the at least one collagen peptide is produced in a recombinant manner.

[0043] Preferably, the at least one collagen peptide is a non-hydroxylated, partially hydroxylated or completely hydroxylated collagen peptide. According to a further embodiment, every proline present in the synthetic or recombinant collagen peptide is hydroxylated.

[0044] Preferably, the at least one collagen peptide is a glycosylated collagen peptide. The collagen peptide, preferably synthetic or recombinant, is glycosylated on at least one hydroxylated lysine. In one embodiment, the at least one collagen component comprises or consists of at least three collagen amino acids, preferably at least four, more preferably at least five collagen amino acids.

[0045] In one embodiment, the at least three collagen amino acids are chosen from: glycine, proline, alanine, hydroxyproline, glutamic acid, arginine, aspartic acid, serine, lysine, leucine, valine, and threonine.

[0046] According to one embodiment, the composition further comprises at least one crosslinker; said crosslinker is preferably chosen from: 1 ,4-butanediol diglycidyl ether (BDDE), divinyl sulphide, glutaraldehyde, PEG derivatives such as PEG diacrylate, ADH (adipic acid dihydrazide), N,N'- dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) or 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and compositions thereof.

[0047] In a preferred embodiment, the at least one crosslinker is 1 ,4- butanediol diglycidyl ether (BDDE).

[0048] In one embodiment, the composition comprises a derivative crosslinker and / or one with an activity or mechanism of action similar to that of the abovementioned crosslinkers.

[0049] In one embodiment, the composition is preferably in the form of a gel or a hydrogel or an oil-in-water or water-in-oil emulsion.

[0050] In a particularly preferred embodiment, the composition is in the form of a hydrogel. In other words, the invention preferably relates to a hyaluronic acid hydrogel, wherein the at least one collagen component or derivative is crosslinked to the hyaluronic acid. Said at least one collagen component or derivative, for example a peptide, is linked to the hyaluronic acid.

[0051] In fact, the at least one collagen component remains included in the network formed by the hyaluronic acid, thanks to a crosslinking process, and it is thus not available outside the network of the gel. The gel thus obtained, therefore, is capable of releasing the peptides and / or amino acids of the collagen component or derivative in a controlled manner when used in vivo. In this manner, at the application sites, the peptides and / or amino acids are freed during the process of absorption of the hyaluronic acid. The at least one collagen component or parts thereof, once freed from the hyaluronic acid network, is available for attack by enzymes (e.g. collagenase) and degraded, in turn, to amino acids, which are thus available at the application site. In this manner, the at least one collagen component or derivative or a part thereof is released from the network in a controlled manner.

[0052] One application of choice of the composition according to the invention is the use thereof as an injectable filler for aesthetic medicine. In this context, the filler acts like a typical hyaluronic acid-based filler, compensating for the lack of tissue in wrinkles or in other skin depressions. As occurs with this type of filler, over time the hyaluronic acid is absorbed. During this process, and from the start, the amino acids are released on the application site and form a reserve of components for the production of new collagen, also stimulated by the presence of the hyaluronic acid. The new collagen can, at least in part, replace the hyaluronic acid that is degraded and prolong the efficacy of the filler even after all the hyaluronic acid has been absorbed. In this manner, the aesthetic effect of the filler is prolonged, and a collagen substrate is formed which can make a possible subsequent application of a filler more effective.

[0053] A second aspect of the present invention regards a process for preparing the composition described above, preferably for preparing a crosslinked hyaluronic acid hydrogel. The process comprises at least one step of crosslinking the hyaluronic acid in the presence of the at least one collagen component or derivative.

[0054] In one embodiment, the process comprises the steps of:

[0055] I) making available a composition comprising at least one collagen component or derivative;

[0056] II) adding hyaluronic acid to the composition;

[0057] III) adding to the composition obtained in step II) at least one crosslinker to obtain a crosslinking composition; and IV) keeping the crosslinking composition at a temperature between 10 and 35°C, more preferably between 15 and 25°C for between 1 hour and 15 days, more preferably between 1 and 7 days.

[0058] In one embodiment, steps l-lll are carried out in any order, thereby obtaining a composition with different characteristics.

[0059] Preferably, the at least one collagen component or derivative is a peptide or at least a portion thereof.

[0060] In a preferred embodiment of the invention, the at least one collagen component or derivative is as described above in detail.

[0061] Preferably, the at least one collagen component or derivative is present in the crosslinking composition in a concentration between 0.005 and 1 % weight / weight (w / w), more preferably between 0.01 and 0.5% weight / weight.

[0062] Preferably, the hyaluronic acid is present in the crosslinking composition in a concentration between 0.1 and 10 w / w, more preferably between 1 and 3% w / w.

[0063] Preferably, the at least one crosslinker is present in the crosslinking composition in a concentration between 0.005 and 0.5% w / w, more preferably between 0.02 and 0.3% w / w.

[0064] A third aspect of the present invention regards a cosmetic use of the composition as described above in detail. Preferably, said cosmetic use is a non-therapeutic and non-surgical use of the composition.

[0065] In one embodiment, the composition is utilised in a non-therapeutic use for aesthetic improvement of the skin, in particular for reducing wrinkles, improving skin elasticity, increasing skin resilience, increasing skin moisture content, reducing cellulite and / or reducing stretch marks of varying origin, include stretch marks due to pregnancy.

[0066] In one embodiment, the composition is utilised in a non-therapeutic use to accelerate nail growth and / or reduce nail fragility, improve hair quality, reduce split ends and / or reduce / delay hair loss. A fourth aspect of the present invention regards the composition as described above in detail for use as a medicament.

[0067] A fifth aspect of the present invention regards the composition as described above in detail for use in the treatment or prevention of a joint disease and / or discopathy in an individual.

[0068] Preferably, the joint disease is chosen from: arthrosis, rheumatoid arthritis, juvenile idiopathic arthritis, neuropathic arthropathy and seronegative spondyloarthropathy, preferably ankylosing spondylitis, Reiter’s syndrome and psoriatic arthritis, infective arthritis (acute or chronic) caused by at least one bacterium and crystal arthritis (gout).

[0069] Preferably, the discopathy is selected from: lumbar discopathy, lumbosacral discopathy, cervical discopathy, multilevel discopathy, degenerative discopathy, inflammatory discopathy, infectious discopathy and traumatic discopathy.

[0070] In one embodiment, the composition, preferably in the form of a hydrogel, is administered parenterally, more preferably by injection. Preferably, the composition is administered by intra-articular or intradiscal injection.

[0071] A sixth aspect of the present invention regards the composition as described above in detail for use in the treatment or prevention of a skin or oral cavity lesion or a cavity wound or an eye disease.

[0072] A seventh aspect of the present invention regards a method for treating or preventing a joint disease and / or discopathy or a skin or oral cavity lesion or a cavity wound or an eye disease in an individual. Said method provides for at least one step of administering the composition described above in detail to the individual.

Claims

CLAIMS1. A composition comprising crosslinked hyaluronic acid with at least one collagen component or derivative, wherein the at least one collagen component or derivative is chosen from: hydrolysed collagen, at least one collagen peptide or at least one portion of said peptide, and combinations thereof, wherein the hydrolysed collagen comprises at least one peptide with a molecular weight between 0.5 and 12 kDa.

2. The composition according to claim 1 , wherein the hydrolysed collagen comprises at least one peptide with a molecular weight between 1 and 8 kDa.

3. The composition according to any one of the preceding claims, wherein hydrolysed collagen is obtained by enzymatic hydrolysis.

4. The composition according to any one of the preceding claims, wherein the collagen component comprises or consists of at least three collagen amino acids, preferably at least four, more preferably at least five collagen amino acids.

5. The composition according to claim 4, wherein the composition comprises at least five amino acids chosen from: glycine, proline, alanine, hydroxyproline, glutamic acid, arginine, aspartic acid, serine, lysine, leucine, valine, threonine.

6. The composition according to claim 5, wherein the collagen component comprises or consists of at least four amino acids chosen from: glycine, proline, alanine, hydroxyproline, glutamic acid, arginine, aspartic acid, serine, lysine, leucine, valine,threonine.

7. The composition according to any one of the preceding claims, wherein the composition is a gel or a hydrogel or an oil-in-water or water-in-oil emulsion.

8. The composition according to any one of the preceding claims, wherein the composition is a hydrogel.

9. A process for preparing the composition according to any one of claims 1-8, comprising the steps of:I) making available a composition comprising at least one collagen component;II) adding hyaluronic acid to the composition;III) adding to the composition obtained in step II) at least one crosslinker to obtain a crosslinking composition; andIV) keeping the crosslinking composition at a temperature between 10 and 35°C for between 1 hour and 15 days, wherein, at least one collagen component is a collagen peptide and / or at least three amino acids isolated from collagen and is in the crosslinking composition in a concentration between 0.005 and 1 w / w %, wherein hyaluronic acid is in the crosslinking composition in a concentration between 0.1 and 10% w / w, and wherein at least one crosslinker is in the crosslinking composition in a concentration between 0.005 and 0.5 % w / w.

10. A cosmetic use of the composition according to any one of claims 1-8.

11. The use according to claim 10, wherein said use is chosen from: aesthetic improvement of the skin, for reducing wrinkles, improvingskin elasticity, increasing skin resilience, increasing skin moisture content, reducing cellulite and / or reducing stretch marks, accelerating nail growth.

12. The composition according to any one of claims 1-8, for use as a medicament.

13. The composition according to any one of claims 1-8, for use in the treatment or prevention of a joint disease and / or discopathy in an individual.

14. The composition for use according to claim 13, wherein the composition is administered by intra-articular or intradiscal injection.

15. The composition according to any one of claims 1-8, for use in the treatment or prevention of a skin or oral cavity lesion or a cavity wound or an eye disease.